WASP-protective small molecules, compositions, methods and uses thereof in the treatment of congenital and acquired immunodeficiency diseases or disorders

Description

FIELD OF THE INVENTION

[0001] The present invention pertains to the field of molecular immunology and hematology. More specifically, the present invention provides specific small molecule compounds that modulate degradation of Wiskott-Aldrich Syndrome protein (WASp), methods and uses thereof in innate and acquired immune-related disorders or conditions.BACKGROUND ART

[0002] References considered to be relevant as background to the presently disclosed subject matter are listed below: H. D. Ochs, A. J. Thrasher, The Wiskott-Aldrich syndrome. The Journal of Allergy and Clinical Immunology 117, 725-738; quiz 739 (2006). M. H. Albert, et al Blood 115, 3231-3238 (2010). J. M. Derry, et al.,Cell 79, following 922 (1994). O. Matalon, et al., Immunological Reviews 256, 10-29 (2013). N. Joseph, Biochimica et Biophysica Acta (BBA) - Biomembranes, 105:481-93 (2013). Y. Jin, et al., Blood 104, 4010-4019 (2004). M. I. Lutskiy, F et al., Journal of Immunology 175, 1329-1336 (2005). D. Buchbinder, et al.,The Application of Clinical Genetics 7, 55-66 (2014). Filipovich, Bone Marrow Transplantation 42 Suppl 1, S49-S52 (2008). C. R. Shin, et al.,Bone Marrow Transplantation 47, 1428-1435 (2012). J. Litzman, et al., Archives of Disease in Childhood 75, 436-439 (1996). L. Khavrutskii, et al.,Journal of Visualized Experiments : JoVE 15, (2013) A. Konno, et al., International Immunology 19, 185-192 (2007). E. Noy, et al., International Journal of Molecular Sciences 13, 7629-7647 (2012). S. Fried, et al., Science Signaling 7, ra60 (2014). B. Reicher, et al.,Molecular and Cellular Biology 32, 3153-3163 (2012) M. Barda-Saad, et al.,Nature Immunology 6, 80-89 (2005) M. I. Lutskiy, et al., British Journal of Haematology 139, 98-105 (2007) A. Shcherbina, et al.,Blood 98, 2988-2991 (2001) J. K. Burkhardt, et al.,Annual Review of Immunology 26, 233-259 (2008). D. Varga-Szabo, et al., Journal of Thrombosis and Haemostasis 7, 1057-1066 (2009). Aiuti, L. et al., Science 341, 1233151 (2013). S. Hacein-Bey Abina, et al.,JAAM 313, 1550-1563 (2015). H. Albert, et al.,Science translational medicine 6, 227ra233 (2014). F. C. Peterson, et al.,The Journal of biological chemistry 282, 8446-8453 (2007). M. H. Pauker, et al., Molecular and cellular biology 31, 2653-2666 (2011). H.M.Pauker, et al.,Science Signaling 5(221):rs3 (2012) F. A. Ran, et al.,Nature protocols 8, 2281-2308 (2013). S. B. Snapper, et al., Immunity 9, 81-91 (1998). J. A. Doudna, et al., Science 346, 1258096 (2014). Charrier, S., et al.,Gene therapy 14 (2007), 415-428. Snapper, S.B., et al.,Journal of leukocyte biology 77 (2005), 993-998. Zhang, H., et al., Immunity 25 (2006), 285-295. Gunn, M.D., et al.,The Journal of experimental medicine 189 (1999), 451-460. Altman, L.C., et al.,The Journal of clinical investigation 54 (1974), 486-493. Linder, S. & Kopp, P. Journal of cell science 118 (2005), 2079-2082. Linder, S., et al.,Proceedings of the National Academy of Sciences of the United States of America 96 (1999), 9648-9653. Zhang, J., et al.,The Journal of experimental medicine 190 (1999), 1329- 1342. Matalon, O., et al.,Science signaling 9 (2016), ra54. Lee, S.H., et al., J Immunol 183 (2009), 7931-7938. Anfossi, N., et al.,Immunity 25 (2006), 331-342. D. Schneidman-Duhovny, et al. Nucleic acids research 33, W363-367 (2005).

[0003] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.BACKGROUND OF THE INVENTION

[0004] Wiskott-Aldrich syndrome (WAS) is a severe primary immunodeficiency whose symptoms include recurrent infections, severe bleedings caused by microthrombocytopenia; a decrease in the number and size of platelets, and an increased incidence of autoimmunity and lymphoma (Ochs et al, 2006). X-linked thrombocytopenia (XLT) is considered a "mild" version of WAS, and is characterized mainly by frequent bleeding events caused by the severe microthrombocytopenia of these patients (Albert et al 2010). The defective gene responsible for WAS or XLT, the WAS gene, is located on the short arm of the X chromosome (Xp11.22-p11.23.1) and encodes a 502-amino acid protein- the WAS protein (WASp) (Derry et al, 1994).

[0005] WASp, which is expressed in hematopoietic cells, is an adaptor protein that facilitates actin cytoskeletal rearrangements, which are essential for normal immune cell responses. WASp-dependent immune cell functions include actin polymerization, sustaining of the immunological synapse, endocytosis, calcium flux, NFAT gene transcription, cellular activation and proliferation (Matalon et al, 2013;Joseph et al, 2013). More than 300 mutations spanning the entire WAS gene have been identified. These mutations reduce WASp expression, which is strongly correlated with the severity of the disease. The severe phenotypes manifested in classical WAS usually occur where WASp is completely absent, while partial or residual WASp expression is associated mainly with the less severe phenotype of XLT (Jin et al, 2004; Lutskiy et al, 2005). WAS and XLT are diagnosed in about 1 to 10 patients per million male newborns worldwide. Without early intervention, most WAS patients die during the first decade of their life from opportunist infections, while XLT patients exhibit a normal life span but frequently suffer from life-threatening hemorrhages (Ochs et al, 2006; Buchbinder et al, 2014).

[0006] Intriguingly, WAS gene mutations are usually normally transcribed, and aberrant WASp expression is therefore the result of post-translational protein instability. Accordingly, the majority of WAS mutations alter WASp binding to WASp-interacting protein (WIP), a chaperone of WASp that protects WASp from proteolysis (Reicher et al, 2012; Lutskiy et al, 2005; Konno et al 2007; Noy et al, 2012). The molecular degradation mechanism of WASp was recently deciphered by the present inventors (Reicher et al, 2012; Fried et al, 2014). In resting cells WASp is auto inhibited and is tightly bound to WIP, which masks its degradation sites, lysine residues 76 and 81, located in a pocket at the N'-terminal WASp-homology-1 (WH1) domain of WASp. Following cellular activation a cascade of signaling events leads to the release of WASp from auto inhibition, its recruitment to the cell membrane and actin rearrangement at the leading edge. Later in the activation process, WASp is phosphorylated on tyrosine 291 and WIP is phosphorylated by PKCθ on serine 488. These phosphorylation events induce the recruitment of Cbl-family E3 ligases to WASp, and trigger a conformational change that releases WIP protection from the degradation pocket of WASp. Subsequently, WASp lysines 76 and 81 are ubiquitylated, marking it for proteasomal degradation. Thus, partial or complete WASp deficiency of WAS / XLT patients is the result of constant, unregulated, ubiquitylation and degradation of WASp that is not properly protected by WIP.

[0007] Unfortunately, currently there are no curative treatments for WAS / XLT, except for allogeneic hematopoietic stem cell transplantation (HSCT), which requires identification of a suitable donor and can result in significant complications (Filipovich et al, 2008; Shin et al, 2012). Moreover, due to high risk-benefit ratio, HSCT is usually not a recommended treatment for XLT patients. For these patients, elective splenectomy is usually the treatment of choice, as removal of the spleen has shown to increase platelet count. However, splenectomy is not curative and has potential risks, such as insufficient production of antibodies and infections (Albert et al 2010; Litzman et al, 1996). Therefore, a safe and effective treatment is needed, which addresses the needs of both WAS and XLT patients.

[0008] WO 2014 / 195857 that is a previous publication by the inventors, discloses liposomal compositions comprising WASp modulators that may be used either in reducing WASp levels in hematopoietic malignancies, or alternatively, enhance WASp levels in WAS, XLT and associated disorders.

[0009] WO 2009 / 062118 A2 describes compounds and compositions for treatment or amelioration of one or more disorders characterized by defects in protein trafficking.

[0010] WO 2012 / 102937 A2 describes compounds and compositions for expanding the number of CD34+ cells for transplantation. Also described is a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation.

[0011] WO 2008 / 082537 A2 describes an assay for the identification of small molecule modulators of integrin CDl lb / CD18 and small molecules capable of modulating activity of this receptor.

[0012] WO 2015 / 065716 A1 describes compounds and methods of modulating 15-PGDH activity, and / or modulating tissue prostaglandin levels.

[0013] WO 2015 / 181394 A1 describes IL-2 / IL-15 Receptor antagonist compounds and uses thereof for the treatment of autoimmune and inflammatory diseases or graft rejection.

[0014] As WASp is a key regulator essential for the activity and function of most immune cells, increasing WASp expression offers a method to potentially boost the performance of the immune response.

[0015] The need for a safe and efficient treatment for both WAS and XLT led the inventors to develop a new and different therapeutic approach, which unlike gene correction, is based on the molecular mechanism of the disease and focuses on defending native WASp from degradation rather than replacing it.SUMMARY OF THE INVENTION

[0016] 1. A first aspect of the invention relates to an effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for modulating the degradation and stability of Wiskott-Aldrich Syndrome protein (WASp) in a cell of a subject in need thereof, said modulator having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0017] A further aspect of the invention relates to an effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a an innate or acquired immune-related disorder or condition in a subject in need thereof, wherein said at least one SMC modulator of WASp is having the general formula (XI) as defined above.

[0018] The invention further provides a SMC modulator of WASp degradation or any pharmaceutical composition thereof, wherein said SMC modulator is having the general formula (XI) as defined above.

[0019] Still further, the invention provides a kit comprising: (a) at least one SMC modulator of WASp having the general formula (XI) as defined above; and at least one of: (b) at least one chemotherapeutic agent; (c) at least one biological therapy agent; and (d) at least one agent that induces differentiation of hematopoietic progenitor cells.

[0020] These and other aspects of the invention will become apparent by the hand of the following drawings. The scope of the invention is defined by the claims. The references to methods of treatment in the summary and detailed description of the invention in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human body by therapy. Any embodiment not falling under the scope of the claims is provided for information purposes only.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: Figure 1A-1C. Structural model of WASp WH1 for virtual screening of WASp-binding SMCs Fig. 1A. shows an NMR model of the EVH1 domain of rat N-WASp conjugated to a WIP polypeptide (PDB ID: 2IFS) that was virtually modified using virtual mutagenesis tool of Discovery Studio 3.0, allowing the model to be representative of the WH1 domain of human WASp. The required site for SMCs binding is marked with a white circle. Fig. 1B-1C. shows a ribbon and surface structures of WASp WH1 model. Lysine residues 76 and 81 are light gray and dark gray, respectively. Figure 2. Schematic workflow of virtual screening for WASp-binding SMCs A schematic representation of the in silico prediction process. Rectangles denote data representative from a single protein-ligand interaction. Stacks of rectangles denote the data representative of all ligand models that were used. Oval shapes denote the major programs that were used in the process. The protein surface diagram denotes the modified NMR model of the N-WASp WH1 domain in PDB format. Using the FAST algorithm, 3D conformations of the various ligands were generated, and inputted to PatchDock with the modified NMR model. Features were extracted from the leading docking model and from the docking scores of all the models generated by PatchDock, and combined into a data vector. Finally, the predictor classified each ligand-protein docking using the data vector, giving each a score denoting whether it is predicted to be representative of a possible binding. Figure 3A-3G. MST analysis validates the binding of virtually-screened SMCs to WASp but not to its homologous, N-WASp and WAVE2 Diluted cell lysates of YFP-WASp / N-WASp / WAVE2-expressing HEK 293T cells were incubated with serially-diluted (100 µM - 3 nM) SMCs. The mixed lysates and SMCs were then loaded into standard-treated Monolith ™< capillaries and the fluorescence of the samples was measured by the Monolith NT.115 instrument at 60% MST power. Binding curves of WASp with SMC #6 (Fig. 3A), SMC #30 (Fig. 3B), SMC #33 (Fig. 3C), SMC #34 (Fig. 3D) and Y-27632 (Fig. 3E) or of N-WASp (Fig. 3F) or WAVE2 (Fig. 3G) with SMC #34 were generated by the NanoTemper Analysis 2.231 software. Normalized fluorescence (hot fluorescence / initial fluorescence) is plotted as a function of SMC concentration. Data shown are representative of at least three independent experiments. Figure 4A-4D. SMC of the invention upregulates WASp expression in platelets and primary lymphocytes Fig. 4A-4B. Freshly-isolated platelets were incubated with SMC#6 or control at 37°C for the indicated times. The platelets were either stimulated (+) with TRAP-6 (10 µM) or left unstimulated (-), followed by lysis. Lysates were analyzed for WASp expression by immunoblotting with anti-WASp and anti-GAPDH as loading control ( Fig. 4A). Relative WASp expression was determined by densitometric analysis and is presented in a summarizing graph of Fig. 4B. Error bars represent the SE from the mean. P values are presented and were calculated by two-tailed Student's t-test. Data are representative of three independent experiments. Fig. 4C-4D. Freshly-isolated PBMCs were incubated with SMC#6 or control at 37°C for the indicated times. The PBMCs were either co-stimulated (+) with anti-CD3 and anti-CD28 or left unstimulated (-), followed by lysis. Lysates were analyzed for WASp expression by immunoblotting with anti-WASp and anti-GAPDH as loading control (Fig. 4C). Relative WASp expression was determined by densitometric analysis and is presented in a summarizing graph of Fig. 4D. Error bars represent the SE from the mean. P values were calculated versus DMSO-treated control cells by two-tailed Student's t-test, and is indicated therein. Data are representative of three independent experiments. Figure 5A-5D. WASp-binding SMCs upregulate WASp expression in T-cells, primary lymphocytes and platelets Jurkat T-cells (Fig. 5A) or Freshly-isolated PBMCs (Fig. 5B) were incubated for 15 min at 37°C with either control or the indicated WASp-binding SMCs, followed by co-stimulation with anti-CD3 and anti-CD28 and lysis. Freshly-isolated platelets were incubated for 15 min at 37°C with either control or the indicated WASp-binding SMCs, followed by stimulation with TRAP-6 (10 µM) and lysis (Fig. 5C). Lysates were analyzed for WASp expression by immunoblotting with anti-WASp and anti-GAPDH as loading control. Western blot is representative of three independent experiments. Fig. 5D shows a summary of WASp expression analysis in PBMCs and platelets. Relative WASp expression was determined by densitometric analysis. Error bars represent the SE from the mean. Data are representative of three independent experiments. Figure 6A-6D. WASp-binding SMCs upregulate WASp expression in platelets Fig. 6A-6B. show freshly-isolated platelets that were incubated for 15 min at 37°C with either DMSO or the indicated WASp-binding SMCs, followed by stimulation (+) with TRAP-6 (10 µM) and lysis. Lysates were analyzed for WASp expression by immunoblotting with anti-WASp and anti-GAPDH as loading control (Fig. 6A). Summarizing graph is presented in Fig.6B. Fig. 6C-6D. show the western blot of freshly-isolated platelets incubated for 15 min at 37°C with either DMSO or potent WASp-binding SMCs that were stimulated with TRAP-6 (10 µM), followed by lysis (Fig. 6C). Error bars represent the SE from the mean. Data are representative of three independent experiments. Summarizing graph is presented in Fig.6D. Figure 7A-7G. Characterization of ubiquitylation-dependent degradation mechanism of WASp in platelets and megakaryocytes Freshly-isolated platelets were stimulated with 10µM of TRAP-6 for the indicated time points, followed by lysis. WIP (Fig. 7A) or WASp (Fig. 7B) were immunoprecipitated from the lysates and analyzed by western blot for co-immunoprecipitation, using anti-WASp, anti-WIP or anti-PKCθ antibodies. WASp immunoprecipitates were immunoblotted for WASp ubiquitylation using anti-ubiquitin (Ub) antibody ( Fig. 7C). Ubiquitylated WASp appears as a smear of bands above the MW of 65 kDa with a prominent band at ~81 kDa. Fig. 7D shows western blot analysis of WASp expression in activated platelets, with (+) or without (-) the addition of MG132 proteasome inhibitor. Blots are representative of three independent experiments. Meg-01 megakaryocyte cell line was activated in the presence (+) or absence (-) of MG132, followed by lysis (Fig. 7E). WASp ubiquitylation was determined by co-immunoprecipitation analysis as in Fig. 7C. Fig. 7F illustrates Meg-01 cells that were transfected with PKCθ-specific siRNA (+) or non-specific (NS) siRNA (-). 24 h later, the cells were stimulated and lysed. PKCθ and WASp protein expression levels were analyzed by western blot with anti-PKCθ and anti-WASp antibodies, and with anti-GAPDH as loading control. Relative protein expression was determined by densitometric analysis and is presented below the corresponding lanes. Fig. 7G. shows western blot analysis of WASp expression in whole cell lysates (W.C.L) of megakaryocyte, with (+) or without (-) the addition of MG132 proteasome inhibitor. Blots are representative of three independent experiments. Figure 8A-8D. WASp-binding SMCs up-regulate lymphocyte activation and proliferation Figures show 1×10 6< PBMC cells / ml stimulated with PMA and Ionomycin that were treated with DMSO or WASp-binding SMCs. After incubation, the cells were stained with PE-Cy5 ™< -conjugated mouse anti-human CD69 and lymphocyte activation was measured by flow-cytometry as described in the Experimental procedures. Histograms of DMSO versus SMC #6 (Fig. 8A), SMC #30 (Fig. 8B), SMC #33(Fig. 8C), and SMC #34 (Fig. 8D)are presented and represent three independent experiments. Figure 9A-9E. WASp-binding SMCs upregulate lymphocyte activation and proliferation Fig. 9A and 9B. show 1×10 6< Jurkat T cells / ml, stimulated with PMA and Ionomycin, were treated with WASp-binding SMC#6 or control. After incubation, the cells were stained with anti-activated LFA-1 antibody (KIM127), followed by staining with Alexa488-Fluor goat anti-mouse IgG 1 secondary antibody (Fig. 9B). Cells were co-stained with PE-Cy5 ™< -conjugated mouse anti-human CD69 and lymphocyte activation was measured by flow-cytometry as described in the Experimental procedures (Fig. 9A). Histograms of negative control versus SMC#6 are presented. Fig. 9C. shows 1×10 6< PBMC cells / ml, stimulated with PMA and Ionomycin that were treated with WASp-binding SMC#6 or DMSO as negative control. After incubation, the cells were stained with anti-activated LFA-1 antibody (KIM127), followed by staining with Alexa488-Fluor goat anti-mouse IgG 1 secondary antibody, and lymphocyte activation was measured by flow-cytometry as described in the Experimental procedures. Histogram of negative control versus SMC#6 is presented. Fig. 9D. shows the mean relative proliferation of stimulated Jurkat T-cells, treated with the indicated WASp-binding SMCs or DMSO as negative control from three independent experiments. Error bars represent the SE from the mean. Fig. 9E. shows the mean relative proliferation of stimulated PBMCs, treated with the indicated WASp-binding SMCs or DMSO as negative control from three independent experiments. Error bars represent the SE from the mean. Figure 10A-10C. WASp-binding SMCs enhance the migration of lymphocytes on ICAM-1 Jurkat T cells were pretreated with DMSO or the indicated WASp-binding SMCs, and cell migration on ICAM-1 / SDF-1α-coated cover glasses was tracked over a 20-min period, as described in Experimental procedures. Each line in Fig. 10A represents one cell. The tracks of five representative cells from each treatment are presented. Fig. 10B. shows mean cell displacement (DMSO: 17.25±1.58 n=337; SMC #6: 29.52±2.96 n=214; SMC #30: 41.07±4.69 n=55; SMC #33: 32.92±4.28 n=50; SMC #34: 48.91±6 n=60). Error bars represent the SE from the mean. P values versus DMSO-treated control cells are presented and were calculated by two-tailed Student's t-test. Fig. 10C. illustrates the final frame of cells treated with DMSO or with the indicated WASp-binding SMCs. Figure 11A-11D. WASp-binding SMCs increase intra-cellular calcium concentration in platelets Freshly-isolated human platelets were incubated with either control DMSO or the indicated WASp-binding SMCs, specifically, SMC#6 (Fig. 11A), SMC#30 (Fig. 11B), SMC#33 (Fig. 11C) and SMC#34 (Fig. 11D). Platelets were stimulated with TRAP-6 and calcium levels were measured by spectrofluorometer, as described in Experimental procedures. Data are representative of three independent experiments. Figure 12A-12D. WASp-binding SMCs decrease WASp ubiquitylation in platelets and primary lymphocytes Figs. 12A and 12B. show freshly-isolated platelets that were either stimulated (+) with TRAP-6 (10 µM) or unstimulated (-) and pre-incubated at 37°C for 15 min with either DMSO or the indicated WASp-binding SMCs (Fig. 12A - SMC #6; Fig. 12B - SMC #33), followed by lysis. Lysates were subjected to immunoprecipitation with anti-WASp antibody and were analyzed by western blotting with anti-ubiquitin (Ub) and with anti-WASp as precipitation control. Ubiquitylated WASp appears as a smear of bands above the molecular weight (MW) of 65 kDa with a prominent band at ~81 kDa. Blots are representative of three independent experiments. Figs 12C and 12D. show freshly-isolated PBMCs that were either co-stimulated (+) with anti-CD3 and anti-CD28 or unstimulated (-). The PBMCs were pre-incubated at 37°C for 15 min with either DMSO or the indicated WASp-binding SMCs (Fig. 12C - SMC #6; Fig. 12D - SMC #33), followed by lysis. WASp ubiquitylation was determined by immunoprecipitation as in Fig. 12A-12B. Ubiquitylated WASp appears as a smear of bands above the MW of 65 kDa with a prominent band at ~81 kDa. Blots are representative of three independent experiments. Figure 13A-13B. FRET analysis of the WIP-WASp interaction in activated T-cells treated with WASp-binding SMC#6, SMC#30, SMC#33 or SMC#34 Fig. 13A: Jurkat T cells stably expressing CFP-WASp and YFP-WIP were treated with WASp-binding SMC#6, SMC#30, SMC#33, SMC#34 or control. The cells were then plated on stimulatory coverslips (coated with an anti-CD3 antibody), and fixed after 5 min. Cells were imaged by confocal microscope, and FRET efficiency was measured by the donor-sensitized acceptor emission technology (see Experimental procedures for details). Fig. 13B: graph summarizing the percentage FRET efficiency in cells plated on the stimulatory coverslips, with the indicated treatment. Data are from four independent experiments. Error bars represent the SE from the mean. P values were calculated by two-tailed Student's t-test. Figure 14A-14E. WASp-binding SMCs restore WASp expression of common WAS / XLT WASp mutations Fig. 14A. presents a FACS analysis of Jurkat T-cells expressing YFP-WASp mutants. Fig. 14B. shows Jurkat T-cells stably expressing YFP-WASp mutants that were pretreated with either negative control or the indicated WASp-binding SMCs. The cells were then co-stimulated with anti-CD3 and anti-CD28, followed by lysis. Lysates were analyzed for WASp expression by immunoblotting with anti-WASp and anti-GAPDH as loading control. Relative protein expression was determined by densitometric analysis and is presented below the corresponding lanes. Western blots are representative of three independent experiments. Fig. 14C. shows western blot analysis of Jurkat T-cell line which have no expression of endogenous WASp wt (WAS - / -< ). Western blot is representative of three independent experiments. Fig. 14D. shows WASp knockout Jurkat T-cell lines that express only exogenous YFP-WASp harboring the common human WAS and XLT mutations, R86C (WAS - / -< / WASp R86C) or Y107C (WAS - / -< / WASp Y107C) that were pretreated with either negative control or SMC#34. The cells were then co-stimulated with anti-CD3 and anti-CD28 and analyzed by western blot as described in Fig. 14B. Endogenous WASp displays a band at 65 kDa and exogenous YFP-WASp displays a band at 92 kDa. Relative protein expression was determined by densitometric analysis and is presented below the corresponding lanes. Fig 14E. shows WASp-binding SMC up-regulates lymphocyte activation. 1×10 6< WASp knockout Jurkat T-cell line that expresses only exogenous YFP-WASp harboring the common human WAS and XLT mutation, R86C (WAS- / - / WASp R86C) was pretreated with either negative control or SMC#34. Cells that completely lack WASp expression (WAS - / -< ) were also treated with the control. The cells were then stimulated with PMA and Ionomycin. After incubation, the cells were stained with PE-Cy5 ™< -conjugated mouse anti-human CD69 and lymphocyte activation was measured by flow cytometry as described in Experimental procedures. Histogram of negative control versus SMC#34 is presented. Figure 15A-15C. WASp-binding SMC#34 enhances the migration of lymphocytes stably expressing common human WAS / XLT WASp mutations WASp knockout Jurkat T-cell lines that express only exogenous YFP-WASp R86C (WAS - / -< / WASp R86C) or Y107C (WAS - / -< / WASp Y107C) were pretreated with SMC#34 in comparison to cells treated with the control. Cells that completely lack WASp expression (WAS - / -< ) were also treated with the control. Cellular migration was tracked over a 20-min period on ICAM-1 / SDF-1α-coated cover glasses, as described in Experimental procedures. Fig. 15A. The last frame in the movie of the control or the indicated WASp-binding SMCs. Fig. 15B. Each line represents one cell. The tracks of five representative cells from each treatment are presented. Fig. 15C. Mean cell displacement (WAS - / -< / WASp R86C, DMSO negative control: 17.74±2.46 n=110, SMC#34: 53.65±4.88 n=138; WAS - / -< / WASp Y107C, DMSO negative control: 17.75±2.06 n=138, SMC#34: 74.24±8.16 n=100; WAS - / -< , DMSO: 5.15±1.09 n=88). Error bars represent the SE from the mean. P values of SMC-treated cells versus DMSO-treated control cells are presented and were calculated by two-tailed Student's t-test. Figure 16. Proposed model for the mechanism of action by which WASp-binding SMCs protect WASp from degradation WASp degradation sites, lysine residues 76 and 81 are located in a pocket at the N'-terminus of WASp. In normal naive cells WIP is tightly bound to WASp and protects it from ubiquitylation and degradation (upper scheme). WIP protection is relieved following cellular activation or alternatively due to WAS / XLT mutations, which abrogate the WIP-WASp interaction. Unprotected, lysine residues 76 and 81 are ubiquitylated and WASp is degraded (lower right). WASp-binding SMCs mask WASp degradation sites by binding in the close proximity of the pocket at the N'-terminus. This masking protects WASp from ubiquitylation and degradation (lower left). DETAILED DESCRIPTION OF THE INVENTION

[0022] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0023] As discussed herein before, so far, the attempts for curative treatments for WAS / XLT patients were focused on restoring WASp expression and function in hematopoietic cells, either by hematopoietic stem cell transplantation (HSCT) or gene therapy. Despite being the only approved restorative treatment for WAS, HSCT is a customized treatment, which requires the availability of a matching donor and early intervention. The graft source (bone marrow, cord blood or peripheral blood) and the intensity of preparatory conditioning are also complex consideration that must be taken prior to transplantation. Post-transplant complications may include autoimmunity, malignancies, viral infections, graft-versus-host disease (GVHD) and infertility. Gene therapy, which is in fact an autologous gene-modified HSCT, is an emerging treatment intended to bypass the obstacle of finding a matching donor, and to avoid GVHD. Ex vivo gene correction in this approach is facilitated by various viral vectors that integrate the correct gene to patient-derived hematopoietic progenitor cells, which are then reinfused back to the patient. Unfortunately however, previous clinical studies reported the onset of leukemia in most of the patients who undergone gene therapy with γ-retroviral vectors, due to vector-related insertional oncogenesis (Aiuti et al, 2013). Current efforts at improving safety and efficacy of gene therapy are focusing on lentiviral vectors, which show some clinical improvement with no insertional oncogenesis-associated events recorded to date (Hacein-Bey Abina et al, 2015). However, more time is needed to follow-up patients in order to assess long-term safety and efficacy. Still, gene therapy carries the other risks of allogeneic HSCT, such as infections and infertility due to the preparatory conditioning.

[0024] These intensive treatments are considered excessively risky for XLT patients, because XLT patients have good long-term survival, with life expectancy that is not substantially different from the normal population. However, XLT patients suffer from severe disease-related complications, with only 27% of XLT patients reach the age of 60 without experiencing severe disease-related events (Albert et al, 2010). Thus, there is currently no generally accepted treatment policy for XLT patients. Splenectomy is offered to WAS / XLT patients in order to increase platelet count, and, therefore to reduce bleeding events. However, splenectomy is associated with increased risk of infections, requiring the patients to receive life-long antibiotic prophylaxis. Moreover, WAS / XLT patients who underwent splenectomy are not compatible for further HCST because they have an increased morbidity and mortality post-HSCT, due to viral infections (Buchbinder et al, 2014).

[0025] The inventors report herein that small molecule compounds (SMCs) restore Wiskott Aldrich Syndrome protein (WASp) expression and function. The inventors further revealed the mechanism underlying this effect of the novel SMCs described herein. More specifically, in normal resting cells WASp is auto inhibited by its tight bond to a protective protein - WIP, which masks WASp degradation sites at lysine residues 76 and 81. In contrast, WAS gene mutations trigger a conformational change that releases WIP protection from the degradation pocket of WASp, subsequently resulting in WASp degradation by uncontrolled ubiquitylation. The resulting WASp deficiency affects a broad spectrum of cell functions, and the severity of the disease is determined by the level of WASp expression. The inventors used an in-silico predictor to screen potential WASp-binding SMCs that protect it from degradation. The binding of potent SMCs was validated using microscale thermophoresis (MST) technology.

[0026] More specifically, in the present disclosure, the inventors provide novel WASp-binding SMCs (EXAMPLE 1, Table 1, Fig. 1, Fig. 3) that potentially protect WASp from degradation, via blocking the ubiquitylation of lysine residues 76 and 81 located in a pocket at WASp WH1 domain. Moreover, the inventors show that by reducing WASp ubiquitylation, the selected SMCs up-regulate WASp expression in T-cell lines, primary lymphocytes and platelets (Fig. 5, Fig. 12). This upregulation of WASp expression by WASp-protecting SMCs, enhanced WASp-dependent cellular function, including cellular activation, intra-cellular calcium influx, proliferation and migration (Fig. 8 - Fig. 11). Strikingly, these SMCs restored the function of mutant WASp-expressing cells (Fig. 14 - Fig. 15). Therefore, the inventors have revealed a novel function of the selected SMCs, namely, attenuation of WASp degradation by binding to WASp. The findings of the invention are highly valuable and may lead to the development of new therapeutic strategies which target WASp expression. Moreover, these findings form a promising treatment modality for hereditary WASp dysfunction disorders such as WAS / XLT as well as for acquired WASp dysfunction disorders as will be elaborated below.

[0027] Thus, in general, disclosed is an effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for modulating the degradation of Wiskott-Aldrich Syndrome protein (WASp) in a cell. The SMC may have the general formula (I): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, branched C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, straight C 1 -C 12 alkoxy, branched C 1 -C 12 alkoxy, a ring system containing five to twelve atoms, each optionally substituted by at least one of straight C 1 -C 5 alkyl,branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, amine, nitro, CF 3 , -C(=O)-O-(CH 2 ) n -CH 3 , R 5 , or -NH-C(=O)-R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include N, O, S, NH, C=N, C=O, S=O or SO 2 and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide and cyano; L1 and L2 are each independently from each other selected to be absent or from - (CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl. The scope of the invention is defined by the claims. Any embodiment not falling under the scope of the claims is provided for information purposes only.

[0028] In some embodiments, a ring system containing five to twelve atoms or five to 15 atoms may be substituted with one or more substituents, in certain embodiments one, two, three or four substituents as detailed herein. It should be noted that when referring to ring system five to twelve atoms or five to 15 atoms, it may optionally include least one of N, O, S, NH, C=N, C=O, S=O, or SO 2 .

[0029] In accordance with this aspect, in some specific embodiments, the compound of general Formula I may provide a compound having the general formula (I'): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, branched C 1 -C 12 alkyl, a ring system containing five to twelve atoms, each optionally substituted by at least one of halide, amide, amine, nitro, -C(=O)-O-(CH 2 ) n -CH 3 ; R 5 or -NH-C(=O)-R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include at least one of N, NH and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-, -,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -;-(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, L1 and L2 may be each independently from each other optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl, each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl.

[0030] In accordance with some embodiments, at least one of R 1 and R 2 is independently from each other selected from H, a ring system containing five to twelve atoms. In accordance with some other embodiments, at least one of R 1 and R 2 is independently from each other selected from H. In some other embodiments, at least one of R 1 and R 2 is independently from each other selected from a ring system containing five to twelve atoms, which is optionally substituted with halide, amide, nitro, -C(=O)-O-(CH 2 ) n -CH 3 , R 5 , or -NH-C(=O)-R 5 . In some embodiments, R 5 is an aryl or thiophene, optionally substituted with at least one halide.

[0031] In some other embodiments, the ring system of at least one of R 1 and R 2 may be an aryl (aromatic ring) or aliphatic ring (non-aromatic ring). In some further embodiments, at least one of R 1 and R 2 may be C 5 -C 12 saturated cycloalkyl, C 5 -C 12 saturated cycloalkylene, C 5 -C 12 aryl or C 5 -C 12 arylene. In some further embodiments, the ring system of at least one of R 1 and R 2 may contain at least two carbon atoms and may include at least one heteroatom ring. In some further embodiments, at least one of R 1 and R 2 may be heteroaryl, heteroarylene, heterocycloalkylene or heterocycloalkyl. In some further embodiments, at least one of R 1 and R 2 may be C 2 -C 12 heterocycloalkyl ring, C 2 -C 12 heteroaryl or C 2 -C 12 heteroarylene. In some embodiments, the heteroatom may be N, O, S. In some other embodiments, at least one of R 1 and R 2 may be thiazole, cyclopentane, naphthalene, aryl, each optionally substituted with -C(=O)-O-(CH 2 )-CH 3 , halide, nitro or -NH-C(=O)-R 5 . In some embodiments, R 5 is an aryl substituted with at least one halide.

[0032] In some other embodiments, at least one of R 1 and R 2 may be thiazole. In some other embodiments, at least one of R 1 and R 2 may be cyclopentane. In some other embodiments, at least one of R 1 and R 2 may be naphthalene. In some other embodiments, at least one of R 1 and R 2 may be an aryl substituted with -C(=O)-O-(CH 2 )-CH 3 . In some other embodiments, at least one of R 1 and R 2 may be an aryl substituted with at least one halide, preferably F. In some other embodiments, at least one of R 1 and R 2 may be an aryl substituted with at two F atoms. In some other embodiments, at least one of R 1 and R 2 may be an aryl substituted with one F and one Cl groups.

[0033] In some other embodiments, at least one of R 1 and R 2 may be an aryl substituted with nitro.

[0034] In some other embodiments, at least one of R 1 and R 2 may be -NH-C(=O)-R 5 . In some embodiments, R 5 is an aryl substituted with at least one halide. In some further embodiments, at least one of R 1 and R 2 may be benzoic acid methyl ester.

[0035] In some other embodiments, R 1 and R 2 are each independently from each other selected from straight or branched C 1 -C 12 alkyl optionally substituted by at least one of amide or thiophene In some other embodiments, at least one of R 1 or R 2 may be CH 2 -CH substituted by at least one of dimethyl amine or thiophene.

[0036] In some other embodiments, R 1 and R 2 are each independently from each other selected from straight C 1 -C 12 alkyl. In some embodiments, R 1 and R 2 are each independently from each other selected from CH 3 .

[0037] In accordance with some embodiments, R 1 and R 2 together with the nitrogen atom they are connected to form a five or six membered saturated or unsaturated ring that may optionally include at least one of N and may be optionally be substituted with at least one of straight or branched C 1 - C 5 alkyl. In some embodiments, R 1 and R 2 together with the nitrogen atom they are connected to form piperidine or piperazine, each optionally substituted with at least one straight or branched C 1 - C 5 alkyl. In some embodiments, R 1 and R 2 together with the nitrogen atom they are connected to form piperidine or piperazine substituted with at least one CH 3 group, at times two CH 3 groups, at times three CH 3 groups.

[0038] In some embodiments, R 1 and R 2 together with the nitrogen atom they are connected to form piperazine substituted with two CH 3 groups. In some embodiments, R 1 and R 2 together with the nitrogen atom they are connected to form piperazine substituted with one CH 3 group.

[0039] In some embodiments, L1 may be absent or may be selected from -CH 2 -CH 2 -C(O)-N-CH 2 -C(O)-NH-CH 2 -,-(CH 2 )-S-, -CH 2 -, -(CH 2 ) -N-C(=O)-, -(CH 2 )-S-,-(CH 2 )-S-(CH 2 ) n -C(O)-NH-(CH2)-, -(CH 2 )-NH-NH-C(=O)-, -NH-(CH 2 )-, each optionally substituted with ethyl, methyl, an aryl optionally substituted with a methyl or ethyl.

[0040] In some embodiments, L2 may be absent or may be selected from -(CH 2 )-O-, S(O) 2 , S(O) 2 -N-, CH 2 , -S(O) 2 -NH-(CH 2 )-, NH each optionally substituted with a methyl, an ethyl, an aryl optionally substituted with a methyl, ethyl.

[0041] In some other embodiments, each of R 3 and R 4 may be absent. In some other embodiments, each of R 3 and R 4 may be selected from a ring system containing five to 15 atoms, optionally substituted as described herein. In some further embodiments, each of R 3 and R 4 may be selected from a ring system containing five to twelve atoms, optionally substituted as described herein.

[0042] In some other embodiments, the ring system of at least one of R 3 and R 4 may be an aryl (aromatic ring) or aliphatic ring (non-aromatic ring). In some further embodiments, at least one of R 3 and R 4 may be C 5 -C 12 saturated cycloalkyl, C 5 -C 12 saturated cycloalkylene, C 5 -C 12 aryl or C 5 -C 12 arylene. In some further embodiments, the ring system of at least one of R 3 and R 4 may contain at least two carbon atoms and may include at least one heteroatom ring. In some further embodiments, at least one of R 3 and R 4 may be heteroaryl, heteroarylene, heterocycloalkylene or heterocycloalkyl. In some further embodiments, at least one of R 3 and R 4 may be C 2 -C 12 heterocycloalkyl ring, C 2 -C 12 heteroaryl or C 2 -C 12 heteroarylene. In some embodiments, the heteroatom may be N, O, S.

[0043] In some other embodiments, at least one of R 3 and R 4 may be thiazole, cyclopentane, naphthalene, triazine, triazole, piperidine, piperazine, quinoline, isoquinoline, phthalazine, tetrahydro-quinoline, tetrahydro-quinazoline pyridine, oxadiazole, aryl, each optionally substituted with at least one of C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, aryl, pyridine, morpholine, S(O) 2 -amide.

[0044] In some other embodiments, at least one of R 3 and R 4 may be triazole, triazine, piperidine, piperazine, , quinoline, isoquinoline, phthalazine, pyridine, tetrahydro-quinoline, tetrahydro-quinazoline oxadiazole, aryl, each optionally substituted with at least one of C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , pyridine, morpholine, S(O) 2 -amide.

[0045] In some other embodiments, R 3 may be triazole, triazine, piperidine, phthalazine, oxadiazole, aryl, each optionally substituted with at least one of CH 3 , (=O), (=S), morpholine.

[0046] In some other embodiments, R 4 may be piperidine, piperazine, quinoline, isoquinoline, phthalazine, tetrahydro-quinoline, pyridine, tetrahydro-quinazoline aryl, each optionally substituted with at least one of C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , morpholine, S(O) 2 -amide.

[0047] In some embodiments, L1 is absent and R 3 is an aryl, optionally substituted.

[0048] In accordance with such embodiments, the present disclosure provides the compound of Formula I that may in some embodiments be presented as a compound having the general formula (II): wherein R1, R2, L2 and R4 are as defined above for a compound having the general formula (I) or for a compound having the general formula (I').

[0049] In some embodiments, L2 is selected from C(O) and S(O) 2 . In some embodiments, L1 is absent, R 3 is an aryl and L2 is selected from C(O) and S(O) 2 .

[0050] In accordance with such embodiments, the present disclosure provides a compound having the general formula (III), that is derived from the compound of Formula I: wherein R1, R2 and R4 are as defined above for a compound having the general formula (I) or for a compound having the general formula (I').

[0051] The present invention relates in particular to an effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for modulating the degradation of Wiskott-Aldrich Syndrome protein (WASp) in a cell of a subject in need thereof, the modulator having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 ), and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0052] In some embodiments, in the SMC modulator for use in accordance with the invention, the R 1 and R 2 are each independently from each other selected from H, C 5 -C 7 saturated cycloalkyl, C 5 -C 7 saturated cycloalkylene, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl, or R 1 and R 2 together with the nitrogen atom they are connected to form a five or six membered saturated or unsaturated ring optionally include at least one of N and optionally substituted with at least one of straight C 3 -C 5 alkyl, L1 may be either absent or may be selected from -CH 2 -S-, -CH 2 -CH 2 -C(O)-N-CH 2 -C(O)-NH-CH 2 , -CH 2 -, each optionally substituted with ethyl, methyl, an aryl optionally substituted with a methyl or ethyl, L2 is absent or -CH 2 -O-, CH 2 ; R 3 and R 4 are each independently from each other absent or selected from C 5 -C 12 heterocycloalkyl ring, C 2 -C 15 heteroaryl or C 2 -C 15 heteroarylene. In some embodiments, the heteroatom may be N, O, S, each optionally substituted with at least one of straight C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0053] In some further embodiments, in the SMC modulator for use in accordance with the invention, the R 1 and R 2 may be each independently from each other selected from H, cyclopentane, or thiazole. Alternatively, R 1 and R 2 together with the nitrogen atom they are connected to form a six membered unsaturated ring substituted with at least one methyl, L1 is absent or is selected from -CH 2 -S-, -CH 2 -CH 2 -C(O)-N-CH 2 -C(O)-NH-CH 2 -, substituted with an aryl optionally substituted with a methyl L2 is absent, CH 2 , or -CH 2 -O-, R 3 and R 4 are each independently from each other absent or selected from the group consisting of piperidine, piperazine, quinoline, isoquinoline, phthalazine, tetrahydro-quinoline, pyridine,tetrahydro-quinazoline 1, 2, 4-triazole, oxadiazole quinoline, pyridine, phenyl, naphthalene substituted with -C(O)-CH 3 or methyl.

[0054] In some particular embodiments of the SMC modulator for use in accordance with the invention, the compound of Formula XI, may provide a compound having the general formula (XII): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 a nd L2 each independently from each other may be absent or selected from -(CH 2 ) n -, (CH 2 ) n -S-,-(CH 2 ) n -O-, and may be optionally substituted with C 1 -C 5 alkyl, n may be an integer selected from 0 or 1, R3 is a ring system containing five atoms, optionally substituted with at least one straight C 1 -C 5 alkyl, or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl, R4 is absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight C 1 -C 5 alkyl.

[0055] In accordance with some embodiments, of the SMC modulator for use, R 1 and R 2 are each independently from each other selected from H, straight C 2 - 4 alkyl, cycloalkyl, each optionally substituted by at least one a ring system containing five to seven atoms, or R 1 and R 2 together with the nitrogen atom they are connected to form a five or six membered unsaturated ring optionally be substituted with at least one of methyl, L1 is -CH 2 -S-, L2 is absent or -CH 2 -O-, R3 is a 5-membered aromatic ring, selected from the group consisting of oxazole, 1, 2, 4-traizole, oxadiazole, each optionally substituted by at least one methyl, R4 is absent or selected from the group consisting of quinoline, pyridine, phenyl, naphthalene.

[0056] In yet some further specific embodiments, the SMC modulator for use in accordance with the invention wherein R 1 and R 2 together with the nitrogen atom they are connected to form a six membered unsaturated ring substituted with at least one methyl, L1 is -CH 2 -S-, L2 is absent or -CH 2 -O-, R3 is 1, 2, 4-triazole, oxadiazole, each optionally substituted by at least one methyl, R4 is absent or selected from the group consisting of quinoline, pyridine.

[0057] In some particular embodiments, specific and non-limiting examples of the SMC modulators for use of the invention, or pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34).

[0058] In yet another alternative, the SMC modulators for use of the invention may be 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7).

[0059] In yet some further particular embodiments, specific and non-limiting examples of the SMC modulators for use of the invention, or pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1) 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10) 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11) 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

[0060] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the invention, may be the compound [5-(Naphthalen-1-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9). (not part of the claims)

[0061] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the invention, may be the compound 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2) (not part of the claims)

[0062] In yet some further particular embodiments, the SMC modulator used by the invention may be any compound defined by Formula XI, Formula XII, with the proviso that the compound is not any of the compounds detailed below: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1) 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (34.13);

[0063] In yet some further particular embodiments, the SMC modulator that may be used by the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (34.9).

[0064] In yet some further particular embodiments, the SMC modulator that may be used by the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2);

[0065] In yet some alternative particular embodiments of the SMC modulator for use in accordance with the invention, the compound of Formula XI, may provide a compound having the general formula (XIV): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H and straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected from -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, R 3 and R4 are each independently from each other absent or selected from an aryl or heteroaryl group optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, halide, nitro and cyano.

[0066] In some embodiments, in the SMC modulator for use in accordance with the invention, R 1 and R 2 are each independently from each other selected from H, methyl and ethyl, at times R 1 and R 2 are each independently from each other selected from H and methyl, L1 may be -CH 2 -S-, L2 may be -CH 2 -O-; R 3 and R4 are each independently from each other absent or selected from an aryl or heteroaryl group optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, halide, nitro and cyano.

[0067] In some further embodiments, in the SMC modulator for use in accordance with the invention, the R 1 and R 2 may be each independently from each other selected from H and methyl, L1 is -CH 2 -S-, L2 is, -CH 2 -O-, R 3 is selected from the group consisting of thiazole, [1,3,4]thiadiazole, [1,3,4]oxadiazole, and R 4 is phenyl.

[0068] In yet some alternative particular embodiments of the SMC modulator for use, the compound of Formula I may provide a compound having the general formula (XV): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl and branched C 1 -C 12 alkyl; L1 and L2 are each independently from each other selected to be absent or from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0069] In some embodiments, R 1 and R 2 are each independently from each other selected from H or straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, -CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 - C 5 alkyl ; each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0070] In some other embodiments, R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 5 alkyl, L1 is absent and L2 is selected from -(CH 2 )-S-,-(CH 2 )-O-, -(CH 2 )-; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0071] In some other embodiments, R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 5 alkyl, L1 is absent and L2 is selected from -(CH 2 )-S-,-(CH 2 )-O-, -(CH 2 )-; R 3 is a bicyclic ring and R4 is an aryl or a heteroaryl.

[0072] In yet some alternative particular embodiments of the SMC modulator for use according to the disclosure, the compound of Formula XI, may provide a compound having the general formula (XIII): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, a ring system containing five to seven atoms, each optionally substituted by at least one of halide, amide, amine, nitro; L1 and L2 if present are each independently may be absent or from each other selected from -CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )- each independently from each other optionally substituted with C 1 -C 5 alkyl, a ring system containing five to seven atoms optionally substituted with C 3 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight C 1 -C 5 alkyl, (=O), (=S), or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl. In more specific embodiments for the compound of Formula XIII, at least one of R 1 and R 2 is C5-C7 saturated cycloalkyl, C5-C7 saturated cycloalkylene, C5-C7 aryl or C5-C7 arylene, L1 may be absent or selected from -CH 2 -CH 2 -C(O)-N-CH 2 -C(O)-NH-CH 2 -, - CH 2 -, each optionally substituted with ethyl, methyl, an aryl optionally substituted with a methyl or ethyl, L2 may be absent or may be selected from CH 2 , at least one of R 3 and R 4 may be C 2 -C 12 heterocycloalkyl ring, C 2 -C 12 heteroaryl or C 2 -C 12 heteroarylene. In some embodiments, the heteroatom may be N, O, S.

[0073] In still further some embodiments, at least one of R 1 and R 2 is selected from the group consisting of cyclopentane or thiazole, L1 is absent or -CH 2 -CH 2 -C(O)-N-CH 2 -C(O)-NH-CH 2 -, substituted with an aryl optionally substituted with a methyl, L2 is absent or selected from CH 2 , at least one of R 3 and R 4 is selected from the group consisting of piperidine, piperazine, quinoline, isoquinoline, phthalazine, tetrahydro-quinoline, pyridine,tetrahydro-quinazoline substituted with -C(O)-CH 3.

[0074] In some particular embodiments, specific examples of the SMC modulators for use disclosed or pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XIII may include: N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33). (not part of the claims)

[0075] Also described herein is: 3-(4-Cyclopentylcarbamoyl-benzyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Designated herein as SMC#30).

[0076] In yet some further embodiments, specific examples of compounds or pharmaceutically acceptable salts or hydrates of the compounds of Formula I include, N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33); (not part of the claims) 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone (Designated herein as SMC #34); 3-(4-Cyclopentylcarbamoyl-benzyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Designated herein as SMC#30); ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate (Designated herein as SMC #23); (not part of the claims) N-[2-(dimethylamino)-2-thiophen-2-ylethyl]-4-[ethyl(phenyl)sulfamoyl]benzamide (Designated herein as SMC #24); (not part of the claims) 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one (Designated herein as SMC #26); (not part of the claims) 2-(4-Morpholin-4-yl-6-phenylamino-[1,3,5]triazin-2-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide (Designated herein as SMC #15); (not part of the claims) 3-(benzylsulfamoyl)-N-[2-(2,6-difluoroanilino)-2-oxoethyl]-N-ethylbenzamide (Designated herein as SMC #25); (not part of the claims) 2-[4-[3-(dimethylsulfamoyl)-4-methylphenyl]-1-oxophthalazin-2-yl]-N,N-dimethylacetamide (Designated herein as SMC #16); (not part of the claims) N-(2,5-difluorophenyl)-2-[2-[1-(4-methylphenyl)sulfonylpiperidine-3-carbonyl]hydrazinyl]acetamide (Designated herein as SMC #21); (not part of the claims) 2-fluoro-N-[4-[[2-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetyl]amino]phenyl]benzamide (Designated herein as SMC #31); (not part of the claims) 2-[2-(naphthalen-2-ylamino)-2-oxoethyl]sulfanyl-N-[(4-propan-2-ylphenyl)methyl]acetamide (Designated herein as SMC #17); (not part of the claims) 1-(3-chloro-4-fluorophenyl)-3-[[1-[(2,5-dimethylphenyl)methyl]piperidin-4-yl]methyl]urea (Designated herein as SMC #28). (not part of the claims)

[0077] Also disclosed are compounds defined by having general formula (I) above provided that the compound is not any one of the compounds detailed below, specifically: N'-[2-(benzylamino)-2-oxoethyll-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC #33); (not part of the claims) 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone (Designated herein as SMC #34); 3-(4-Cyclopentylcarbamoyl-benzyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Designated herein as SMC #30); ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate (Designated herein as SMC #23); N-[2-(dimethylamino)-2-thiophen-2-ylethyl]-4-[ethyl(phenyl)sulfamoyl]benzamide (Designated herein as SMC #24); 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one (Designated herein as SMC #26); 2-(4-Morpholin-4-yl-6-phenylamino-[1,3,5]triazin-2-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide (Designated herein as SMC #15); 3-(benzylsulfamoyl)-N-[2-(2,6-difluoroanilino)-2-oxoethyl]-N-ethylbenzamide (Designated herein as SMC #25); 2-[4-[3-(dimethylsulfamoyl)-4-methylphenyl]-1-oxophthalazin-2-yl]-N,N-dimethylacetamide Designated herein as SMC #16); N-(2,5-difluorophenyl)-2-[2-[1-(4-methylphenyl)sulfonylpiperidine-3-carbonyl]hydrazinyl]acetamide (Designated herein as SMC #21); 2-fluoro-N-[4-[[2-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetyl]amino]phenyl]benzamide (Designated herein as SMC #31); 2-[2-(naphthalen-2-ylamino)-2-oxoethyl]sulfanyl-N-[(4-propan-2-ylphenyl)methyl]acetamide (Designated herein as SMC #17); 1-(3-chloro-4-fluorophenyl)-3-[[1-[(2,5-dimethylphenyl)methyl]piperidin-4-yl]methyl]urea (Designated herein as SMC #28);

[0078] Still further, in some embodiments, the SMC is N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide having a structure: (denoted herein as SMC #33) (SMC# 15-17 ,21, 23- 26, 28, 31 and 33 are not part of the claims)

[0079] In some embodiments, the SMC is 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone having a structure (denoted herein as SMC #34);

[0080] In some embodiments, the SMC is ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure (denoted herein as SMC #23);

[0081] In some embodiments, the SMC is 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26);

[0082] In accordance with some other aspects, the present disclosure provides a compound having the general formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of X, Y, Z, V, W, T and S may be selected from N, NH and C, R 6 and R 7 are the same or are different and are independently selected from each other may be L3-R 8 , L3 may be selected from -(CH 2 )n, -NH-C(O) and C(O)-NH, S(O) 2 , C(O), n is an integer between 0 to 5; R 8 may be selected from a ring system containing five to twelve atoms, each optionally substituted by at least one of straight or branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, nitro and hydroxyl, CF 3 .

[0083] In accordance with some embodiments, the compound having the general formula (V) may be represented by the general formula (VI): wherein each one of X, Y, Z, V, W, T, S, R 6 and R 7 are as defined in formula (V).

[0084] In accordance with some embodiments, the compound having the general formula (V) may be represented by the general formula (VII): wherein each one of X, Y, Z, V, W, T, S, R 6 and R 7 are as defined in formula (V).

[0085] In accordance with some embodiments, the compound having the general formula (V) may be represented by the general formula (VIII): wherein X, Y, Z, W and T may be selected from N and V is selected from NH; L3 may be selected from -(CH 2 )-, and -S(O) 2 ; R 8 may be an aryl optionally substituted by at least one halide or CF 3 .

[0086] In some embodiments, specific examples of compounds or pharmaceutically acceptable salts or hydrates of the compounds of Formula V include, without limitation: 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32);

[0087] In some alterative embodiments, the compound of the disclosure may be any compound defined by having general formula (V) above provided that the compound is not 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32);

[0088] In accordance with some other aspects, the present disclosure provides a compound having the general formula (IX): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein L4 may be absent or may be selected from -(CH 2 ) n -, -S-(CH 2 ) n -, -(CH 2 ) n -S-; n is an integer between 0 and 5; R 10 and R 11 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 .

[0089] In some embodiments, L4 is selected from -S-(CH 2 )-. In some other embodiments, R 10 and R11 are each independently from each other absent or selected from triazine, piperidine each optionally substituted with at least one NH 2 .

[0090] In some embodiments, specific examples of compounds or pharmaceutically acceptable salts or hydrates of the compounds of Formula IX include, without limitation: 8-[(4-amino-6-piperidin-1-yl-1,3,5-triazin-2-yl)methylsulfanyl]-7-ethyl-1,3-dimethylpurine-2,6-dione (Designated herein as SMC #18).

[0091] In yet some alterative embodiments, the compound of the disclosure may be any compound defined by having general formula (IX) above provided that the compound is not 8-[(4-amino-6-piperidin-1-yl-1,3,5-triazin-2-yl)methylsulfanyl]-7-ethyl-1,3-dimethylpurine-2,6-dione (Designated herein as SMC #18).

[0092] In accordance with some other aspects, the present disclosure provides a compound having the general formula (X): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein R 13 and R14 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 1 -C 5 alkoxy, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 , NH-C(O)-CH 3 .

[0093] In some other embodiments, R 10 and R11 are each independently from each other absent or selected from aryl each optionally substituted with at least one OCH, NH-C(O)-CH 3 .

[0094] In some embodiments, specific examples of compounds or pharmaceutically acceptable salts or hydrates of the compounds of Formula X include, without limitation: N-[4-[3-(2,4-dimethoxyphenyl)-4-oxo-1,2-dihydroquinazolin-2-yl]phenyl]acetamide (Designated herein as SMC #22).

[0095] In yet some alterative embodiments, the compound of the disclosure may be any compound defined by having general formula (X) above provided that the compound is not N-[4-[3-(2,4-dimethoxyphenyl)-4-oxo-1,2-dihydroquinazolin-2-yl]phenyl]acetamide (Designated herein as SMC #22).

[0096] Still further, in some embodiments, the compound for use in accordance with the uses of the invention may be the SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0097] In yet some alternative embodiments, the invention provides the uses of any of the SMCs disclosed herein, provided that said SMC is not SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0098] The term "alkyl " as used herein refers to a linear, branched saturated hydrocarbon having from 1 to 20 carbon atoms. The term "C 1 -C 12 alkyl " or "C 1 -C 12 alkylene " refers to a linear (straight), branched saturated hydrocarbon having from 1 to 12 carbon atoms, in some embodiments, contain from 2 to 8 carbons, in yet some embodiments from 2 to 5 carbons, in yet some further embodiments, from 1 to 3 carbon atoms. It should be noted that alkyl refers to an alkyl end chain and alkylene refers to a middle chain alkyl. Representative C 1 -C 12 alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, pentyl, iso-pentyl, neopentyl, tert-pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, sec-octyl (1-methylheptyl), and cyclooctyl.

[0099] The term "C 1 -C 12 haloalkyl " as used herein refers to a C 1 -C 12 alkyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0100] The term "alkenyl " as used herein refers to a linear (straight), branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon double bond. The term "C 2 -C 12 alkenyl " or "C 2 -C 12 alkenylene " as used herein refers to a linear, branched unsaturated hydrocarbon having from 2 to 12 carbon atoms and at least one carbon-carbon double bond, in some embodiments from 3 to 8 carbons, in yet some further embodiments, from 3 to 5 carbon atoms and at least one double bond. It should be noted that alkenyl refers to an alkyl end chain and alkenylene refers to a middle chain alkyl.

[0101] The term " C 2 -C 12 haloalkenyl " as used herein refers to a C 2 -C 12 alkenyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0102] The term "alkynyl " as used herein refers to a linear, branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon triple bond. The term "C 2 -C 12 alkynyl " or "C 2 -C 12 alkynylene " as used herein refers to a linear, branched unsaturated hydrocarbon having from 2 to 12 carbon atoms in certain embodiments, from 3 to 8 carbons, and at least one triple bond (at least one carbon-carbon triple bond). It should be noted that alkynyl refers to an alkyl end chain and alkynylene refers to a middle chain alkyl.

[0103] The term "C 2 -C 12 haloalkynyl " as used herein refers to a C 2 -C 12 alkynyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0104] As used herein "alkoxy " refers to an alkyl group bonded to an oxygen atom. Similarly, the term "C 1 -C 12 alkoxyl " as used herein refers to a C 1 -C 12 alkyl group linked to an oxygen. At times, the alkyl group may include one to twelve carbon atoms, at times between one to eight carbon atoms, at times one to five carbon atoms and at times one to three carbon atoms. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, and hexoxy, isohexoxy. In certain embodiments, the alkoxy is ethoxy.

[0105] The term "halogen " (halo or halide) refers to F, Cl, Br or I.

[0106] As used herein, a ring system containing five to twelve atoms refers to a mono- or multi- cyclic ring system having 5 to 12 atoms. The ring system containing five to twelve atoms may be saturated, unsaturated or aromatic rings including for example cycloalkyl, heterocycloalkyl, aryl, arylene, aromatic, heteroaromatic rings. A ring system containing five to twelve atoms may contain two rings (bicyclic, etc.), for example aromatic rings and in such case the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). In some embodiments, a ring system containing five to twelve atoms is a carbocyclic ring or heterocyclic ring. The term "carbocyclic ring" refers to cyclic compounds containing only carbon atoms. The carbocyclic ring may be optionally substituted by one or more substituents, and may be saturated, unsaturated or aromatic. The term "heterocyclic ring" refers to cyclic compounds where one or more carbons are substituted by heteroatoms. Exemplary heteroatoms include nitrogen, sulfur, and oxygen. The heterocyclic ring may be optionally substituted, and may be saturated, unsaturated or aromatic. The term "saturated" as used herein means that the compound does not contain double or triple bonds. The term "unsaturated" as used herein means that the compound contains at least one double or triple bond. The term "aromatic" as used herein means that the compound contains alternating double and single bonds.

[0107] As used herein, "aryl " refers to aromatic ring systems having between 5 to 12 atoms. Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups having between 5 to 12 atoms. Non-limiting examples include phenyl, biphenyl or naphthyl. The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. As used herein, "C 5 -C 12 aromatic " refers to aromatic ring systems having 5 to 12 carbon atoms, such as phenyl, and naphthalene.

[0108] As used herein, the term "heteroaryl " refers to aryls as defined above where one or more carbons are substituted by heteroatoms. Exemplary heteroatoms include nitrogen, sulfur, and oxygen. As used herein, "heteroaromatic " refers to refers to a monocyclic or multi-cyclic (fused) aromatic ring system, where one or more of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including nitrogen, oxygen or sulfur. The term "heteroaromatic " used interchangeably with the term "heteroaryl " denotes a heterocyclic aromatic ring systems containing 5 to 12 atoms, with at least one, preferably two carbon atoms and one or more heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples include furan, thipohene, pyrrole, oxazole, oxadiazole, thiazole, imidazole, pyrazole, isoxazole, thiazolem benzofurna, indole, benzothiophene, benzoimidazole, indazole, benzoxazole, benzoisoxazole, benzothiazole, isobenzfuran, isoidole, purine, pyridine, pyrazine, pyrimidine, pyrisazine, quinoline, quinozaline, quinazoline, isoquinoline, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, [1,3,4]thiadiazole, thiadiazole, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, and acridinyl.

[0109] As used herein, "C 5 -C 12 saturated cycloalkyl " refers to a saturated mono- or multi-cyclic ring system having 5 to 12 carbon atoms, preferably having 5 to 7 carbon atoms.

[0110] Example of "C 5 -C 12 cycloalkyl" groups include cyclopentyl, cyclohexyl and cycloheptyl.

[0111] As used herein, "heterocycloalkyl " or "heterocyclyl " or the term "heterocyclic " refers to a monocyclic or multi-cyclic non-aromatic ring system having 5 to 12 members, preferably having 5 to 7 carbon atoms, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including nitrogen, oxygen or sulfur. Examples of "heteroalkyl " include pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene. The term heterocycloalkyl " also encompasses non-aromatic ring being unsaturated or having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO 2 , O, or N. "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" include tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

[0112] The term "bicyclic ring" or "bicyclic group" as used herein refers to system or group that features two joined rings and encompasses a carbocyclic (all of the ring atoms are carbons), or heterocyclic (the rings atoms consist of at least two different elements). The bicyclic group can be aromatic, aliphatic or a combination of aliphatic and aromatic. The bicyclic group for example can be any one of the following (i) the two rings share only one single atom, (ii) fused bicyclic compounds, two rings share two adjacent atoms, (iii) bridged bicyclic compounds the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. The bicyclic group can be optionally substituted as detailed herein.

[0113] Non-limiting example of bicyclic group include benzofuran, isobenzofuran,. isoindole, benzothiophene, benzo[c]thiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, naphthalene, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine.

[0114] The term "N-containing group " is used herein a chemical group containing a nitrogen atom for example as amino group. The term "amino " as used herein encompass primary, secondary, tertiary or quaternary amines where the point of attachment is through the nitrogen atom which is substituted. For example, the "N-containing group" include N, NH, NH 2 , tertiary amine (tertiary alkyl amine), quaternary ammonium (quaternary alkyl ammonium). The nitrogen atom may be substituted with alkyl. In case of a tertiary amine or quaternary amines, the substituent may be the same or may be different.

[0115] The term "bond " as used herein denotes a covalent bond. The bond may be between two similar atoms or between different atoms. Non-limiting examples include C-C, C-S, CO, C-N. S-O, S-N, and N-O. It should be noted that a bond as defined above, for example, C-S encompasses both C-S and S-C and this holds for the bonds as defined herein.

[0116] The term "optionally substituted " refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. The term substituted as used herein means that the compounds may contain one or more substituents, including optionally substituted OH, CF 3 , halogen, C(=O), -COOH, -NH 2 , CN, alkyl, alkenyl, alkynyl, alkylene, straight alkenylene, alkynylene, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, carboxyl, halogen, ring system including five to twelve atoms, aromatic or heteroaromatic ring, C(=O)- alkyl. The scope of the invention is defined by the claims. Any embodiment not falling under the scope of the claims is provided for information purposes only.

[0117] It should be noted that the carbon number, as used herein, refers to the carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions.

[0118] The invention provides new SMC that act as WASp modulators. A small molecule in the context of the present disclosure refers to a low molecular weight organic compound, having a molecular weight lower than 900 Daltons. In accordance with the present disclosure, when referring to a small molecule it includes also crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form" or "polymorph," as used herein include all crystalline and amorphous forms of a small molecule, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0119] In accordance with the present disclosure, the term "small molecule" may include pharmaceutically acceptable forms of the recited compounds, including chelates, noncovalent complexes, prodrugs, and mixtures thereof. Further and in accordance with the preset disclosure, the term "small molecule" includes also pharmaceutically acceptable forms of a particular molecule and as such the term small molecule also encompasses pharmaceutically acceptable salts.

[0120] As detailed above, in accordance with the first aspect, the present disclosure provides small molecule compounds that bind to the N'-terminus of WASp for use in modulating WASp degradation and / or stability in a cell. More specifically, in some embodiments, the SMC modulator of the invention specifically binds to WASp degradation pocket. In more specific embodiments, WASp degradation pocket is located at the N-terminal WASp-homology-1 (WH1) domain of WASp. More specifically, this pocked comprise at least one of lysine residues 76 and 81. Thus, in more specific embodiments, the SMCs of the invention are specifically directed to the N-terminal WH1 domain of WASp.

[0121] As used herein, WASp (Wiskott - Aldrich syndrome protein) is a 502-amino acid protein encoded by a gene located at the short arm of the X chromosome (Xp11.22-p11.23.1). WASp serves as an adaptor protein that facilitates actin cytoskeletal rearrangements that are essential for normal immune cell responses. More specifically, WASp is a member of a distinct family of proteins that participate in the transduction of signals from the cell surface to the actin cytoskeleton. This family is characterized by a C-terminal tripartite domain containing a common actin monomer-binding motif, WASp-homology domain 2 (WH2) or verprolin homology domain (V), and a central-acidic (CA) region which is capable of activating the actin related protein (Arp)2 / 3 complex, a potent nucleator of actin polymerization. The activities of WASp family members are normally tightly controlled within a cell, allowing for both spatial and temporal regulation of actin polymerization. WASp is regulated by several mechanisms including the adoption of an auto inhibited conformation in which the VCA domain forms a hydrophobic interaction with the GTPase binding domain (GBD, residues 230-288) and adjacent C-terminal residues. Binding of GTP-loaded Cdc42 and phosphatidylinositol 4, 5-bisphosphate (PIP2) appears to cooperatively disrupt this interaction, thereby freeing the C-terminus for binding to the Arp2 / 3 complex. Serine and tyrosine phosphorylation of WASp also acts to directly regulate its activity, although until recently this has been relatively unexplored, particularly in vivo. The N-terminus of WASp / N-WASp contains an Ena / VASP homology 1 (EVH1), which binds the widely expressed verprolin homologue, WIP (WASp interacting protein). The majority of WASp in cells is complexed with WIP, and the WIP / WASp interaction is important for WASp activation by Cdc42 through Toca-1. WIP is a molecular chaperone crucial for the stability of WASp, which otherwise is susceptible to proteolytic cleavage through calpain and possibly the 26S ubiquitin proteasome systems.

[0122] As used herein, WASp is a protein exclusively expressed in hematopoietic cells. In some embodiments, said WASp may be a human WASp. In more specific embodiments, said human WAS protein may comprise the amino acid sequence as denoted by Accession number P42768 (CCDS: CCDS14303.1). In more specific embodiments, the amino acid sequence of WASp is as denoted by SEQ ID NO. 1. In some specific embodiments said WASp is encoded by the cDNA of Accession number NM_000377. In more specific embodiments, said cDNA sequence of WASp is denoted by SEQ ID NO. 2.

[0123] As demonstrated in Figures 13, the SMC modulators of the invention, specifically, any of the modulators disclosed by the invention in connection with any aspects thereof, may enhance and stabilize the protective interaction between WASp and WIP. Therefore, in certain embodiments, the SMC modulators of the invention may act as enhancers and stabilizers of the WASp and WIP interaction. In yet some further alternative embodiments, the compounds of the invention may act as WIP mimetic compounds, thereby protecting WASp from proteolysis.

[0124] As shown in Figure 7, by binding to the degradation pocket in WASp, the SMC modulators of the invention modulate WASp ubiquitylation. Thus, in some embodiments, binding of the SMC modulators of the invention (specifically, any of the modulators disclosed by the invention in connection with any aspects thereof), to WASp may lead to modulation of WASp ubiquitylation in a cell. It should be noted that "modulation" as used herein encompasses either "inhibition of ubiquitylation, or alternatively, enhancement".

[0125] More specifically, the terms "inhibition", "moderation", "reduction" or "attenuation" as referred to herein, relate to the retardation, restraining or reduction of WASp ubiquitylation by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%. Alternatively, the terms "increase", "augmentation" and "enhancement" as used herein relate to the act of becoming progressively greater in size, amount, number, or intensity. Particularly, an increase of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 70%, 800%, 900%, 1000% or more of WASp ubiquitylation as compared to a suitable control. It should be appreciated that 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively. 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively. Therefore, the term increase refers to an increase of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 folds or more.

[0126] More specifically, the invention provides different SMCs that following binding to WASp, specifically mask its degradation sites at lysine residues 76 and 81, located in a pocket at the N'-terminal WASp-homology-1 (WH1) domain of WASp. Thus, in some embodiments, SMC binding to WASp induces modulation of ubiquitin proteasome-mediated degradation of WASp in a cell.

[0127] "Ubiquitylation-dependent proteosomal degradation" as used herein, is a classical protein degradation pathway within a cell that includes hydrolysis by the proteasome after conjugation of polyubiquitin chains. Before the degradation by the proteasome, a protein undergoes phosphorylation-dependent ubiquitylation. The ubiquitin-proteasome system plays important role in several biological processes such as antigen presentation, endocytosis and cell stress response and represents one of the most important degradation systems in the cell. Misfolded and unfolded proteins are targets for degradation by proteasome in order to maintain cell integrity and survival. Protein ubiquitylation usually requires three processes involving ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2s) and ubiquitin ligases (E3s).

[0128] As clearly demonstrated in EXAMPLE 3, the prevention of degradation of WASp by the SMC modulators of the invention refers to the ubiquitylation-dependent proteosomal degradation mechanism of WASp in hematopoietic cells, specifically, in platelets, megakaryocytes and lymphocytes.

[0129] Thus, in some particular embodiments for the SMC modulator for use in accordance with the invention, any of the described SMC modulator compounds, may attenuate WASp ubiquitylation thereby reducing ubiquitin proteasome-mediated degradation of WASp in a cell.

[0130] In more specific embodiments of the SMC modulator of the invention for use, the reduced degradation of WASp caused by the SMC modulator / s may restore, enhance or extend at least one of WASp levels and function in the cell.

[0131] It should be understood that where referring to levels of WASp, the invention further encompasses WASp expression and / or stability. "Expression", as used herein generally refers to the process by which gene-encoded information is converted into the structures present and operating in the cell. Therefore, according to the invention "expression" of a gene, specifically, may refer to transcription into a polynucleotide, translation into a protein, or even posttranslational modification of the protein. Protein stability, as used herein, refers to the physical (thermodynamic) stability, and chemical stability of the protein and relates to the net balance of forces, which determine whether a protein will be in its native folded conformation or a denatured state. More specifically, the levels of proteins within cells are determined not only by rates of synthesis as discussed above, but also by rates of degradation and the half-lives of proteins within cells that vary widely, from minutes to several days. In eukaryotic cells, two major pathways mediate protein degradation, the ubiquitin-proteasome pathway, mentioned herein before, and lysosomal proteolysis.

[0132] According to some embodiments, wherein indicate "increasing" or "enhancing" the expression or the levels of WASp, it is meant that such increase or enhancement may be an increase or elevation of between about 10% to 100% of the expression and / or stability of WASp. The terms "increase", "augmentation" and "enhancement" as used herein relate to the act of becoming progressively greater in size, amount, number, or intensity. Particularly, an increase of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 70%, 800%, 900%, 1000% or more of the expression as compared to a suitable control. It should be further noted that increase or elevation may be also an increase of about 2 to 10 6< folds or more. Still further, it should be appreciated that the increase of the levels or expression of said WASp may be either in translation or the stability of said WASp. With regards to the above, it is to be understood that, where provided, percentage values such as, for example, 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively. Therefore, the term increase refers to an increase of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 folds or more.

[0133] As noted above, WASp is a multifunction protein, acting as an adaptor protein that facilitates actin cytoskeletal rearrangements in response to signals arising at the cell membrane, which are essential for normal immune cell responses. In particular its function includes actin polymerization, sustaining of the immunological synapse, endocytosis, calcium flux, NFAT gene transcription, cellular activation and proliferation.

[0134] Moreover, WASp emerges as an important platform for regulating actin polymerization through activation of the Arp2 / 3 complex, which is a key for cytoskeletal reorganization. It is therefore not surprising that lack of WASp results in a wide range of defects of cellular function involving all hematopoietic cell lineages.

[0135] It is thus appreciated that the SMC modulators of the invention may restore WASp function, or phenotype in a cell. The term "phenotype of WASp" as used herein defines the extent of expression of mRNA of WASp, as well as an amount and function of the WAS protein, wherein "restoration of WASp phenotype" means a return of the expression, amount and function to normal levels.

[0136] Therefore, in some embodiments, the SMC modulators of the invention protect from WASp degradation and thereby restore the phenotype of WASp in a cell. Specifically the SMCs of the invention restore the expression, amount and function of WASp within a cell. Restore, as used herein in connection with the levels and function of WASp, refers to reinstate, bring back, reinstitute, re-impose, reinstall, reestablish, repair, renovate, recover, elevate, improve, reconstitute, revive, renew, rescue or refresh WAPs levels and / or function, specifically, in a cell displaying abnormal levels of WASp, by the SMCs of the invention in about 5% to 100% or more of the normal WASp levels or function as compared to cells displaying abnormal WASp levels that are not treated with the SMCs of the invention. More specifically, the SMCs of the invention restore about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 70%, 800%, 900%, 1000% or more of WASp levels or function of normal cells as compared to cells displaying abnormal WASp levels that were not treated by the SMCs of the invention.

[0137] In certain embodiments, the SMCs of the invention may restore WASp levels and function by attenuating its degradation in hematopoietic cells, for example, leukocytes, platelets and megakaryocytes. As detailed in EXAMPLES 2 and 3, the specific SMC modulators of the invention decreased WASp degradation and thereby restored WASp expression in platelets, peripheral blood mononuclear cells (Fig. 4, Fig. 5, Fig. 6) and T cell lymphocytes (Fig. 5). Retention of WASp levels results in restoration of WASp-mediated cellular function / s.

[0138] In some specific embodiment, the cell treated by the SMC modulator / s used in accordance with the invention, may be a hematopoietic cell, more specifically, a non-erythroid hematopoietic cell.

[0139] In more specific embodiments, the SMC modulators used by the invention reduce WASp degradation in a non-erythroid hematopoietic cell that may be in some embodiments, at least one of a lymphocyte, platelet, megakaryocyte, granulocyte and monocyte. Thus, in certain specific embodiments, the SMC modulators of the invention may modulate, and specifically, reduce, the WASp ubiquitylation in at least one of lymphocyte, platelet, megakaryocyte, granulocyte and monocyte.

[0140] "Hematopoietic cells" are cellular blood components all derived from hematopoietic stem cells in the bone marrow. It should be appreciated that in certain embodiments, hematopoietic cells as used herein include cells of the myeloid and the lymphoid lineages of blood cells. More specifically, myeloid cells include monocytes, (macrophages and dendritic cells (DCs)), granulocytes (neutrophils), basophils, eosinophils, erythrocytes, and megakaryocytes or platelets. The Lymphoid cells include T cells, B cells, and natural killer (NK) cells. Thus, in certain embodiments, the cells treated by the SMC modulators of the invention may be any hematopoietic cell described herein. Generally, blood cells are divided into three lineages: red blood cells (erythroid cells) which are the oxygen carrying, white blood cells (leukocytes, that are further subdivided into granulocytes, monocytes and lymphocytes) and platelets (thrombocytes).

[0141] In certain embodiments, the hematopoietic cells treated by the SMC modulators of the invention may be non-erythroid hematopoietic cells. The term "non-erythroid hematopoietic cell" refers to the cells derived from white blood cell precursors and from megakaryocytes and include at least one of granulocytes (neutrophils, basophils, eosinophils), monocytes, lymphocytes, macrophages, dendritic cells and platelets.

[0142] In some embodiments, the cell is lymphocyte. In some other embodiments, the cell is T lymphocyte. In some further embodiments, the cell is platelet. In some other embodiments, the cell is megakaryocyte.

[0143] Thus, as demonstrated in EXAMPLE 4 (Fig. 8- Fig. 11) addition of the SMC modulators of the invention to lymphocytes, platelets and megakaryocytes not only causes upregulation of WASp expression in these cells but also results in an increase in a specific function of each one of these cells as detailed herein below.

[0144] In some specific embodiments, the SMC modulator of the invention may attenuate WASp ubiquitylation in lymphocyte / s, specifically, T lymphocyte / s.

[0145] In yet some further specific embodiments, the SMC modulator / s of the invention may attenuate WASp ubiquitylation in platelet / s.

[0146] Still further, the SMC modulator / s of the invention may attenuate WASp ubiquitylation in megakaryocyte / s.

[0147] As indicated above and demonstrated in the Examples, attenuation of WASp ubiquitylation in a cell restores the levels (Figures 4-6) and function (Figures 8-11) of WASp in a cell. In more specific embodiments, function of WASp may result in at least one of cell activation, cell proliferation, cell migration, cell homing, cell spreading, cell aggregation, elevation in intracellular calcium concentration, cell adhesion, phagocytosis, and cytolytic activity.

[0148] In some specific embodiments, the invention relates to restoring or expending WASp levels and function in lymphocyte / s.

[0149] "Lymphocytes" are mononuclear nonphagocytic leukocytes found in the blood, lymph, and lymphoid tissues. They comprise the body's immunologically competent cells and their precursors. They are divided on the basis of ontogeny and function into two classes, B and T lymphocytes, responsible for humoral and cellular immunity, respectively. Most are small lymphocytes 7-10 µm in diameter with a round or slightly indented heterochromatic nucleus that almost fills the entire cell and a thin rim of basophilic cytoplasm that contains few granules. When "activated" by contact with antigen, small lymphocytes begin macromolecular synthesis, the cytoplasm enlarges until the cells are 10-30 µm in diameter, and the nucleus becomes less completely heterochromatic; they are then referred to as large lymphocytes or lymphoblasts. These cells then proliferate and differentiate into B and T memory cells and into the various effector cell types: B cells into plasma cells and T cells into helper, cytotoxic, and suppressor cells.

[0150] More specifically, lymphocytes as used herein include T cells, B cells and NK cells. A "T cell " or "T lymphocyte " as used herein is characterized by the presence of a T-cell receptor (TCR) on the cell surface. It should be noted that T-cells include helper T cells ("effector T cells" or "Th cells"), cytotoxic T cells ("Tc," "CTL" or "killer T cell"), memory T cells, and regulatory T cells as well as natural killer T cells, Mucosal associated invariants and Gamma delta T cells.

[0151] More specifically, Thymocytes are hematopoietic progenitor cells present in the thymus. Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers. The earliest thymocyte stage is the double negative (DN) stage (negative for both CD4 and CD8), which more recently has been better described as Lineage-negative, and which can be divided into four sub-stages. The next major stage is the double positive (DP) stage (positive for both CD4 and CD8). The final stage in maturation is the single positive (SP) stage (positive for either CD4 or CD8).

[0152] B cells or B lymphocytes, develop from hematopoietic stem cells (HSC) that originate from bone marrow. B cells function in the humoral immunity component of the adaptive immune system by secreting antibodies. B cells are characterized by the expression of B cell receptor (BCR) that allows specificity to antigen, against which it will initiate an antibody response. Additionally, B cells present antigen (classified as professional antigen-presenting cells (APCs)) and secrete cytokines. Their development into B cells occurs in several stages, each marked by various gene expression patterns and immunoglobulin H chain and L chain gene loci arrangements, the latter due to B cells undergoing V(D)J recombination as they develop.

[0153] Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL). The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to viral-infected cells, acting at around three days after infection, and respond to tumor formation. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the initial notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1.

[0154] In some specific embodiment, the SMC modulator / s of the invention may up-regulate lymphocyte activation. "Lymphocyte activation" as used herein refers to stimulation of lymphocytes by specific antigen or nonspecific mitogens that result in synthesis of RNA, protein, and DNA and the production of cytokines. This process is followed by proliferation and differentiation of various effector and memory cells. Activation is accompanied by morphologic changes known as lymphocyte transformation, in which small, resting lymphocytes are transformed into large, active lymphocytes (lymphoblasts). As shown by the invention, lymphocyte activation may be evaluated by expression of activation markers. Thus, in some specific embodiments, the SMC modulator / s of the invention may lead to lymphocyte / s activation as demonstrated by expression of lymphocyte activation markers, specifically, CD69 and integrins LFA-1), proliferation and migration.

[0155] "Lymphocyte proliferation" relates to the ability of lymphocytes to respond to mitogens, specific antigens, or allogenic cells. More specifically, cell proliferation is the process that results in an increase of the number of cells, and is defined by the balance between cell divisions and cell loss through cell death or differentiation.

[0156] As shown in Figure 10, the SMCs of the invention enhance T lymphocyte migration. Thus, in yet some further embodiments, the SMC modulators of the invention induce lymphocyte migration. "Lymphocyte Migration" refers to continually re-circulating lymphocytes between the blood and the tissues via the lymph. In order to maintain immune surveillance, the majority of lymphocyte traffic occurs through lymph nodes in vivo. Although a great deal of work has been done to elucidate the molecular mechanisms whereby lymphocytes leave the blood and enter the lymph node, lymphocyte traffic also requires that the lymphocyte successfully transit extravascular tissue and enter the lymph following transendothelial migration.

[0157] As part of lymphocyte activation and restoring the functions of WASp, the SMC modulators of the invention may also enhance, participate or induce formation of immunological synapse (IS) by a T lymphocyte. Thus, the present invention may be further articulated from the point view of a lymphocyte forming an immunological synapse (IS) as the target for the presently conceived modulators. The IS model in relating to features such as T cell membrane structure, T cell polarity, signaling pathways, and antigen-presenting cells (APC), provides a comprehensive view on T cells maturation and activation. Originally the term 'IS' denoted a crucial junction between a T cell and APC at which T cell receptors (TCRs) interact with MHC molecules. Today however this term has been expended to include different types of immune cells, as well as non-immune cells. Thus, the term 'IS' herein denotes a specific arrangement of molecules in an immune cell at the interface with another cell. Molecules related to IS formation may include receptors, signaling molecules, cytoskeletal elements and cellular organelles. When referring to arrangement of said molecules is meant, for example, accumulation of molecules in distinct regions within an activating IS to form a supramolecular activation cluster (SMAC), which may be further segregated into peripheral (pSMAC) and central (cSMAC) zones. This term further encompasses other features, such as engagement of individual receptors, or involvement of microclusters of cell-surface, and signaling molecules that support cell activation and maturation of IS.

[0158] As indicated herein before, WASp-dependent immune cell functions include actin polymerization, sustaining of the immunological synapse, endocytosis, calcium flux, NFAT gene transcription, cellular activation and proliferation. Thus, in certain embodiments, by restoring WASp levels and function, the SMC modulators of the invention may modulate actin polymerization. The term 'actin' has been articulated herein in various contexts. In the above described aspects and embodiments it was used to convey actin functionality and structural meaning. In most general terms, 'actin' is a ubiquitous globular protein that is one of the most highly-conserved proteins known. Structurally, the term 'actin' refers to the two main states of actin: the G-actin - the globular monomeric form and the F-actin forming helical polymers. Both G- and F-actin are intrinsically flexible structures - a feature vital in actin's role as a dynamic filament network. In terms of functionality, the F-actin polymers form microfilaments - polar intracellular 'tracks' for kinesin motor proteins, allowing the transport of vesicles, organelles and other cargo. Further, actin is a component of the cytoskeleton and links to alpha-actinin, E-cadherin and beta-catenin at adherent junctions. This gives mechanical support to cells and attaches them to each other and the extracellular matrix. Using energy from the hydrolysis of ATP, myofibrils undergo cyclic shortening through actin-myosin head interactions, which represents the mechanics of muscle contraction. Finally, actin has a role in cell motility through polymerization and depolymerization of fibrils.

[0159] In further embodiments, the SMC modulators of the invention may upregulate platelet and / or megakaryocyte activation. In yet some other embodiments, the SMC modulators of the invention may activate platelet / s and / or megakaryocyte / s as manifested by at least one of cell spreading, cell aggregation, elevation in intracellular calcium concentration, cell adhesion, phagocytosis, and cytolytic activity.

[0160] A megakaryocyte is a large bone marrow cell with a lobulated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes are derived from hematopoietic stem cell precursor cells in the bone marrow.

[0161] The "platelet / s" as used herein, are one of the key elements of human blood, playing a central role in the process of thrombus formation. The main function of platelets is the formation of mechanical plugs during the normal hemostatic response to the vessel wall injury. Platelets are derived from the megakaryocytes in the bone marrow. These megakaryocytes arise by a process of differentiation from the haemopoietic stem cell and undergo fragmentation of their cytoplasm to produce platelets. Platelet production is under the control of humoral agents such as thrombopoietin. The platelet is an enucleate cell that beside nucleus includes intracellular organelles in the cytoplasm. Resting platelets are discoid and have a smooth, rippled surface. The platelet surface has various receptors to which various stimulants (agonists) bind and thereby activate platelets producing changes within the platelet as well as a change in platelet shape from discoid to spherical, adhesion and aggregation of platelets. One of the methods to evaluate "platelet activation" in response to agonists is by measuring intracellular calcium concentration. Another method is to quantify platelet release products in the plasma. More specifically, resting platelets maintain active calcium efflux via a cyclic AMP activated calcium pump. Intracellular calcium concentration determines platelet activation status, as it is the second messenger that drives platelet conformational change and degranulation. Platelet activation begins seconds after adhesion occurs. Thrombin is a potent platelet activator. Thrombin also promotes secondary fibrin-reinforcement of the platelet plug. Platelet activation in turn degranulates and releases factor V and fibrinogen, potentiating the coagulation cascade. Following their activation and F-actin polymerization, platelets must spread over intact blood vessels in the process of clot formation. Adhesion of platelets to fibrinogen is a key process in platelet aggregation, mediated by integrins, such as αIIbβ3. WASp is important for αIIbβ3-mediated-cell adhesion of platelets and megakaryocytes. Platelets contain dense granules, lambda granules and alpha granules. Activated platelets secrete the contents of these granules through their canalicular systems to the exterior.

[0162] In yet some further embodiments, the SMCs of the invention may decrease degradation of WASp in any non-erythroid hematopoietic cell, for example, any one of Granulocytes, neutrophils, Eosinophils, Basophils, Monocytes, Macrophages, and Dendritic cells (DCs).

[0163] More specifically, Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shapes of the nucleus, which is usually lobed into three segments. This distinguishes them from the mononuclear granulocytes.

[0164] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells. Once neutrophils have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection. Neutrophils do not return to the blood; they turn into pus cells and die. Mature neutrophils are smaller than monocytes, and have a segmented nucleus with several sections (two to five segments); each section is connected by chromatin filaments. Neutrophils do not normally exit the bone marrow until maturity, but during infection neutrophil precursors called myelocytes and promyelocytes are released.

[0165] Neutrophils display three strategies for directly attacking micro-organisms: phagocytosis (ingestion), release of soluble anti-microbials (including granule proteins), and generation of neutrophil extracellular traps (NETs). The intracellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties.

[0166] Eosinophils play a crucial part in the killing of parasites (e.g., enteric nematodes) because their granules contain a unique, toxic basic protein and cationic protein (e.g., cathepsin). These cells also have a limited ability to participate in phagocytosis, but are professional antigen-presenting cells. They are able to regulate other immune cell functions (e.g., CD4+ T cell, dendritic cell, B cell, mast cell, neutrophil, and basophil functions) and are involved in the destruction of tumor cells. In addition, they promote the repair of damaged tissue.

[0167] Basophils are one of the least abundant cells in bone marrow and blood. The cytoplasm of basophils contains a varied amount of granules; these granules are usually numerous enough to partially conceal the nucleus. Granule contents of basophils are abundant with histamine, heparin, chondroitin sulfate, peroxidase, platelet-activating factor, and other substances. When an infection occurs, mature basophils will be released from the bone marrow and travel to the site of infection. When basophils are injured, they will release histamine, which contributes to the inflammatory response that helps fight invading organisms. Mast cells also contain many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and blood-brain barrier function. The mast cell is very similar in both appearance and function to the basophil.

[0168] Monocytes are a type of white blood cell, or leukocyte. They are the largest type of leukocyte and can differentiate into macrophages and myeloid lineage dendritic cells.

[0169] Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific to healthy body cells on its surface in a process called phagocytosis. These large phagocytes are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. They take various forms (with various names) throughout the body (e.g., histiocytes, Kupffer cells, alveolar macrophages, microglia, and others), but all are part of the mononuclear phagocyte system. Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as lymphocytes. For example, they are important as antigen presenting cells to T cells.

[0170] Dendritic cells (DCs) as used herein are antigen-presenting cells (also known as accessory cells) of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems. Dendritic cells are present in the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. Once activated, DCs migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response.

[0171] As noted above and exemplified by the following examples, WASp is a key regulator of immune cell function. By promoting cytoskeletal polymerization and reshaping, WASp is critical for immune cell stimulation, allowing a rapid and effective immune response. WASp is exclusively expressed in hematopoietic cells, and as such, may serve as a specific target for boosting the immune response. Activities supported by WASp include immune cell activation, proliferation, chemotaxis, migration and cell-cell interactions. Most importantly, WASp is a master regulator of leukocyte effector functions including, phagocytosis, cytolytic activity and cytokine transcription and secretion. Cells that are regulated by WASp include the lymphoid cells (T, B and Natural Killer cells), monocytes / macrophages, dendritic cells (DCs) and neutrophils as discussed above. WASp is also present in platelets and in their precursors, the megakaryocytes. WASp expression was found to be crucial for both platelet production by megakaryocytes, as well as for their activation and effector function. WASp levels are regulated by two degradative pathways: proteolysis by the calpain cysteine protease, and ubiquitin-mediated proteolysis. The SMCs of the invention were shown as effective agents for blocking WASp degradation and increasing its levels and function. Thus, in addition to the use of this strategy as therapeutic approach for treating the primary, innate immuno-deficiencies such as WAS / XLT, the SMCs of the invention also offers a powerful approach for boosting the immune response in acquired immune deficiencies or other immune disorders. Increasing WASp expression and function could be useful for increasing white blood cell (WBC) number and activity in immunopathologies such as leukopenia, neutropenia and thrombocytopenia. Remedying these hematological disorders may be helpful following or during conventional cancer treatments such as chemotherapy and radiotherapy, diseases caused by viral, bacterial and parasitic pathogens, thrombocytopenia caused by blood loss or autoimmunity e.g. immune thrombocytopenic purpura (ITP). Furthermore, such a strategy could serve as supportive therapy for rapid reconstitution following bone marrow (BM) transplantation, ex vivo and / or in vivo expansion of hematopoietic cells for use in autologous or allogenic hematopoietic stem cell transplantation (HSCT), gene therapy or adoptive cell transfer, and upregulating the immune response against cancers of non-hematopoietic origin.

[0172] Thus, in some embodiments, the SMC modulator of the invention may be used to restore, enhance and / or increase WASp levels and activity in a cell of a subject suffering from an innate or acquired immune-related disorder or condition. Thus, the aforementioned SMCs are suitable for the treatment, prevention an amelioration of immune-related disorder. An "Immune-related disorder" or "Immune-mediated disorder", as used herein encompasses any condition that is associated with the immune system of a subject, more specifically through inhibition of the immune system, or that can be treated, prevented or ameliorated by reducing degradation of a certain component of the immune response in a subject, such as the adaptive or innate immune response. An immune-related disorder may include infectious condition (e.g., viral infections), metabolic disorders and a proliferative disorder, specifically, cancer.

[0173] In some specific embodiments wherein the immune-related disorder or condition may be a primary or a secondary immunodeficiency.

[0174] Thus, due to the wide range of activities of WASp, WASp-stabilizing SMCs are a promising therapeutic modality for a variety of innate and acquired immunodeficiencies caused by immunosuppressive treatments (chemo- and radiotherapy), pathogenic infections, cancer and HSCT.

[0175] More specifically, Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. Most cases of immunodeficiency are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include viral infection, specifically, HIV, extremes of age, and environmental factors, such as nutrition. In the clinical setting, the immunosuppression by some drugs, such as steroids, can be either an adverse effect or the intended purpose of the treatment. Examples of such use are in organ transplant surgery as an anti-rejection measure and in patients suffering from an overactive immune system, as in autoimmune diseases. Immunodeficiency also decreases cancer immunosurveillance, in which the immune system scans the cells and kills neoplastic ones.

[0176] Still further, Primary immunodeficiencies (PID), also termed innate immunodeficiencies, are disorders in which part of the organism immune system is missing or does not function normally. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immune-deficiencies are genetic disorders; the majority is diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs.

[0177] There are several types of immunodeficiency that include, Humoral immune deficiency (including B cell deficiency or dysfunction), which generally includes symptoms of hypogammaglobulinemia (decrease of one or more types of antibodies) with presentations including repeated mild respiratory infections, and / or agammaglobulinemia (lack of all or most antibody production) and results in frequent severe infections (mostly fatal); T cell deficiency, often causes secondary disorders such as acquired immune deficiency syndrome (AIDS); Granulocyte deficiency, including decreased numbers of granulocytes (called as granulocytopenia or, if absent, agranulocytosis) such as of neutrophil granulocytes (termed neutropenia); granulocyte deficiencies also include decreased function of individual granulocytes, such as in chronic granulomatous disease; Asplenia, where there is no function of the spleen; and Complement deficiency in which the function of the complement system is deficient.

[0178] WASp was first discovered as the protein mutated in patients of Wiskott-Aldrich syndrome (WAS). WAS-mutations were found to cause the rapid degradation of WASp, strongly reducing WASp expression in patient cells. WAS is characterized by severe clinical characteristics including immunodeficiency, recurrent infections, eczema, and susceptibility to autoimmune diseases and cancer, highlighting the importance of WASp for immune cell function. Additionally, WAS, as well the milder WAS variant, X-linked thrombocytopenia (XLT), are characterized by severe bleeding caused by reduced platelet number and size, and by disrupted blood clotting, demonstrating the importance of WASp for platelet generation and function. WASp degradation in WAS and XLT was found to be linked to the mechanism by which WASp levels and activity are regulated. Normally, when activated, WASp undergoes partial detachment from its chaperone, WASp Interacting Protein (WIP), allowing it to be ubiquitylated on lysine residues 76 and 81 by the Cbl E3 ubiquitin ligases, leading to its proteasomal degradation. In the primary immunodeficiencies, WAS / XLT, mutations on WASp disrupt its interaction with WIP, causing WASp to be readily ubiquitylated and degraded, regardless of its activation state.

[0179] In some embodiments, the SMC modulator of the invention may be used to restore, enhance or increase WASp levels and activity in a cell of a subject suffering from a primary immunodeficiency. It should be appreciated that in certain embodiments, the SMCs of the invention may be applicable for any of the PIDs disclosed herein. In yet some more specific embodiments, such immunodeficiency may be a hereditary or acquired disorder associated with WASp dysfunction.

[0180] In more specific embodiments, hereditary disorder associated with WASp dysfunction may be at least one of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT), or any condition or disorder associated therewith.

[0181] Increasing WASp levels can be of significant benefit not only for primary immunodeficiency diseases (PIDD) caused by inherited or genetic defects but also for secondary immunodeficiencies that occur when the immune system is compromised due to environmental factors. Such factors include radiotherapy as well as chemotherapy. While often used as fundamental anti-cancer treatments, these modalities are known to suppress immune function, leaving patients with an increased risk of infection; indeed, infections were found to be a leading cause of patient death during cancer treatment. Neutropenia was specifically associated with vulnerability to life-threatening infections following chemotherapy and radiotherapy. WASp plays key roles in upregulating the proliferation and function of lymphocytes, and in enhancing the function of myeloid cells. Increasing myeloid cell activity as well as lymphoid cell proliferation and activation by using a WASp-stabilizing SMC treatment offers a promising approach for ameliorating radiotherapy and chemotherapy-induced immune suppression and to protect recovering cancer patients from opportunistic pathogens. Such a strategy is also expected to be generally useful in the treatment of infections; increasing WASp expression and activity is likely to enhance key immune cell functions required for robust immune responses. These include chemotaxis and immune cell infiltration to inflammatory sites (by all WBCs), phagocytosis (by neutrophils, monocytes / macrophages, and dendritic cells (DCs)), and cell-mediated cytotoxicity (by cytotoxic T lymphocytes (CTLs), or natural killer (NK) cells). Thus, this novel approach for stabilizing WASp using SMCs is expected to improve clinical outcomes of secondary immune deficiencies by (1) increasing the proliferation and survival of all lymphoid cell populations (T, B and NK cells), and by (2) boosting the activation and function of both lymphoid and myeloid cells (monocytes, macrophages, dendritic cells).

[0182] Thus, in some embodiments, the SMC modulator / s of the invention may be used to restore, enhance or increase WASp levels and activity in a cell of a subject suffering from a secondary immunodeficiency. In more specific embodiments, such secondary immunodeficiency may be caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

[0183] More specifically, WASp was shown to promote lymphocyte growth and survival in both mice and humans. Proliferation of T or B lymphocytes in response to stimulation by anti-T cell antigen receptor (TCR) or anti-IgM, respectively, are impaired in WASp-deficient lymphocytes. Furthermore, similar proliferation defects were detected following interaction of WAS KO DCs with normal CD4+ and CD8+ T lymphocytes. Restoration of WASp expression has been shown to significantly mitigate these defects. Still further, reduced leukocyte number is a common side effect of chemotherapy and radiotherapy, which exposes cancer patients to life threatening infections. The approach of the present invention of increasing WASp levels and function using the SMCs of the invention has the potential to expedite hematopoietic rejuvenation following chemo- and radiotherapies by enhancing lymphocyte growth and survival.

[0184] Thus, in some embodiments, the SMC modulator of the invention may be used to restore, enhance or increase WASp levels and activity in a cell of a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0185] Still further, WASp is a key regulator of actin cytoskeleton polymerization and reshaping in all white blood cells, as well as in platelets. As such, WASp is involved in multiple immune cell functions such as cellular activation, migration, cell to cell interaction, proliferation, and phagocytosis, all of which are actin dependent processes. Indeed, the restructuring of the actin cytoskeleton was found to be a fundamental process controlling immune cell function. The formation of actin filaments (F-actin) from actin monomers (G-actin) and the complementary process of actin filament breakdown enable the actin cytoskeleton to dynamically adapt to facilitate a variety of cellular activities.

[0186] Actin filament formation is a highly regulated process; the spontaneous generation of filaments is prevented by the intrinsic instability of actin dimers, necessitating the simultaneous association of three or more actin subunits to establish a stable anchor from which polymerization can proceed. These initial polymers are called actin nuclei, and their formation is mediated by actin nucleation proteins. Arp2 / 3 is an actin nucleation complex that promotes actin filament branching from an existing filament, allowing the formation of complex actin structures. Arp2 / 3 activity depends on binding to proteins of the nucleation-promoting factor (NPF) family and WASp is a central NPF.

[0187] In some embodiments, the SMCs used by the invention may enhance leukocyte migration and homing in subjects suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0188] In yet some further embodiments, the SMCs of the invention may induce and enhance migration and adhesion of neutrophils in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0189] In yet some further embodiments, the SMCs of the invention may enhance or increase recruitment of phagocytes in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0190] In some further embodiments, the SMCs of the invention may induce polarization and migration of monocytes, specifically, dendritic cells (DC) in response to inflammatory chemokines in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0191] WASp deficiency, either in humans or mice, results in multiple dysfunctions in most immune cell lineages, giving rise to combined cellular and humoral immune deficiencies. These dysfunctions include significantly impaired formation of membrane structures such as lamelliopodia, fillopodia and podosomes in all myeloid and lymphoid immune cells. Impaired assembly of these structures results in diminished growth and / or survival of hematopoietic cells, defective phagocytosis due to the reduced formation of the actin-rich phagocytic cup, impaired polarization and migration, impaired homing to sites of inflammation and compromised initiation of the adaptive immune response in secondary lymphoid tissues. For example, abnormal homing of DCs prevent appropriate priming and activation of key effector cells such as NK cells, T cells and B cells, thereby diminishing the overall efficiency of the immune response.

[0192] Still further, it should be noted that podosomes play a crucial role in cellular motility and invasion. These structures are localized in close proximity with the leading edge of migrating cells, and their formation and function are dependent on WASp activity.

[0193] Thus, in some embodiments, the SMCs of the invention may enhance or increase podosome formation and function in macrophages and DCs in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0194] More specifically, Podosomes are conical, actin-rich structures found on the outer surface of the plasma membrane of animal cells. While usually situated on the periphery of the cellular membrane, these unique structures display a polarized pattern of distribution in migrating cells, situating at the front border between the lamellipodium and lamellum. Their primary purpose is connected to cellular motility and invasion; therefore, they serve as both sites of attachment and degradation along the extracellular matrix. Many different specialized cells exhibit these dynamic structures such as certain immune cells like macrophages and dendritic cells, endothelial cells, osteoclasts, vascular smooth muscle cells and also invasive cancer cells.

[0195] In some embodiments, the SMCs of the invention may reduce degradation of WASp, thereby enhancing formation of membrane structures such as lamelliopodia and fillopodia in all myeloid and lymphoid immune cells. The lamellipodium as used herein is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate. Within the lamellipodia are ribs of actin called microspikes, which, when they spread beyond the lamellipodium frontier, are called filopodia.

[0196] In yet some further embodiments, the SMCs of the invention may enhance, increase or induce secretion of cytokines upon TCR activation in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0197] In certain embodiments, the SMCs of the invention may rescue NK cell function, specifically, the ability of NK cells to lyse susceptible target cells, in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0198] In yet some further embodiments, the SMCs used by the invention may restore and enhance phagocytosis and the formation of phagocytic cup. Still further, Phagocytosis is the process by which a cell engulfs a solid particle to form an internal compartment known as a phagosome. In an organism's immune system, phagocytosis is a major mechanism used to remove pathogens and cell debris. For example, when a macrophage ingests a pathogenic microorganism, the pathogen becomes trapped in a phagosome which then fuses with a lysosome to form a phagolysosome. Within the phagolysosome, enzymes and toxic peroxides digest the pathogen.

[0199] In yet some further embodiments, the SMCs of the invention may enhance, increase or rescue macrophages or DC functions following chemotherapy or radiotherapy (phagocytic activity of bone marrow macrophages or DCs) in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0200] Still further, in some embodiments, the SMCs of the invention may reverse the chemotherapy or radiotherapy damage to the B-cell follicle, as well as the marginal zone (MZ) architecture in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0201] In some further embodiments, the SMCs of the invention may lead to reduced secretion of inflammatory cytokines, specifically, IFNγ and IL-2 by the T cells upon restoration of Treg suppressive function in a subject suffering from a secondary immunodeficiency caused by at least one of chemotherapy, radiotherapy, biological therapy or any combinations thereof.

[0202] Still further, it should be noted that additional secondary immuno-deficiencies may result following bone marrow (BM) transplantation, gene therapy or adoptive cell transfer. The success of hematopoietic stem cell transplantation (HSCT) is dependent on the timely establishment of the graft and the reconstitution of the immune system, which is preceded by a period characterized by high risk for complications and infections, prior to engraftment. By enhancing immune cell proliferation, migration and function, the use of a WASp stabilizing SMCs of the invention to enhance the host immune system may provide crucial protection for recovering hematopoietic stem cell transplantation patients during this critical time frame.

[0203] Thus, in some further embodiments, the SMCs of the invention may induce and enhance migration and adhesion of neutrophils in a subject suffering from a secondary immunodeficiency caused by bone marrow (BM) transplantation, gene therapy or adoptive cell transfer.

[0204] In some specific embodiments, SMCs of the invention may induce and enhance hematopoietic system reconstitution in a subject suffering from a secondary immunodeficiency caused by bone marrow (BM) transplantation, gene therapy or adoptive cell transfer.

[0205] Still further, in some embodiments, the SMCs of the invention may induce and enhance treatment of neutropenia in a subject suffering from a secondary immunodeficiency caused by bone marrow (BM) transplantation, gene therapy or adoptive cell transfer.

[0206] In yet some further embodiments, the SMCs of the invention may induce and enhance expansion of hematopoietic cells in culture, e.g., for bone marrow transplant and use in ex vivo expansion of hematopoietic cells. In yet some further embodiments, the SMCs of the invention may be useful in increasing the number of hematopoietic stem cells in a donor subject in case of allogeneic HSCT.

[0207] Moreover, infectious diseases constitute a major risk to human health. It is estimated that the yearly death toll of infectious diseases is 15 million. Moreover, pathogenic infections disrupt regular life routines, resulting in decreased productivity; influenza alone is estimated to cause, on average, the loss of 3.7 to 5.9 workdays per employee, annually. In the US alone, influenza is estimated to result in 140,000 to 710,000 hospitalizations per year. Limiting the number of required hospitalizations and / or reducing hospitalization times can decrease healthcare costs. Reducing the burden of infectious diseases can thus be expected to have a significant economic potential.

[0208] Thus, in some embodiments, the SMC modulators of the invention may be used to restore, enhance and / or increase WASp levels and activity in a cell of a subject suffering from immune-related disorder or condition, specifically, a pathologic condition caused by at least one pathogen.

[0209] By restoring WASp levels and activity, the SMCs of the invention improve the ability of the immune system to deal with pathogenic challenges (viral, (e.g. CMV, EBV, influenza), or bacterial antigens [e.g. Mycobacterium tuberculosis, MTB; Streptococcus pneumoniae, pneumococcus or S. pneumoniae).]

[0210] In some further specific embodiments, the SMCs of the invention may improve ability to phagocytose pathogens (for pathogen clearance, and also presenting foreign antigens to the adaptive arm of the immune system) of a subject suffering from a pathologic condition caused by at least one pathogen.

[0211] In certain specific embodiments, the SMCs of the invention may induce formation of actin-based membrane invaginations, called phagocytic cups in a subject suffering from a pathologic condition caused by at least one pathogen.

[0212] In further embodiments, the SMCs of the invention may increase or enhance the ability of macrophages and DCs to phagocytose apoptotic cells in a subject suffering from a pathologic condition caused by at least one pathogen.

[0213] Still further, in some embodiments, the SMCs of the invention may enhance B cell activation against a pathogenic antigen (increasing IgM levels) infectious diseases and related conditions, specifically, sepsis in a subject suffering from a pathologic condition caused by at least one pathogen. It should be appreciated that pathogens described in more detail hereinafter in connection with other aspects of the invention, are applicable in connection with the present aspect as well.

[0214] WASp was found to also affect platelets, as demonstrated by severe bleeding in WAS / XLT patients caused by reduced platelet number, size and function. Consistent with these findings, WASp-stabilizing SMCs efficiently increased WASp expression levels and enhanced human platelet activation responsible for their adhesion and coagulation (Figure 4A-4B, Figure 5C-5D and Figure 11). Thus, a WASp-stabilizing SMC-based treatment may provide a potent therapeutic approach for thrombocytopenia. Specifically, in idiopathic thrombocytopenic purpura (ITP), SMC treatment may be used to enhance platelet function as well as the production of new platelets by megakaryocytes in order to offset antibody-mediated platelet destruction, improving clinical outcomes.

[0215] Thus, in some embodiments, the SMC modulators of the invention may be used to restore, enhance and / or increase WASp levels and activity in a cell of a subject suffering from immune-related disorder or condition, specifically, thrombocytopenia.

[0216] In some further embodiments, the SMC modulators of the invention may be used to restore, enhance and / or increase WASp levels and activity in a cell of a subject suffering from thrombocytopenia cause by bleeding, chemo- or radiotherapy, or autoimmunity (ITP).

[0217] In some specific embodiments, the SMC modulators of the invention may be used to restore, enhance and / or increase WASp levels and activity in a cell of a subject suffering from ITP.

[0218] Still further, in some embodiments, the SMCs of the invention may lead to increase in platelet number (production from megakaryocytes), aggregation and activation in a subject suffering from thrombocytopenia, specifically, ITP.

[0219] In yet some further embodiments, the SMCs of the invention may enhance F-actin content in a subject suffering from thrombocytopenia, specifically, ITP.

[0220] In certain embodiments, the SMCs of the invention may lead to increased αIIbβ3 integrin activation in a subject suffering from thrombocytopenia, specifically, ITP.

[0221] Still further, in some embodiments, the SMCs of the invention may enhance platelets adhesion and spreading capacity in a subject suffering from thrombocytopenia, specifically, ITP.

[0222] In certain embodiments, the SMCs of the invention may reduce platelet clearance by macrophages and the premature release of platelets from their precursors into the BM in a subject suffering from thrombocytopenia, specifically, ITP.

[0223] Still further, SMC-based treatment in accordance with the invention may also be used to enhance anti-tumor immunity. CTLs, as well as NK cells serve as the primary mediators of immune response against cancer cells. WASp was shown to be essential for NK-cancer cell conjugate formation and cytotoxic capacity. NK cells from WAS patients exhibit defective cytotoxicity. Thus, WASp enhancing SMCs may increase the potency of this response by improving the ability of the cells to migrate into the tumor, as well as improving activation and cytotoxic granule release. Furthermore, the tumor microenvironment induces suppression and reduced activity of NK and T cells, through the secretion of inhibitory factors suppressing the anti-tumor response, a phenomenon known as exhaustion. Increasing WASp, a mediator of activating immune signaling may counteract this increased inhibitory signaling and allow a robust T cell and NK cell mediated cytotoxic response.

[0224] Thus, in some further embodiments, the SMC modulators of the invention may be used to restore, enhance or increase WASp levels and activity in a cell of a subject suffering from an immune-related disorder or condition that may be a cancer of a non-hematopoietic origin.

[0225] In yet some further embodiments, the SMCs of the invention may be used as a supportive treatment for boosting the immune-system, specifically, cytotoxic lymphocytes activity in a subject suffering from a cancer of a non-hematopoietic origin.

[0226] In certain embodiments, the SMCs of the invention may enhance activation and function of cytotoxic lymphocytes, thereby enhancing tumor surveillance in a subject suffering from a cancer of a non-hematopoietic origin.

[0227] In some further embodiments, the SMC modulator used by the invention may restore or enhance WASp function and / or levels in a cell of a subject suffering from immune-related disorder or condition, for example, cancer of a non-hematopoietic origin. It should be understood that in some embodiments, the SMCs of the invention may be used as a supportive treatment for boosting the immune-system, specifically, cytotoxic lymphocytes activity against the cancer.

[0228] The SMC modulators of the invention may be used in some embodiments, in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a an innate or acquired immune-related disorder or condition in a subject in need thereof.

[0229] In some embodiments, the immune-related disorder or condition may be a primary or a secondary immunodeficiency.

[0230] In yet some further embodiments, the subjects may suffer of a primary immunodeficiency that may be a hereditary or acquired disorder associated with WASp dysfunction. In further embodiments, the subjects may suffer of a hereditary disorder associated with WASp dysfunction is at least one of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT), or any condition or disorder associated therewith.

[0231] In yet some further embodiments, the subjects may suffer of a secondary immunodeficiency that may be caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

[0232] Still further, in some embodiments, the subjects may suffer of a pathologic condition caused by at least one pathogen.

[0233] In further embodiments, the subjects may suffer from thrombocytopenia. In more particular embodiments, the thrombocytopenia may be cause by bleeding or as a result of chemo- or radiotherapy. Alternatively, such thrombocytopenia may be an autoimmune disease, specifically, ITP.

[0234] In yet some additional embodiments, the SMC modulators of the invention may be used in treating subjects that may suffer of a cancer of a non-hematopoietic origin. In more specific embodiments, the SMCs of the invention may be thus used as a supportive treatment for boosting the immune-system, specifically, cytotoxic lymphocytes activity. In yet a further aspect, the invention relates to a method for modulating degradation and / or stability of WASp in a cell. More specifically, the method may comprise in some embodiments the step of contacting the cell with an effective amount of at least one SMC modulator of WASp degradation, or any vehicle, matrix, nano- or micro-particle or any composition comprising the same. More specifically, the method comprises the step of contacting the cell with an effective amount of at least one of any of the SMC modulators of WASp as described herein.

[0235] In some aspects, the method of the disclosure may comprise the step of contacting the cell with an effective amount of at least one SMC modulator of WASp having the general formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, any combination thereof, or any vehicle, matrix, nano- or micro-particle, or composition comprising the same, wherein R 1 and R 2 are each independently from each other selected from H, straight or branched C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, straight or branched C 1 -C 12 alkoxy, a ring system containing five to twelve atoms, each optionally substituted by at least one of halide, hydroxyl, ester, ether, amide, amine, nitro, -C(=O)-O-(CH 2 ) n -CH 3 , Rs, or -NH-C(=O)-R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include N, O, S,NH, C=N, C=O, S=O, or SO 2 and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide and cyano; L1 and L2 are each independently from each other to be absent or to be selected from - (CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 )n, -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be are each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl.

[0236] The invention further provides in some aspects thereof, a method for modulating degradation of WASp in a cell in a subject in need thereof. More specifically, the method may comprise in some embodiments the step of contacting the cell with an effective amount of at least one SMC modulator of WASp degradation, or any vehicle, matrix, nano- or micro-particle or any composition comprising the same. In more specific embodiments, the SMC / s used by the methods of the invention may have the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected from - CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0237] In some specific embodiments, the SMC modulator used by the methods of the invention may be at least one pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII. In more specific example, such compounds may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); or 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7).

[0238] In yet some further particular embodiments, specific and non-limiting examples of the SMC modulators that may be used by the methods of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, that may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (34.8 SMC); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10) 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

[0239] In yet some further particular embodiments, an additional example of a SMC modulator that may be used may be the compound [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0240] In yet some further alternative and particular embodiments, the SMC modulator used by the method of the invention may be any compound defined by Formula XI, Formula XII, with the proviso that the compound is not any of the compounds detailed below: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1). 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3) N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8) 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10). 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11). 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12). 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

[0241] In yet some further particular embodiments, the SMC modulator that may be used by the method of the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0242] In yet some further particular embodiments, the SMC modulator that may be used by the method of the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2).

[0243] In yet some further specific embodiments, the SMC modulator used by the methods of the invention may be at least one pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XIII. In a more specific example of the disclosure, such compounds may include: N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33).

[0244] In yet some further embodiments, the method comprises the step of contacting the cell with an effective amount of N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide having a structure: (denoted herein as SMC #33)

[0245] In some other embodiments, the method comprises the step of contacting the cell with an effective amount of 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone having a structure: (denoted herein as SMC #34)

[0246] In some embodiments, the method comprises the step of contacting the cell with an effective amount of ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure: (denoted herein as SMC #23)

[0247] In some embodiments, the method comprises the step of contacting the cell with an effective amount of 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26)

[0248] In accordance with some other aspects, the method comprises the step of contacting the cell with an effective amount of at least one SMC modulator of WASp having the general formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of X, Y, Z, V, W, T and S may be selected from N, NH and C, R 6 and R 7 are the same or are different and are independently selected from each other may be L3-R 8 , L3 may be selected from -(CH 2 )n, -NH-C(O) and C(O)-NH, S(O) 2 , C(O), n is an integer between 0 to 5; R 8 may be selected from a ring system containing five to twelve atoms, each optionally substituted by at least one of straight or branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, nitro and hydroxyl, CF 3 .

[0249] In some embodiments, the method comprises the step of contacting the cell with an effective amount of 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32).

[0250] In accordance with some other aspects, the method comprises the step of contacting the cell with an effective amount of at least one SMC modulator of WASp having the general formula (IX): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein L4 may be absent or may be selected from -(CH 2 ) n -, -S-(CH 2 ) n -, -(CH 2 ) n -S-; n is an integer between 0 and 5; R 10 and R11 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 .

[0251] In some embodiments, L4 is selected from -S-(CH 2 )-. In some other embodiments, R 10 and R 11 are each independently from each other absent or selected from triazine, piperidine each optionally substituted with at least one NH 2 .

[0252] In accordance with some other aspects, the method comprises the step of contacting the cell with an effective amount of at least one SMC modulator of WASp having the general formula (X): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein R 13 and R14 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 1 -C 5 alkoxy, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 , NH-C(O)-CH 3 .

[0253] In some other embodiments, R 10 and R11 are each independently from each other absent or selected from aryl each optionally substituted with at least one OCH, NH-C(O)-CH 3 .

[0254] Still further, in some embodiments, the compound used in the methods of the invention may be the SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0255] In yet some alternative embodiments, the invention provides methods using of any of the SMCs disclosed herein, provided that said SMC is not SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0256] In more specific embodiments, the method of the invention may use any of the SMC modulator / s of the invention as defined herein, or any combinations thereof.

[0257] In some specific embodiments, the modulation of WAPs degradation by the methods of the invention may result in reduced WASp degradation in a cell.

[0258] In more specific embodiments, the methods of the invention may lead to reduced degradation of WASp and thereby restores, enhances and / or extends at least one of WASp levels and function in the treated cell.

[0259] In some specific embodiments, the cell modulated by the method of the invention may be a hematopoietic cell, more specifically, any cell of the lymphoid or the myeloid lineages. In yet some further embodiments, the hematopoietic cell according to the invention may be a non-erythroid hematopoietic cell.

[0260] In yet some further embodiments, the SMCs used by the methods of the invention may modulate WASp levels and / or function in a non-erythroid hematopoietic cell that may be least one of a lymphocyte, platelet, megakaryocyte, granulocyte and monocyte.

[0261] In some embodiments, the WASp function in a cell restored, extended or enhanced by the SMCs used by the methods of the invention may be at least one of cell activation, cell proliferation, cell migration, cell homing, cell spreading, cell aggregation, elevation in intracellular calcium concentration, cell adhesion, phagocytosis, and cytolytic activity.

[0262] In yet some further embodiments, the SMCs used by the methods of the invention may modulate, specifically, enhance and / or restore WASp levels and / or function as described above, in a cell of a subject suffering from an innate or acquired immune-related disorder or condition.

[0263] In some embodiments, the immune-related disorder or condition may be a primary or a secondary immunodeficiency. In yet some further specific embodiments, the primary immunodeficiency may be a hereditary or acquired disorder associated with WASp dysfunction. Still further, in some embodiments, the hereditary disorder associated with WASp dysfunction may be at least one of WAS and XLT, or any condition or disorder associated therewith.

[0264] In yet some further embodiments, acquired disorders or conditions associated with WAS and XLT, may include autoimmune disorders, inflammatory disorders, atopic eczema.

[0265] As shown by the EXAMPLES, application of the WASp-binding SMC modulators of the invention that potentially protect WASp from degradation, lead to increased WASp expression in T-cell lines, primary lymphocytes, megakaryocytes and platelets by reducing WASp ubiquitylation ( Fig. 4, 6, 7, 12, 14 and 15). This increase in WASp levels by the SMC modulators enhanced WASp-dependent cellular functions, including cellular activation, intra-cellular calcium influx, proliferation and migration ( Fig. 8, 9-11).In addition, treatment with SMCs not only reconstituted the expression of common WASp mutants but also restored the function of mutant WASp-expressing cells. ( Fig. 14, 15).

[0266] As therapeutic agents, SMCs have several advantages over proteins and peptides, including superior bio-availability and less immunogenicity. Currently MSCs cannot be tested in vivo due to the lack of valid animal models. The only available animal model for studying WAS is the WAS knockout mouse, which is completely devoid of the WAS gene and as such is not a suitable model for testing post translational pathways. Because the rarity of WAS / XLT, the inventors established WASp-deficient T cell lines, reconstituted with WAS / XLT mutant WASp, as a mid-step towards evaluation of WASp-protecting SMCs. The data presented in EXAMPLES 4, 5 and 6 provide proof of concept for using rationally-selected WASp-binding SMCs as a suitable treatment for WASp dysfunction disorders.

[0267] Therefore, attenuation of WASp degradation by WASp-binding SMC modulators of the invention is suggested as a promising treatment option for Wiskott-Aldrich Syndrome and X-linked thrombocytopenia.

[0268] In yet some alternative embodiments, the secondary immunodeficiency may be caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

[0269] It should be appreciated that in case of bone marrow transplantations, by restoring, enhancing and / or extending at least one of WASp levels and function in a cell using the SMC modulators described herein, the invention further encompasses an in vitro method for expansion of cells in culture, e.g., for bone marrow transplant and use in ex vivo expansion of hematopoietic cells.

[0270] In yet some further embodiments, the method of the invention may be applicable in restoring, enhancing or extending at least one of WASp levels and function in a cell of a subject suffering from a pathologic condition caused by at least one pathogen.

[0271] In yet some further embodiments, the method of the invention may be applicable in restoring, enhancing or extending at least one of WASp levels and function in a cell of a subject suffering from thrombocytopenia. More specifically, thrombocytopenia cause by bleeding, chemo- or radiotherapy, or autoimmunity (ITP).

[0272] In yet some certain embodiments, the method of the invention may be applicable in restoring, enhancing and / or extending at least one of WAS p levels and function in a cell of a subject suffering from cancer of a non-hematopoietic origin. In more specific embodiments, such method may be used as a supportive treatment for boosting the immune-system, specifically, cytotoxic lymphocytes activity in the treated subjects.

[0273] Still further, in some embodiments, for modulating the WASp levels / activity in a cell, the SMC modulators of the invention may be contacted with the cell. The term "contacting" as used herein, means to bring, put, incubate or mix together. As such, a first item is contacted with a second item when the two items are brought or put together, e.g., by touching them to each other or combining them. In the context of the present invention, the term "contacting" includes all measures or steps, which allow interaction between the compounds of the invention and the cells or subjects to be modulated, as specified herein after.

[0274] As indicated above, the present invention provides methods for modulating WASp degradation levels in a cell. The term modulation as used herein refers to reduction or alternatively, to elevation of WASp degradation in said cell.

[0275] In yet more specific embodiments, the SMC of the invention may lead to decrease, reduction, elimination, attenuation or inhibition of the WASp degradation of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or about 100% in a cell contacted with, or in a subject administered with the SMC of the invention as compared with a cell or a subject not treated with the SMC of the invention.

[0276] In yet a further aspect, the invention relates to uses in methods for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need thereof. More specifically, the method may comprise administering to the subject a therapeutically effective amount of at least one SMC modulator of WASp as described herein.

[0277] Disclosed is a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need comprise administering to the subject a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, any combinations thereof, or of any vehicle, matrix, nano- or micro-particle or composition comprising the same, wherein R 1 and R 2 are each independently from each other selected from H, straight or branched C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, straight or branched C 1 -C 12 alkoxy, a ring system containing five to twelve atoms, each optionally substituted by at least one of halide, hydroxyl, ester, ether, amide, amine, nitro, -C(=O)-O-(CH 2 ) n -CH 3 , R 5 , or -NH-C(=O)-R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include N, O, S, NH, C=N, C=O, S=O or SO 2 and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide and cyano; L1 and L2 are each independently from each other selected to be absent or from - (CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be are each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 i an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl.

[0278] In some specific embodiments, the method of the invention may use any of the SMC modulator / s defined by the invention or any combinations thereof. The scope of the invention is defined by the claims. The references to methods of treatment in the summary and detailed description of the invention in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis). Any embodiment not falling under the scope of the claims is provided for information purposes only.

[0279] In some embodiments of this aspect, the SMC is N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide having a structure: (denoted herein as SMC #33);

[0280] In some embodiments of this aspect, the SMC is 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone having a structure (denoted herein as SMC #34);

[0281] In some embodiments of this aspect, the SMC is ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure (denoted herein as SMC #23);

[0282] In some embodiments of this aspect, the SMC is 10-(3-Chloro-benzyl)-8-(4-methylpiperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26);

[0283] In still some further aspects thereof, the invention provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need thereof. More specifically, the method may comprise administering to the treated subject a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected from - CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0284] In some particular embodiments, specific and non-limiting examples of the SMC modulators used by the methods of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, that may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); or 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7).

[0285] In yet some further particular embodiments, specific examples of the SMC modulators that may be used by the methods of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, that may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13);

[0286] In yet some further particular embodiments, an additional example of a SMC modulator that may be used by the method of the disclosure, may be the compound: [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0287] In yet some further particular embodiments, an additional example of a SMC modulator that may be used by the method of the invention, may be the compound: In yet some further particular embodiments, an additional example of a SMC modulator that may be used by the method of the disclosure, may be the compound: 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2).

[0288] In yet some further alternative and particular embodiments, the SMC modulator used by the method invention may be any compound defined by Formula XI, Formula XII, with the proviso that the compound is not any of the compounds detailed below: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

[0289] In yet some further particular embodiments, the SMC modulator that may be used by the method of the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0290] In yet some further particular embodiments, the SMC modulator that may be used by the method of the invention, may be any of the compounds disclosed by the invention provided that said compound is not the compound: 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2).

[0291] In some particular embodiments, specific examples of the SMC modulators used by the methods of the disclosure, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XIII, that may include: N'-[2-(benzylamino)-2-oxocthyl]-N'-(2-methyvIlphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33).

[0292] In accordance with some other aspects, the method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need comprise administering to the subject a therapeutically effective amount of at least one SMC modulator of WAS having the general formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of X, Y, Z, V, W, T and S may be selected from N, NH and C, R 6 and R 7 are the same or are different and are independently selected from each other may be L 3 -R 8 , L3 may be selected from -(CH 2 ) n , -NH-C(O) and C(O)-NH, S(O) 2 , C(O), n is an integer between 0 to 5; R 8 may be selected from a ring system containing five to twelve atoms, each optionally substituted by at least one of straight or branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, nitro and hydroxyl, CF 3 .

[0293] In some embodiments of this aspect, the method comprises administering to the subject a therapeutically effective amount of 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethy1)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32).

[0294] In accordance with some other aspects, the method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need comprise administering to the subject a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (IX): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein L4 may be absent or may be selected from -(CH 2 ) n -, -S-(CH 2 ) n -, -(CH 2 ) n -S-; n is an integer between 0 and 5; R 10 and R11 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 .

[0295] In some embodiments, L4 is selected from -S-(CH 2 )-. In some other embodiments, R 10 and R11 are each independently from each other absent or selected from triazine, piperidine each optionally substituted with at least one NH 2 .

[0296] In accordance with some other aspects, the method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need comprise administering to the subject a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (X): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein R 13 and R14 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 1 -C 5 alkoxy, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 , NH-C(O)-CH 3 .

[0297] In some other embodiments, R 10 and R11 are each independently from each other absent or selected from aryl each optionally substituted with at least one OCH, NH-C(O)-CH 3 .

[0298] Still further, in some embodiments, the compound used in the methods of the invention may be the SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0299] In yet some alternative embodiments, the invention provides methods using of any of the SMCs disclosed herein, provided that said SMC is not SMC#6, specifically, N-[(2R,4R,6S)-2-(4-chlorophenyl)-6-(1-methylbenzotriazol-5-yl)oxan-4-yl]acetamide.

[0300] In some embodiments, the methods of the invention may be particularly applicable for treating an immune-related disorder or condition that may be a primary or a secondary immunodeficiency. Specifically, any of the primary or a secondary immunodeficiency disorders described herein before in connection with other aspects of the invention.

[0301] In yet some further specific embodiments, the methods of the invention may be applicable in the treatment of a primary immunodeficiency, specifically, a hereditary or acquired disorder associated with WASp dysfunction.

[0302] In more specific embodiments, such hereditary disorder associated with WASp dysfunction may be at least one of WAS and XLT, or any condition or disorder associated therewith.

[0303] In some specific embodiments the SMC modulators of the invention may be suitable for treating Wiskott-Aldrich Syndrome.

[0304] The "Wiskott-Aldrich syndrome" (WAS) is a rare (affects 4 of every 1 million males worldwide) X-linked disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, immunodeficiency, and a high incidence of autoimmune diseases and malignancies. A classic WAS phenotype is generally associated with null-mutations of the WAS gene located on the short arm of the X chromosome (Xp11.22) that encode the WAS protein (WASp).

[0305] It should be appreciated that in certain embodiments, the SMCs of the invention may be relevant for the treatment of any disease caused by a mutation in the WAS gene. In yet some further embodiments, the SMCs of the invention may be applicable for any WASp mutant, wherein the translated WAS protein maintains or retains, at least in part, the WASp-homology-1 (WH1) domain corresponding to the interaction site with WIP also named WASp degradation pocket.

[0306] The term "mutation" is used herein to describe any inherited or sporadic change in the nucleotide sequence or arrangement of DNA that results in a dysfunctional or absent protein including the following: nucleotide substitutions (e.g. missense mutations, nonsense mutations, non-stop mutations, RNA processing mutations, splice-site mutations, regulatory mutations, nucleotide transitions and nucleotide transversions), insertions or deletions of one or more nucleotides, truncations, duplications of any nucleotide sequence, repeat expansion mutations (e.g. trinucleotide repeats, etc.) and frameshift mutations. In some embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp with a missense mutation. In other embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp with any mutation as discussed above. In yet some further embodiments, the SMCs of the invention may be applicable for any known WASp mutation, specifically any of the WASp mutations disclosed herein after or any combinations thereof. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R86C mutant (specifically, substitution of Arginine to Cysteine in position 86 of WASp as denoted by the amino acid sequence of SEQ ID NO. 1). In other specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp Y107C mutant (specifically, substitution of Tyrosine to Cysteine in position 107 of WASp as denoted by the amino acid sequence of SEQ ID NO. 1). In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp A134T mutant (specifically, substitution of Alanine to Threonine in position 134 of WASp as denoted by the amino acid sequence of SEQ ID NO. 1). In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp T45M mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R86S mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R86G mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R86H mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R86L mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp R211stop codon mutant (truncation). In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp mutant with deletion of Exon 8. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp E31K mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp E133K mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp E133D mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp C73Y mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp C73W mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp V75M mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp V51F mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp W97C mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp C43W mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp A56V mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of WASp P58A mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S24P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S24F mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L27F mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L35H mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L39P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp A47D mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp T48I mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp P58R mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp W64R mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp F74S mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp K76T mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp D77H mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp D77G mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S82P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp W97X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp Q99X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp E100D mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L105P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G119E mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp C122X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G125R mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L126P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp F128L mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp F128S mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp E131K, E133K double mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp E131K, R86K double mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp A134V mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S228X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp A236G mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp E285X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp Q297X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp M307V mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp R321X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp P361T mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp R364X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp I481N mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp X503S mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp V75L mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp V75L mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S2T mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp M6I mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp L39P mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp D58A mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp E67K mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp Q80R mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp Y83X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp Y88C mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G89D mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G119R mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp N169X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp H180N mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp S242C mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G334X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G363X mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp G477K mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp D485N mutant. In some specific embodiments, the SMCs of the invention are particularly relevant for reducing degradation of the WASp D485G mutant.

[0307] It should be appreciated that the specific WASp mutants referred to herein are indicated using the conventional nomenclature for one letter code of the substituted amino acid residue. Specifically, Ala or A for alanine, Arg or R for arginine, Asn or N for Asparagine, Asp or D for Aspartic acid, Cys or C for Cysteine, Glu or E for Glutamic acid, Gln or Q for Glutamine, Gly or G for Glycine, His or H for Histidine, Ile or I for Isoleucine, Leu or L for Leucine, Lys or K for Lysine, Met or M for Methionine, Phe or F for Phenylalanine, Pro or P for Proline, Ser or S for Serine, Thr or T for Threonine, Trp or W for Tryptophan, Tyr or Y for Tyrosine and Val or V for Valine. Still further, Asx or B for aspartic acid or aspargine, Llx or Z for Glutamine or Glutamic acid, Xle or J for Leucine or Isoleucine, and Xaa or X, for any amino acid. The substituted position is referred to herein in relation to the wild type sequence of the human WASp as denoted by the amino acid sequence of SEQ ID NO. 1.

[0308] In some specific embodiments, SMC#34, is particularly relevant for reducing degradation of the WASp R86C mutant or the WASp Y107C mutant or the WASp A134T mutant.

[0309] In further specific embodiments, SMC#6 is particularly relevant for reducing degradation of the WASp R86C mutant or the WASp Y107C mutant or the WASp A134T mutant. In more specific embodiments, SMC#33 is particularly relevant for reducing degradation of the WASp R86C mutant or the WASp Y107C mutant or the WASp A134T mutant.

[0310] It should be appreciated that the method of the invention may be applicable also to disorders or conditions associated with WAS. More specifically, the intrinsic defects in phagocytosis, chemotaxis, cytotoxicity, apoptosis and cell signaling appear to contribute to more than just the immunodeficiency observed in WAS that has high incidence of autoimmunity, inflammatory conditions and vasculitis. Still further, WAS results from a hematopoietic-cell-specific defect in actin reorganization and cell signaling due to WASp deficiency. Patients lacking WASp expression or expressing abnormal WASp have NK cells with decreased cytolytic capacity. Clinically, patients with WAS are susceptible to herpes viruses and can develop HLH.

[0311] Clinically, the genetic defect produces cellular and humoral immunodeficiency, high susceptibility to autoimmune diseases, and increased risk for developing hematologic malignancies. This is the classic presentation, but the disease has a broad clinical spectrum that tends to correlate with the location and nature of the causative mutation. More than 300 mutations have been described, and the clinical picture varies from mild microthrombocytopenia alone (also called X-linked thrombocytopenia) to the full-blown syndrome.

[0312] Still further, in other specific embodiments the SMC modulators of the invention may be suitable for treating X-linked thrombocytopenia.

[0313] More specifically, a milder phenotype, "X-linked thrombocytopenia" (XLT), is often associated with mutations that result in expression of mutated protein. XLT patients have either no or very mild eczema and few problems, if any, with infections, autoimmunity, and malignancy. Amino acid substitutions within the guanosine triphosphatase-binding domain of WASP interfere with the intramolecular autoinhibitory mechanism, resulting in gain of function impaired actin polymerization, causing X-linked neutropenia. By definition, WAS and XLT patients have congenital thrombocytopenia in the range of 20,000 to 60,000 / L and microplatelets, but normal numbers of megakaryocytes. Hemorrhagic problems may be mild, consisting of bruises and petechiae, or serious, including gastrointestinal and central nervous system hemorrhages. Patients with classic WAS acquire bacterial, fungal, and viral infections.

[0314] Because of the poor long-term outcome, early allogeneic hematopoietic stem cell transplantation is the treatment of choice, however, this procedure is associated with many risks. Haploidentical transplantation is not recommended. Splenectomy ameliorates the bleeding tendency by increasing the number of blood platelets. However, splenectomy substantially increases the risk of septicemia, sometimes in spite of antibiotic prophylaxis, and often results in fatal bacterial infections. Patients with XLT have better prognosis, but may develop complications including serious bleeding, autoimmune diseases, and malignancies. Furthermore patients that are treated by splenectomy are not chosen for bone marrow transplantation or gene therapy due to their impaired immune response.

[0315] Still further, as indicated above, it should be appreciated that the invention further encompasses methods for treating WAS, XLT and any conditions or disorders associated therewith. Such disorders or conditions may include Microthrombocytopenia, inflammatory skin chronic conditions such as eczema, autoimmune conditions, immunodeficiency and tumors.

[0316] The term "Microthrombocytopenia" as used herein, refers to a decrease in thrombocyte (platelet) number and to a small size of generating platelets, which is the most consistent feature of WASP-associated disease. The mechanism of the abnormal size remains incompletely understood. Mutant WASP is uniformly absent in platelets, even in the mildest patient phenotypes, suggesting a direct role of WASP deficiency in producing thrombocytopenia (a decrease in platelet number) and microthrombocytopenia.

[0317] Among clinical manifestations, hemorrhages are frequent (80% incidence) in WAS and XLT patients and range from non- life-threatening bleeding to severe bleedings, such as intestinal and intracranial bleeding. Bleeding is the result of severe thrombocytopenia. Platelets of WAS and XLT have reduced size, which is the most common finding (100% incidence). Thrombocytopenia occurs irrespectively of the severity of the mutation and is possibly caused by instability of mutated WASp in platelets. Despite intensive research, the mechanisms underlying WASp-related thrombocytopenia and hemorrhages are not completely understood. Peripheral destruction of platelets in the spleen is thought to play an important role in inducing thrombocytopenia because a substantial correction of the platelet count and size after splenectomy has been reported. Overall, a full comprehension of the mechanisms causing thrombocytopenia still needs to be achieved.

[0318] In yet some more specific embodiments, the method of the invention may be applicable for treating inflammatory chronic skin conditions, specifically, eczema. The typical skin lesions in WAS and XLT patients resemble acute or chronic eczema in appearance and distribution. Eczema develops in 80% of the patients and is heterogeneous in severity and persistence. Indeed, in its most severe form, eczema is resistant to therapy, persists into adulthood, and facilitates opportunistic skin infections (Molluscum contagiosum, herpes simplex, or bacteria). The incidence and severity of eczema are significantly lower in patients with residual WASp expression. The causes of eczema in WAS patients are currently unknown.

[0319] Still further embodiments, related to the method of the invention that may be suitable for treating autoimmune conditions. WAS-associated autoimmune complications are frequently observed. The incidence of autoimmunity in classic WAS is high in the US and European populations (40%-72%), whereas a lower incidence was reported in Japan (22%). The most common manifestations are autoimmune hemolytic anemia, cutaneous vasculitis, arthritis, and nephropathy. Less common autoimmune manifestations include inflammatory bowel disease, idiopathic thrombocytopenic purpura, and neutropenia. Patients frequently have multiple autoimmune manifestations at the same time. Development of autoimmunity can have a prognostic value. Indeed, it has been reported that WAS patients who develop autoimmune hemolytic anemia or autoimmune thrombocytopenia early (180 days) after splenectomy have a poor prognosis. Moreover, autoimmunity is associated with a higher risk of a later development of tumors and an increased risk of mortality. Until now, the mechanisms of WAS-associated autoimmunity have not been clarified. It has been proposed that autoimmunity could be the result of a bystander tissue damage originating from the chronic inflammatory state that is established after incomplete pathogen clearance.

[0320] Still further embodiments relate to the applicability of the methods of the invention in the treatment of tumors in WAS patients. Recent surveys reported an increased tumor incidence in WAS patients. Tumors can arise during childhood (especially myelodysplasia) but are more frequent in adolescents and young adults. WAS-associated tumors are mainly lymphoreticular malignancies, with leukemia, myelodysplasia, and lymphoma resulting in up to 90% of the cases. WAS-associated malignancies have a poor prognosis because less than 5% of patients survive 2 years after diagnosis, and result in up to 25% of death cases. Immune deficiency can contribute to the genesis of tumors.

[0321] One of the known abnormalities associated with WAS are dysfunction of dendritic cells (DC), which are bone marrow-derived antigen presenting cells that are required for the initiation of immune responses. A prominent role for DC has been proposed in many clinical situations including autoimmunity, transplantation, malignancy and vaccination. It is probable that other molecularly undefined immunodeficiencies have defects in this cell population, and that disruption of DC polarization and motility, involving WASp could contribute to more common inflammatory conditions such as atopic eczema and autoimmunity. Intrinsic dysfunction of the DC population may also have an important role in the pathogenesis of other primary immunodeficiency syndromes, while changes in DC cytoskeletal signaling pathways may contribute to the initiation of acquired immunological and inflammatory disorders.

[0322] It was also found that WASP has a role in regulating IL-2 production, which is independent of its role in immune synapse formation. Therefore, disorders associated with impaired IL2 production may benefit from WASp upregulation. Thus, in some embodiments, the invention may further provide methods for treating disorders associated with impaired IL-2 production.

[0323] As noted above, acquired disorders associated with WASp dysfunction may include autoimmune disorders, inflammatory disorders and atopic eczema. Therefore, in further embodiments the pharmaceutical compositions and methods of the invention may be suitable for treatment of acquired disorders related to WASp dysfunction.

[0324] Still further, in certain embodiments, the methods and compositions of the invention may be applicable for treating disorders associated with immunodeficiency. 'Immunodeficiency', primary or secondary, meaning inherited or acquired, respectively. The term 'immunodeficiency' is intended to convey a state of an organism, wherein the immune system's ability for immuno-surveillance of infectious disease or cancer is compromised or entirely absent.

[0325] According to the International Union of Immunological Societies, more than 150 primary immunodeficiency diseases (PIDs) have been characterized, and the number of acquired (or secondary) immuno-deficiencies exceeds the number of PIDs. PIDs are those caused by inherited genetic mutations. Secondary immuno-deficiencies are caused by various conditions, aging or agents such as viruses or immune suppressing drugs.

[0326] Thus, in certain embodiments, the methods of the invention may be applicable for subjects suffering from secondary immunodeficiency. In yet some further embodiments, such immunodeficiency may be caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

[0327] As indicated above, the in some further embodiments, the SMCs of the invention may be applicable in boosting the immune response of a subject suffering from a secondary immunosuppression caused by chemotherapy, specifically, treatment with a chemotherapeutic agent.

[0328] "chemotherapeutic agent" or "chemotherapeutic drug" (also termed chemotherapy) as used herein refers to a drug treatment intended for eliminating or destructing (killing) cancer cells or cells of any other proliferative disorder. The mechanism underlying the activity of some chemotherapeutic drugs is based on destructing rapidly dividing cells, as many cancer cells grow and multiply more rapidly than normal cells. As a result of their mode of activity, chemotherapeutic agents also harm cells that rapidly divide under normal circumstances, for example bone marrow cells, digestive tract cells, and hair follicles. Insulting or damaging normal cells result in the common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immuno-suppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).

[0329] Various different types of chemotherapeutic drugs are available. A chemotherapeutic drug may be used alone or in combination with another chemotherapeutic drug or with other forms of cancer therapy, such as a biological drug, radiation therapy or surgery.

[0330] Certain chemotherapy agents have also been used in the treatment of conditions other than cancer, including ankylosing spondylitis, multiple sclerosis, hemangiomas, Crohn's disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, lupus and scleroderma.

[0331] Chemotherapeutic drugs affect cell division or DNA synthesis and function and can be generally classified into groups, based on their structure or biological function. The present invention generally pertains to chemotherapeutic agents that are classified as alkylating agents, anti-metabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, and other anti-tumor agents such as DNA-alkylating agents, anti-tumor antibiotic agents, tubulin stabilizing agents, tubulin destabilizing agents, hormone antagonist agents, protein kinase inhibitors, HMG-CoA inhibitors, CDK inhibitors, cyclin inhibitors, caspase inhibitors, metalloproteinase inhibitors, antisense nucleic acids, triple-helix DNAs, nucleic acids aptamers, and molecularly-modified viral, bacterial or exotoxic agents.

[0332] However, several chemotherapeutic drugs may be classified as relating to more than a single group. It is noteworthy that some agents, including monoclonal antibodies and tyrosine kinase inhibitors, which are sometimes referred to as "chemotherapy", do not directly interfere with DNA synthesis or cell division but rather function by targeting specific components that differ between cancer cells and normal cells and are generally referred to as "targeted therapies", "biological therapy" or "immunotherapeutic agent" as detailed below.

[0333] More specifically, as their name implies, alkylating agents function by alkylating many nucleophilic functional groups under conditions present in cells. Examples of chemotherapeutic agents that are considered as alkylating agents are cisplatin and carboplatin, as well as oxaliplatin. Alkylating agents impair cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in various biologically-significant molecules. Examples of agents which function by chemically modifying DNA are mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide. An additional agent acting as a cell cycle non-specific alkylating antineoplastic agent is the alkyl sulfonate agent busulfan (also known as Busulfex). alkylating chemotherapeutic agent cyclophosphamide

[0334] In some particular embodiments, the immune-suppressive condition may be caused by treatment with oxaliplatin. More specifically, Oxaliplatin is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as Folfox for the treatment of colorectal cancer. Compared to cisplatin the two amine groups are replaced by cyclohexyldiamine for improved antitumour activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility. Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin ®< .

[0335] Still Further, anti-metabolites (also termed purine and pyrimidine analogues) mimic the structure of purines or pyrimidines which are the building blocks of DNA and may thus be incorporated into DNA. The incorporation of anti-metabolites into DNA interferes with DNA syntheses, leading to abnormal cell development and division. Anti-metabolites also affect RNA synthesis. Examples of anti-metabolites include 5-fluorouracil (5-FU), azathioprine and mercaptopurine, fludarabine, cladribine (2-chlorodeoxyadenosine, 2-CdA), pentostatin (2'-deoxycoformycin, 2'-DCF), nelarabine, Floxuridine (FUDR), gemcitabine (Gemzar, a synthetic pyrimidine nucleoside) and Cytosine arabinoside (Cytarabine).

[0336] In yet some further embodiments, the SMCs of the invention may be applicable for boosting an immune-response in a subject treated with a chemotherapeutic agent that may be at least one Plant alkaloid and terpenoid. Plant alkaloids and terpenoids are agents derived from plants that block cell division by preventing microtubule function, thereby inhibiting the process of cell division (also known as "mitotic inhibitors" or "anti-mitotic agents"). Examples of alkaloids include the vinca alkaloids (e.g. vincristine, vinblastine, vinorelbine and vindesine) and terpenoids include, for example, taxanes (e.g. paclitaxel and docetaxel). Taxanes act by enhancing the stability of microtubules, preventing the separation of chromosomes during anaphase.

[0337] In further embodiments, the SMCs of the invention may be applicable for boosting an immune-response in a subject treated with chemotherapeutic agent that may be at least one Topoisomerase inhibitor. Topoisomerases are essential enzymes that maintain DNA topology (i.e. the overall three dimensional structure of DNA). Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by inhibiting proper DNA supercoiling. Type I topoisomerase inhibitors include camptothecins [e.g. irinotecan and topotecan (CPT11)] and examples of type II inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide.

[0338] Still further, Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy that are derived from the streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, uterine, ovarian, and lung cancers. These agents include, inter alia, the drugs daunorubicin (also known as Daunomycin), and doxorubicin and many other related agents (e.g., Valrubicin and Idarubicin). For example, the anthracycline agent Idarubicin acts by interfering with the enzyme topoisomerase II.

[0339] In further embodiments, the SMCs of the invention may be applicable for boosting an immune-response in a subject treated with Doxorubicin. The chemotherapeutic agent Doxorubicin (also known by the trade name Adriamycin and by the name hydroxydaunorubicin) is an anthracycline antibiotic that is closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA. The most serious adverse side effect of using this agent is the life-threatening heart damage. It is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas.

[0340] In certain embodiments, the SMCs of the invention may be applicable for boosting an immune-response in a subject treated with chemotherapeutic agent that may be at least one Cytotoxic antibiotics. The anthracyclines agents described above are also classified as "cytotoxic antibiotics". Cytotoxic antibiotics also include the agent actinomycin D (also known generically as Actinomycin or Dactinomycin), which is the most significant member of the actinomycines class of polypeptide antibiotics (that were also isolated from streptomyces). Actinomycin D is shown to have the ability to inhibit transcription by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase. Other cytotoxic antibiotics include bleomycin, epirubicin and mitomycin.

[0341] Still further, in some embodiments the SMCs of the invention may be applicable for subjects suffering from immune-deficiency caused by immune-therapy or a biological therapy. More specifically, cancer vaccines, antibody treatments, and other "immunotherapies" are potentially more specific and effective and less toxic than the current approaches of cancer treatment and are generally termed "immunotherapy", and therefore, an agent used for immunotherapy, is defined herein as an immunotherapeutic agent. The term immunotherapy as herein defined (also termed biologic therapy or biotherapy) is a treatment that uses certain components of the immune system to fight diseases (e.g. cancer), by, inter alia, stimulating the immune system to become more efficient in attacking cancer cells (e.g., by administering vaccines) or by administering components of the immune system (e.g., by administering cytokines, antibodies, etc.).

[0342] In the last few decades immunotherapy has become an important part of treating several types of cancer with the main types of immunotherapy used being monoclonal antibodies (either naked or conjugated), cancer vaccines (i.e. that induce the immune system to mount an attack against cancer cells in the body) and non-specific immunotherapies.

[0343] Antibody-mediated therapy as referred to herein refers to the use of antibodies that are specific to a cancer cell or to any protein derived there-from for the treatment of cancer. As a non-limiting example, such antibodies may be monoclonal or polyclonal which may be naked or conjugated to another molecule. Antibodies used for the treatment of cancer may be conjugated to a cytotoxic moiety or radioactive isotope, to selectively eliminate cancer cells.

[0344] It should be noted that the term "biological treatment" or "biological agent", as used herein refers to any biological material that affects different cellular pathways. Such agent may include antibodies, for example, antibodies directed to cell surface receptors participating in signaling, that may either activate or inhibit the target receptor. Such biological agent may also include any soluble receptor, cytokine, peptides or ligands. Non limiting examples for monoclonal antibodies that are used for the treatment of cancer include bevacizumab (also known as Avastin), rituximab (anti CD20 antibody), cetuximab (also known as Erbitux), anti-CTLA4 antibody and panitumumab (also known as Vectibix) and anti Gr1 antibodies.

[0345] More specifically, cancer vaccines as referred to herein are vaccines that induce the immune system to mount an attack against cancer cells in the body. A cancer treatment vaccine uses cancer cells, parts of cells, or pure antigens to increase the immune response against cancer cells that are already in the body. These cancer vaccines are often combined with other substances or adjuvants that enhance the immune response.

[0346] Non-specific immunotherapies as referred to herein do not target a certain cell or antigen, but rather stimulate the immune system in a general way, which may still result in an enhanced activity of the immune system against cancer cells. A non-limiting example of non-specific immunotherapies includes cytokines (e.g. interleukins, interferons). It should be thus appreciated that in some embodiments, the SMCs of the invention may be used as a combined supportive treatment for patients suffering from immune suppression. This supportive treatment may be combined with other supportive therapies as discussed herein.

[0347] Thus, in yet other embodiments, SMCs of the invention may be applicable for subjects undergoing at least one of adoptive cell transfer, a cancer vaccine, antibody-based therapy, a hormone, a cytokine or any combination thereof.

[0348] As indicated above, in some embodiments, the SMCs of the invention may be used for hematopoietic cell reconstitution in subjects undergoing radiotherapy. Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is therapy using ionizing radiation, generally as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor (for example, early stages of breast cancer). According to some specific embodiment, the radiation is ionizing radiation, which may be any one of X-rays, gamma rays and charged particles. In other embodiments, the radiation may be employed in the course of total body irradiation, brachytherapy, radioisotope therapy, external beam radiotherapy, stereotactic radio surgery (SRS), stereotactic body radiation therapy, particle or proton therapy, or body imaging using the ionizing radiation.

[0349] As indicated above, in some embodiments, the SMCs of the invention may be used for hematopoietic cell reconstitution in subjects undergoing gene therapy. Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease. The most common form uses DNA, optionally packed in a vector, that encodes a functional, therapeutic gene to replace a mutated gene.

[0350] In yet some further embodiments, the SMCs of the invention may be used for enhancing reconstitution of leukocyte and megakaryocyte populations in a subject that undergoes adoptive transfer. The term "adoptive transfer" as herein defined applies to all the therapies that consist of the transfer of components of the immune system that are already capable of mounting a specific immune response. Examples of adoptive transfer include both the transfer of antibodies and also, in adoptive cell transfer, specific types of cells that are capable of mediating antigen-specific tumor regression such as LAK and T cells. Cell-based therapies with various lymphocytes and antigen-presenting cells are promising approaches for cancer immunotherapy. The transfusion of T lymphocytes, also called adoptive cell therapy (ACT), is an effective treatment for viral infections and has induced regression of cancer in early stage clinical trials.

[0351] As noted above, conditions alleviated or modulated by the administration of the SMCs are typically those characterized by a reduced hematopoietic or immune function and more specifically, a reduced neutrophil count. Such conditions may be induced as a course of therapy for other purposes, such as chemotherapy or radiation therapy. Such conditions may result from infectious disease, such as bacterial, viral, fungal, or other infectious disease. For example, sepsis results from bacterial infection. Or, such condition may be hereditary or environmentally caused, such as severe chronic neutropenia. Age may also play a factor, as in the geriatric setting; patients may have a reduced neutrophil mobilization, reduced hematopoietic function, reduced immune function, reduced neutrophil count, reduced platelets count, sepsis, severe chronic neutropenia, infectious diseases, leukopenia, thrombocytopenia, anemia, enhancing engraftment of bone marrow during transplantation, enhancing bone marrow recovery in treatment of radiation, chemical or chemotherapeutic induced bone marrow aplasia or myelosuppression, and acquired immune deficiency syndrome.

[0352] Leukopenia is a decrease in the number of white blood cells (leukocytes) found in the blood, which places individuals at increased risk of infection. Neutropenia, a subtype of leukopenia, refers to a decrease in the number of circulating neutrophil granulocytes, the most abundant white blood cells. Low white cell count may be due to acute viral infections. It has been associated with chemotherapy, radiation therapy, myelofibrosis, aplastic anemia (failure of white cell, red cell and platelet production), stem cell transplant, bone marrow transplant, AIDS, and steroid use.

[0353] Other causes of low white blood cell count include systemic lupus erythematosus, Hodgkin's lymphoma and some types of cancer, typhoid, malaria, tuberculosis, dengue, rickettsial infections, enlargement of the spleen, folate deficiencies, psittacosis, sepsis, Sjögren's syndrome and Lyme disease. It has also been shown to be caused by deficiency in certain minerals, such as copper and zinc. The SMCs of the invention may be applicable for any of the conditions disclosed above.

[0354] In some further embodiments, the methods of the invention may be applicable for immune-related disorder or condition that may be a pathologic condition caused by at least one pathogen.

[0355] It should be appreciated that an infectious disease as used herein also encompasses any infectious disease caused by a pathogenic agent, specifically, a pathogen. Pathogenic agents include prokaryotic microorganisms, lower eukaryotic microorganisms, complex eukaryotic organisms, viruses, fungi, prions, parasites, yeasts, toxins and venoms.

[0356] A prokaryotic microorganism includes bacteria such as Gram positive, Gram negative and Gram variable bacteria and intracellular bacteria. Examples of bacteria contemplated herein include the species of the genera Treponema sp., Borrelia sp., Neisseria sp., Legionella sp., Bordetella sp., Escherichia sp., Pseudomonas sp. (e.g., P. aeruginosa), Salmonella sp., Shigella sp., Klebsiella sp., Yersinia sp., Vibrio sp., Hemophilus sp., Rickettsia sp., Chlamydia sp., Mycoplasma sp., Staphylococcus sp., Streptococcus sp., (e.g., Streptococcus pneumonia), Bacillus sp., Clostridium sp., Corynebacterium sp., Proprionibacterium sp., Mycobacterium sp., (e.g., Mycobacteria tuberculosis), Ureaplasma sp. and Listeria sp.

[0357] A lower eukaryotic organism includes a yeast or fungus such as Pneumocystis carinii, Candida albicans, Aspergillus, Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Trichophyton and Microsporum.

[0358] A complex eukaryotic organism includes worms, insects, arachnids, nematodes, aemobe, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, Trypanosoma brucei gambiense, Trypanosoma cruzi, Balantidium coli, Toxoplasma gondii, Cryptosporidium or Leishmania.

[0359] In yet some further embodiments, the SMCs of the invention may be applicable in boosting the immune response against a pathogen that may be in further specific embodiment, a viral pathogen or a virus. The term "viruses" is used in its broadest sense to include viruses of the families adenoviruses, papovaviruses, herpesviruses: simplex, varicella-zoster, Epstein-Barr (EBV), Cytomegalo virus (CMV), pox viruses: smallpox, vaccinia, hepatitis B (HBV), rhinoviruses, hepatitis A (HBA), poliovirus, rubella virus, hepatitis C (HBC), arboviruses, rabies virus, influenza viruses A and B, measles virus, mumps virus, human deficiency virus (HIV), HTLV I and II and Zika virus.

[0360] Of particular relevance for acquired immunodeficiency caused by a viral pathogen, is any immunodeficiency caused by HIV. More specifically, in some further embodiments, the SMCs of the invention may be applicable for AIDS. Acquired immunodeficiency syndrome (AIDS) is defined in terms of either a CD4+ T cell count below 200 cells per µL or the occurrence of specific diseases in association with an HIV infection. In the absence of specific treatment, around half of people infected with HIV develop AIDS within ten years. The most common initial conditions that alert to the presence of AIDS are pneumocystis pneumonia (40%), cachexia in the form of HIV wasting syndrome (20%), and esophageal candidiasis. Other common signs include recurring respiratory tract infections.

[0361] In yet some further embodiments, the SMCs of the invention may be applicable in boosting the immune response against a pathogen that may be a fungal pathogen. The term "fungi" includes for example, fungi that cause diseases such as ringworm, histoplasmosis, blastomycosis, aspergillosis, cryptococcosis, sporotrichosis, coccidioidomycosis, paracoccidio-idoinycosis, and candidiasis.

[0362] Still further, the term parasite includes infections caused by somatic tapeworms, blood flukes, tissue roundworms, ameba, and Plasmodium, Trypanosoma, Leishmania, and Toxoplasma species.

[0363] In certain additional embodiments, the methods of the invention may be applicable for immune-related disorder or condition that may be thrombocytopenia. More particularly, thrombocytopenia cause by bleeding, chemo- or radiotherapy, or autoimmunity (ITP).

[0364] The proposed therapeutic approaches can also benefit several orphan diseases such as Idiopathic thrombocytopenic purpura (ITP). ITP is a type of thrombocytopenic purpura defined as isolated low platelet count (thrombocytopenia) with normal bone marrow and the absence of other causes of thrombocytopenia. It causes a characteristic purpuric rash and an increased tendency to bleed. ITP is an autoimmune disease with antibodies detectable against several platelet surface antigens. ITP is diagnosed by a low platelet count in a complete blood count (a common blood test).

[0365] As shown by the examples, the SMCs of the invention induce platelets activation and as such may modulate and enhance coagulation processes. Induction of coagulation may be applicable in prevention and ameliorating conditions that may involve bleeding. Thus, in some embodiments, the SMCs of the invention may be applicable for treating acquired hemostatic disorders. The acquired hemostatic disorder may be at least one of surgery-induced bleeding, trauma-induced bleeding, acute gastrointestinal bleeding, bleeding associated with burns, hemorrhagic stroke, lung injury associated with emphysema and chronic obstructive pulmonary disease (COPD), bleeding associated with childbirth, disseminated intravascular coagulation (DIC), and bleeding resulting from fibrinolytic or thrombolytic therapy.

[0366] In some specific embodiments, the SMCs of the invention may be applicable for treating, preventing, reducing, attenuating, and inhibiting bleeding associated with surgical procedures, specifically, minor or major surgical procedures.

[0367] In a further specific embodiment the method of the invention may be suitable for treating trauma-induced bleeding (traumatic bleeding). Traumatic bleeding can be caused by any type of injury, for example any injury caused by, work and car accidents, combats or falls. There are different types of traumatic wounds which may cause bleeding. In general, trauma causes damage to a blood vessels that in turn causes blood to flow externally outside the body or internally into body organs such as brain, lung, liver, kidney, spleen or into body cavities, such as thorax and abdomen.

[0368] In some specific embodiments the SMCs of the invention may be suitable for treatment of acute or chronic gastrointestinal bleeding, that may include upper gastrointestinal bleeding and lower gastrointestinal bleeding.

[0369] In yet further embodiments the SMCs of the invention may be applicable for the treatment of hemorrhagic stroke or any other brain injury or trauma.

[0370] In certain specific embodiments, the SMCs the invention may be suitable for treating, preventing, reducing, attenuating, and inhibiting bleeding associated with surgical intervention, specifically, a minor or a major surgery. More specifically, it should be understood that in cases the surgical procedures are elective, expected or not urgent (e.g., cesarean surgery, or any other major surgery that allow sufficient time for pre-operative preparations), the SMCs of the invention may be used for pre-operative treatment to facilitate prevention or reduction of excessive bleeding during the surgical intervention.

[0371] Major surgery is defined as any surgical procedure that involves anesthesia or respiratory assistance. In more specific embodiments, major surgery may be an open heart surgery. In yet some other embodiments a major surgery may be liver transplantation surgery.

[0372] It should be further recognized that the treatment with the SMCs of the invention may be particularly applicable for treating the bleeding manifestations induced by thrombolytic / fibrinolytic therapy. As used herein, the term "anticoagulant agent" is intended to mean any agent which interferes with the clotting of blood. Some anticoagulants, such as the coumarin derivatives bishydroxycoumarin (Dicumarol) and warfarin (Coumadin) inhibit synthesis of prothrombin, a clot-forming substance, and other clotting factors. Anticoagulants can include compounds acting as beta2 Adrenoreceptor Antagonists, Neuropeptide V2 Antagonists, prostacyclin analogs, thromboxane synthase inhibitors, calcium agonists, coumarin derivatives, elastase inhibitors, Non-steroidal anti-inflammatories thrombin inhibitors, lipoxygenase inhibitors, Factor Vila inhibitors, Factor Xa inhibitors, phosphodiesterase III inhibitors, Heparins, and fibrinogen glucoprotein Ilb / IIIa Antagonists.

[0373] SMC-based treatment may also be used to enhance anti-tumor immunity. CTLs, as well as NK cells serve as the primary mediators of immune response against cancer cells. WASp was shown to be essential for NK-cancer cell conjugate formation and cytotoxic capacity. NK cells from WAS patients exhibit defective cytotoxicity. Thus, WASp enhancing SMCs may increase the potency of this response by improving the ability of the cells to migrate into the tumor, as well as improving activation and cytotoxic granule release.

[0374] The term "anti-tumor immunity" refers to innate and adaptive immune responses which may lead to tumor control.

[0375] The immune system can be activated by tumor antigens and, once primed, can elicit an antitumor response. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. Critical aspects in the tumor-immune system interface include the processing and presentation of released antigens by antigen-presenting cells (APCs), interaction with T lymphocytes, subsequent immune / T-cell activation, trafficking of antigen-specific effector cells, and, ultimately, the engagement of the target tumor cell by the activated effector T cell.

[0376] Nevertheless, although often successful in preventing tumor outgrowth, this "cancer-immunity cycle" can be disrupted by artifices involved in immune escape and development of tolerance, culminating with the evasion and proliferation of malignant cells.

[0377] Furthermore, the tumor microenvironment induces suppression and reduced activity of NK and T cells, through the secretion of inhibitory factors suppressing the anti-tumor response, a phenomena known as exhaustion. Increasing WASp, a mediator of activating immune signaling may counteract this increased inhibitory signaling and allow a robust T cell and NK cell mediated cytotoxic response.

[0378] In still some further embodiments, the methods of the invention may be applicable for immune-related disorder or condition that may be a cancer. In some embodiments, such cancer may be either of a non-hematopoietic origin or alternatively, of a hematological origin. It should be appreciated that is some embodiments, the methods of the invention may be used as a supportive treatment for boosting the immune-system, specifically, cytotoxic lymphocytes activity.

[0379] As used herein to describe the present invention, "cancer", "proliferative disorder", "tumor" and "malignancy" all relate equivalently to a hyperplasia of a tissue or organ. If the tissue is a part of the lymphatic or immune systems, malignant cells may include non-solid tumors of circulating cells. Malignancies of other tissues or organs may produce solid tumors. In general, the SMC modulators and methods of the present invention may be applicable for the treatment of a patient suffering from any one of non-solid and solid tumors.

[0380] Malignancy, as contemplated in the present invention may be any one of carcinomas, melanomas, sarcomas and also in some embodiments, may include lymphomas, leukemia and myeloma.

[0381] More specifically, carcinoma as used herein refers to an invasive malignant tumor consisting of transformed epithelial cells. Alternatively, it refers to a malignant tumor composed of transformed cells of unknown histogenesis, but which possess specific molecular or histological characteristics that are associated with epithelial cells, such as the production of cytokeratins or intercellular bridges.

[0382] Melanoma as used herein, is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye. Melanoma can occur in any part of the body that contains melanocytes.

[0383] Sarcoma is a cancer that arises from transformed connective tissue cells. These cells originate from embryonic mesoderm, or middle layer, which forms the bone, cartilage, and fat tissues. This is in contrast to carcinomas, which originate in the epithelium. The epithelium lines the surface of structures throughout the body, and is the origin of cancers in the breast, colon, and pancreas.

[0384] Further malignancies that may find utility in the present invention can comprise various solid tumors including GI tract, colon, lung, liver, breast, prostate, pancreas and Kaposi's sarcoma. The invention may be applicable as well for the treatment or inhibition of solid tumors such as tumors in lip and oral cavity, pharynx, larynx, paranasal sinuses, major salivary glands, thyroid gland, esophagus, stomach, small intestine, colon, colorectum, anal canal, liver, gallbladder, extraliepatic bile ducts, ampulla of vater, exocrine pancreas, lung, pleural mesothelioma, bone, soft tissue sarcoma, carcinoma and malignant melanoma of the skin, breast, vulva, vagina, cervix uteri, corpus uteri, ovary, fallopian tube, gestational trophoblastic tumors, penis, prostate, testis, kidney, renal pelvis, ureter, urinary bladder, urethra, carcinoma of the eyelid, carcinoma of the conjunctiva, malignant melanoma of the conjunctiva, malignant melanoma of the uvea, retinoblastoma, carcinoma of the lacrimal gland, sarcoma of the orbit, brain, spinal cord, vascular system, hemangiosarcoma and Kaposi's sarcoma.

[0385] As noted above, in some specific embodiments, the SMC modulators of the invention may be applicable in upregulating the immune-response against cancers of non-hematopoietic origin. Specifically, any of the caner disorders disclosed above. More specifically, cancer that is of a non-hematologic origin or non-hematological cancer or malignancy may be any cancer originated from any cell that is not of a lymphoid or myeloid origin. In some embodiments however, the SMCs of the invention may be applicable for hematological cancers, specifically, leukemia, lymphoma and myeloma.

[0386] More specifically, leukemia refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the blood-leukemic or aleukemic (subleukemic).

[0387] Myeloma as mentioned herein is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies. Collections of abnormal cells accumulate in bones, where they cause bone lesions, and in the bone marrow where they interfere with the production of normal blood cells. Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems and interferes with the production of normal antibodies leading to immunodeficiency. Hypercalcemia (high calcium levels) is often encountered.

[0388] Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. These malignant cells often originate in lymph nodes, presenting as an enlargement of the node (a tumor). It can also affect other organs in which case it is referred to as extranodal lymphoma. The term lymphoma as used herein encompasses T cell as well as B cell lymphoma. Non limiting examples for lymphoma include Hodgkin's disease, non-Hodgkin's lymphomas and Burkitt's lymphoma.

[0389] Hematological malignancies (including lymphoma, leukemia and myeloproliferative disorders, as described above), may further include hypoplastic and aplastic anemia (both virally induced and idiopathic), myelodysplastic syndromes, all types of paraneoplastic syndromes (both immune mediated and idiopathic).

[0390] In yet some further embodiments, where the SMCs of the invention are used for boosting the immune-system of a subject that suffers of a secondary-immunosuppression caused by chemo- or radiotherapy. In more specific embodiments, such radio- or chemotherapy may be applied on a subject suffering from a malignant disorder. In yet some further embodiments the subject may be affected by a non-hematopoietic malignancy. In yet some further embodiments, the subject may be affected by a hematopoietic malignancy. It should be noted that any of the malignancies discussed herein above are relevant for any aspect of the invention and for any use of the SMCs, specifically, any of the uses disclosed by the invention.

[0391] In yet some further embodiments, the methods of the invention may be applicable for a subject that suffers from a cancer and undergoes at least one of chemotherapy, radiotherapy, biological therapy, or any combinations thereof. In some specific embodiments, such subject may be suffering from a non-hematologic cancer and undergoes a chemotherapy, radiotherapy, a biological therapy or any combinations thereof. Alternatively, the subject may be suffering from hematologic cancer and undergoes a chemotherapy, radiotherapy, a biological therapy or any combinations thereof. In yet some further specific embodiments, such method may further comprise the step of administering to the treated subject before, simultaneously with, after or any combination thereof, the administration of the SMC modulator / s of the invention, at least one agent that induces differentiation of hematopoietic progenitor cells. In some specific and non-limiting embodiments, such treatment may be any supportive treatment. In yet some further particular embodiments, such treatment may include G-CSF and / or any analogs thereof.

[0392] As indicated above, the methods of the invention may be used in some embodiments, for treating any autoimmune disorder. It should be noted that an "autoimmune disorder" is a condition associated with dysfunction of the immune system of a subject, either through activation or suppression of the immune system or that can be treated, prevented or diagnosed by targeting a certain component of the immune response in a subject, such as the adaptive or innate immune response. Such disorder may be any one of an inflammatory disease or an autoimmune disease.

[0393] In other embodiments, the pharmaceutical compositions and methods of the invention can be suitable for treatment of inflammatory disorders. Based on the insufficient availability of specific anti-inflammatory treatments and the awareness of the roles of WASp in the pathogenesis of several groups of disorders, the development of new anti-inflammatory treatments is anticipated. Thus, there is a current need for the employment of the present invention in therapy.

[0394] The general term "inflammatory disorder" relates to disorders where an inflammation is a main response to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective response that involves immune cells, blood vessels, and molecular mediators, as well as the end result of long-term oxidative stress. More specifically, inflammatory disorders are a large group of disorders that underlie a vast variety of human diseases. Also, the immune system can be involved in inflammatory disorders, stemming from abnormal immune response of the organism against substances of its own, or initiation the inflammatory process for unknown reason, i.e. autoimmune and auto-inflammatory disorders, respectively. Non-immune diseases with etiological origins in inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.

[0395] The term "inflammatory disorders associated with WASp dysfunction" as used herein relates to at least one of the following: arthritis (ankylosing spondylitis, systemic lupus erythematosus, osteoarthritis, rheumatoid arthritis, psoriatic arthritis), asthma, atherosclerosis, inflammatory bowel disease (Crohn's disease, ulcerative colitis) and dermatitis (including psoriasis).

[0396] In more specific embodiments, the SMC modulators of the invention or any pharmaceutical compositions thereof, as well as methods of the invention may be applicable for preventing, treating, ameliorating or inhibiting inflammatory bowel disease (IBD), specifically, ulcerative colitis and Crohn's disease.

[0397] Inflammatory bowel diseases (IBD) are common gastrointestinal disorders, that can be perceived as being the result of a disbalance between Th1-pro-inflammatory and Th2-anti-inflammatory subtypes of immune responses. IBD is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis (UC). Other forms of IBD account for far fewer cases. These are collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, and indeterminate colitis, in cases where it is impossible to make a definitive diagnosis distinguishing Crohn's disease from ulcerative colitis.

[0398] The main difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's disease can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the whole bowel wall. Finally, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. Crohn's disease and ulcerative colitis share the same symptoms such as diarrhea, vomiting, weight loss, fever and abdominal pain.

[0399] According to other unlimited embodiments, the SMC modulators, compositions, and methods of the invention may be used for preventing, treating, ameliorating or inhibiting atopic eczema.

[0400] "Atopic eczema", also known as atopic dermatitis, is the most common form of eczema. It mainly affects children, but can also affect adults. Eczema is a condition that causes the skin to become itchy, red, dry and cracked. It is a long-term (chronic) condition in most people, although it can improve over time, especially in children. Atopic eczema can affect any part of the body, but the most common areas to be affected are: backs or fronts of the knees, outside or inside of the elbows, around the neck, hands, cheeks and scalp. The exact cause of atopic eczema is unknown, but it's clear it's not down to one single thing. It often occurs in people who get allergies - "atopic" means sensitivity to allergens. There is currently no cure for atopic eczema, but symptomatic treatment can help relieve the symptoms and many cases improve over time. However, severe eczema often has a significant impact on daily life and may be difficult to cope with physically and mentally.

[0401] In yet another aspect disclosed is the use of an effective amount of at least one SMC modulator of WASp having the general formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or any combination thereof, or any vehicle, matrix, nano- or micro-particle comprising the same, in the preparation of a composition or medicament for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight or branched C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, straight or branched C 1 -C 12 alkoxy, a ring system containing five to twelve atoms, each optionally substituted by at least one of halide, hydroxyl, ester, ether, amide, amine, nitro, -C(=O)-O-(CH 2 ) n -CH 3 , R 5 , or -NH-C(=O)-R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include N, O, S, NH, C=N, C=O S=O, or SO 2 and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide and cyano; L1 and L2 are each independently from each other be absent or selected from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be are each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl.

[0402] Still further, the invention in some other aspects thereof, provides the use of an effective amount of at least one SMC modulator of WASp having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or any combination thereof, or any vehicle, matrix, nano- or micro-particle comprising the same, in the preparation of a composition for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition in a subject in need thereof. In more specific embodiments, R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected to be absent or from -CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0403] In more specific embodiments, the invention provides the use of any of the SMC modulators as defined by the claims.

[0404] As used herein, "disease", "disorder", and "condition", as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms. It should be appreciated that the invention provides therapeutic methods applicable for any of the disorders disclosed above, as well as to any condition or disease associated therewith. It is understood that the interchangeably used terms "associated", "linked" and "related", when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder condition or pathology causes the second disease, disorder, condition or pathology. More specifically, as used herein, "disease", "disorder", "condition", and "pathology", as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms.

[0405] The terms "effective amount" or "sufficient amount" mean an amount necessary to achieve a selected result. The "effective treatment amount" is determined by the severity of the disease in conjunction with the preventive or therapeutic objectives, the route of administration and the patient's general condition (age, sex, weight and other considerations known to the attending physician).

[0406] The terms "treat, treating, treatment" as used herein and in the claims mean ameliorating one or more clinical indicia of disease activity by administering a pharmaceutical composition of the invention in a patient having a pathologic disorder.

[0407] "The term "treatment" as used herein refers to the administering of a therapeutic amount of the composition of the present invention which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.

[0408] The term "amelioration" as referred to herein, relates to a decrease in the symptoms, and improvement in a subject's condition brought about by the compositions and methods according to the invention, wherein said improvement may be manifested in the forms of inhibition of pathologic processes associated with the immune-related disorders described herein, a significant reduction in their magnitude, or an improvement in a diseased subject physiological state.

[0409] The term "inhibit" and all variations of this term is intended to encompass the restriction or prohibition of the progress and exacerbation of pathologic symptoms or a pathologic process progress, said pathologic process symptoms or process are associated with.

[0410] The term "eliminate" relates to the substantial eradication or removal of the pathologic symptoms and possibly pathologic etiology, optionally, according to the methods of the invention described below.

[0411] The terms "delay", "delaying the onset", "retard" and all variations thereof are intended to encompass the slowing of the progress and / or exacerbation of a pathologic disorder or an infectious disease and their symptoms slowing their progress, further exacerbation or development, so as to appear later than in the absence of the treatment according to the invention.

[0412] More specifically, treatment or prevention include the prevention or postponement of development of the disease, prevention or postponement of development of symptoms and / or a reduction in the severity of such symptoms that will or are expected to develop. These further include ameliorating existing symptoms, preventing- additional symptoms and ameliorating or preventing the underlying metabolic causes of symptoms. It should be appreciated that the terms "inhibition", "moderation", "reduction" or "attenuation" as referred to herein, relate to the retardation, restraining or reduction of a process by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%.

[0413] With regards to the above, it is to be understood that, where provided, percentage values such as, for example, 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively.

[0414] The present invention as defined by the claims, the contents of which are to be read as included within the disclosure of the specification, and will now be described by way of example with reference to the accompanying Figures.

[0415] The present invention relates to the treatment of subjects, or patients, in need thereof. By "patient" or "subject in need' it is meant any organism who may be infected by the above-mentioned pathogens, and to whom the preventive and prophylactic kit / s, system / s and methods herein described is desired, including humans, domestic and non-domestic mammals such as canine and feline subjects, bovine, simian, equine and murine subjects, rodents, domestic birds, aquaculture, fish and exotic aquarium fish. It should be appreciated that the treated subject may be also any reptile or zoo animal. More specifically, the kit / s and method / s of the invention are intended for preventing pathologic condition in mammals. By "mammalian subject" is meant any mammal for which the proposed therapy is desired, including human, equine, canine, and feline subjects, most specifically humans. It should be noted that specifically in cases of non-human subjects, the method of the invention may be performed using administration via injection, drinking water, feed, spraying, oral lavage and directly into the digestive tract of subjects in need thereof. The present invention relates to the treatment of subjects, or patients, in need thereof. It should be further noted that particularly in case of human subject, administering of the compositions of the invention to the patient includes both self-administration and administration to the patient by another person.

[0416] In yet a further aspect, the invention provides a SMC modulator of WASp degradation having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected from - CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0417] In some particular embodiments, specific and non-limiting examples of the SMC modulators of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII. More specifically, such compounds may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13); or N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33).

[0418] In yet some further particular embodiments, specific examples of the SMC modulators of the invention, or pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

[0419] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the disclosure, may be the compound [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0420] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the disclosure, may be the compound 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2);

[0421] In some particular embodiments, specific and non-limiting examples of the SMC modulators of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XIII. More specifically, such compounds may include: N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33). (not part of the invention as claimed)

[0422] In some further embodiments, the invention provides an SMC that may be ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure (denoted herein as SMC #23)

[0423] In yet some other embodiments, the invention provides an SMC that may be 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26). (not part of the invention as claimed)

[0424] In yet some alternative particular embodiments of the SMC modulator for use in accordance with the invention, the compound of Formula XI, may provide a compound having the general formula (XIV): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H and straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other may be absent or selected from -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, R 3 and R4 are each independently from each other absent or selected from an aryl or heteroaryl group optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, halide, nitro and cyano.

[0425] In some embodiments, in the SMC modulator for use in accordance with the invention, R 1 and R 2 are each independently from each other selected from H, methyl and ethyl, at times R 1 and R 2 are each independently from each other selected from H and methyl, L1 may be -CH 2 -S-, L2 may be -CH 2 -O-; R 3 and R4 are each independently from each other absent or selected from an aryl or heteroaryl group optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, halide, nitro and cyano.

[0426] In some further embodiments, in the SMC modulator for use in accordance with the invention, the R 1 and R 2 may be each independently from each other selected from H and methyl, L1 is -CH 2 -S-, L2 is, -CH 2 -O-, R 3 is selected from the group consisting of thiazole, [1,3,4]thiadiazole, [1,3,4]oxadiazole, and R 4 is phenyl.

[0427] In yet some alternative particular embodiments of the SMC modulator for use, the compound of Formula I, may provide a compound having the general formula (XV): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl and branched C 1 -C 12 alkyl; L1 and L2 are each independently from each other selected to be absent or from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0428] In some embodiments, R 1 and R 2 are each independently from each other selected from H or straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -(CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n , -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, -CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 - C 5 alkyl ; each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0429] In some other embodiments, R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 5 alkyl, L1 is absent and L2 is selected from -(CH 2 )-S-,-(CH 2 )-O-, -(CH 2 )-; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or branched C 1 -C 5 alkyl.

[0430] In some other embodiments, R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 5 alkyl, L1 is absent and L2 is selected from -(CH 2 )-S-,-(CH 2 )-O-, -(CH 2 )-; R 3 is a bicyclic ring and R4 is an aryl or a heteroaryl.

[0431] Also disclosed is least one SMC modulator of WASp having the general formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of X, Y, Z, V, W, T and S may be selected from N, NH and C, R 6 and R 7 are the same or are different and are independently selected from each other may be L3-R 8 , L3 may be selected from -(CH 2 )n, -NH-C(O) and C(O)-NH, S(O) 2 , C(O), n is an integer between 0 to 5; R 8 may be selected from a ring system containing five to twelve atoms, each optionally substituted by at least one of straight or branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, nitro and hydroxyl, CF 3 .

[0432] In some embodiments, disclosed is an SMC that may be any one of: 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32); N-[2-(dimethylamino)-2-thiophen-2-ylethyl]-4-[ethyl(phenyl)sulfamoyl]benzamide (Designated herein as SMC #24); 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one (Designated herein as SMC #26); 2-(4-Morpholin-4-yl-6-phenylamino-[1,3,5]triazin-2-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide Designated herein as SMC #15); 3-(benzylsulfamoyl)-N-[2-(2,6-difluoroanilino)-2-oxoethyl]-N-ethylbenzamide (Designated herein as SMC #25); 2-[4-[3-(dimethylsulfamoyl)-4-methylphenyl]-1-oxophthalazin-2-yl]-N,N-dimethylacetaniide (Designated herein as SMC #16); N-(2,5-difluorophenyl)-2-[2-[1-(4-methylphenyl)sulfonylpiperidine-3-carbonyl]hydrazinyl]acetamide (Designated herein as SMC #21); 2-fluoro-N-[4-[[2-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetyl]amino]phenyl]benzamide (Designated herein as SMC #31); 2-[2-(naphthalen-2-ylamino)-2-oxoethyl]sulfanyl-N-[(4-propan-2-ylphenyl)methyl]acetamide (Designated herein as SMC #17) 1-(3-chloro-4-fluorophenyl)-3-[[1-[(2,5-dimethylphenyl)methyl]piperidin-4-yl]methyl]urea (Designated herein as SMC #28).

[0433] In yet a further aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one SMC modulator of WASp of the invention as described herein. The scope of the invention is defined by the claims. Any embodiment not falling under the scope of the claims is provided for information purposes only.

[0434] It should be noted that the composition of the invention may optionally further comprise at least one pharmaceutically acceptable carrier / s, excipient / s, auxiliaries, and / or diluent / s.

[0435] Some aspects of the disclosure relate to a pharmaceutical composition comprising a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or any vehicle, matrix, nano- or micro-particle comprising the same, said composition optionally further comprises at least one pharmaceutically acceptable carrier / s, excipient / s, auxiliaries, and / or diluent / s, wherein R 1 and R 2 are each independently from each other selected from H, straight or branched C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, straight or branched C 1 -C 12 alkoxy, a ring system containing five to twelve atoms, each optionally substituted by at least one of halide, hydroxyl, ester, ether, amide, nitro, -C(=O)-O-(CH 2 ) n -CH 3 , R 5 , or -NH-C(=O)- R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl; or R 1 and R 2 together with the nitrogen atom they are connected to form a five to twelve membered saturated or unsaturated ring that may optionally include N, O, S, NH, C=N, C=O, S=O, or SO 2 and may be optionally be substituted with at least one of straight or branched C 1 -C 5 alkyl, hydroxyl, halide and cyano; L1 and L2 are each independently from each other may be absent or selected from - (CH 2 ) n -(CH 2 -C(O)-N) n -(CH 2 ) n , -(CH 2 ) n -S-,-(CH 2 ) n -O-, S(O) 2 , S(O) 2 -N-(CH 2 ) n , -(CH 2 )n, -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -S-, NH, -(CH 2 ) n -S-(CH 2 ) n -C(O)-NH-(CH2) n -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -, -NH-(CH 2 ) n -, -C(=O)-NH-(CH 2 ) n -; -S-S-(CH 2 ) n -; -O-(CH 2 ) n -; -NH-(CH 2 ) n -; C(=O)-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-S(=O) n -(CH 2 ) n -, - CH 2 -S-C(O)-NH-CH 2 -, -(CH 2 ) n -(NH) n -C(=O) -(CH 2 ) n -N-C(=O)-, S(O) 2 -N-(CH 2 ) n , -(CH 2 ) n -(NH) n -C(=O)-, -(CH 2 ) n -N-C(=O)- L1 and L2 may be are each independently from each other optionally substituted with C 1 - C 5 alkyl, a ring system containing five to twelve atoms substituted with C 1 - C 5 alkyl each n, is an integer being independently from each other selected from be 0 to 5; R 3 and R4 are each independently from each other be absent or selected from a ring system containing five to 15 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), (O) 2 , -C(O)-CH 3 , -C(O)-O-CH 3 , halide, CF 3 , nitro, amide, or R 5 , R 5 is an a ring system containing five to twelve atoms optionally substituted by at least one halide or straight or branched C 1 -C 5 alkyl.

[0436] The composition of the invention may comprise at least one SMC modulator of WASp degradation having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein R 1 and R 2 are each independently from each other selected from H, straight C 1 -C 12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl or R 1 and R 2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C 1 -C 5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH 2 -(CH 2 -C(O)-N)-(CH 2 ) 2 , -(CH 2 )-S-, -(CH 2 )- ,-(CH 2 )-O-, -NH-(CH 2 )-, and each optionally substituted with C 1 -C 5 alkyl, a ring system containing five to twelve atoms optionally substituted with C 1 -C 5 alkyl ; R 3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S) or R 5 , R 5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C 1 -C 5 alkyl.

[0437] In some particular embodiments, specific examples of the SMC modulators of the compositions of the invention, may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII. More specifically, such compounds may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); or 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7).

[0438] In yet some further particular embodiments, specific and non-limiting examples of the SMC modulators of the compositions of the invention, or pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XII, may include: 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13)

[0439] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the disclosure, may be the compound [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9).

[0440] In yet some further particular embodiments, a further example of a SMC modulator that may be used by the disclosure, may be the compound [5-(Naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetic acid methyl ester (SMC 34.9). 8-(5-Isopropyl-[1,3,4]oxadiazol-2-ylmethoxy)-quinoline (34.2)

[0441] In some other particular embodiments, specific and non-limiting examples of the SMC modulators of the compositions of the invention may be pharmaceutically acceptable salts or hydrates of the compounds of Formula XI, or in some further specific embodiments, pharmaceutically acceptable salts or hydrates of the compounds of Formula XIII. More specifically, such compounds may include: (a) N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33). (not part of the claims)

[0442] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide having a structure: (denoted herein as SMC #33) (not part of the claims)

[0443] In some other embodiments, the pharmaceutical composition comprising a therapeutically effective amount of 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone having a structure (denoted herein as SMC #34);

[0444] In some further embodiments, the pharmaceutical composition comprising a therapeutically effective amount is ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure (denoted herein as SMC #23); (not part of the claims)

[0445] In yet some other embodiments, the pharmaceutical composition comprising a therapeutically effective amount of 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26);

[0446] In accordance with some other aspects, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein each one of X, Y, Z, V, W, T and S may be selected from N, NH and C, R 6 and R 7 are the same or are different and are independently selected from each other may be L3-R 8 , L3 may be selected from -(CH 2 )n, -NH-C(O) and C(O)-NH, S(O) 2 , C(O), n is an integer between 0 to 5; R 8 may be selected from a ring system containing five to twelve atoms, each optionally substituted by at least one of straight or branched C 1 -C 5 alkyl, halide, hydroxyl, ester, ether, amide, nitro and hydroxyl, CF 3 .

[0447] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of 3-[(3-fluorophenyl)methyl]-5-[1-[2-(trifluoromethyl)phenyl]sulfonylpiperidin-4-yl]-2H-triazolo[4,5-d]pyrimidin-7-one (Designated herein as SMC #32)

[0448] In accordance with some other aspects, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (IX): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein L4 may be absent or may be selected from -(CH 2 ) n -, -S-(CH 2 ) n -, -(CH 2 ) n -S-; n is an integer between 0 and 5; R 10 and R11 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 .

[0449] In some embodiments, L4 is selected from -S-(CH 2 )-. In some other embodiments, R 10 and R11 are each independently from each other absent or selected from triazine, piperidine each optionally substituted with at least one NH 2 .

[0450] In accordance with some other aspects, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one SMC modulator of WASp having the general formula (X): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, wherein R 13 and R14 are each independently from each other absent or selected from a ring system containing five to twelve atoms, each optionally substituted with at least one of straight or branched C 1 -C 5 alkyl, C 1 -C 5 alkoxy, (=O), (=S), -C(O)-CH 3 , -C(O)-O-CH 3 , halide, nitro, NH 2 , NH-C(O)-CH 3 .

[0451] In some other embodiments, R 10 and R11 are each independently from each other absent or selected from aryl each optionally substituted with at least one OCH, NH-C(O)-CH 3 .

[0452] In some specific embodiments, the pharmaceutical composition may comprise any of the SMC modulator / s as described by the invention or any vehicle, matrix, nano- or micro-particle comprising the same.

[0453] In yet some further embodiments, the invention provides the pharmaceutical compositions of the invention as described herein for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition.

[0454] In some embodiments , the pharmaceutical composition for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition, comprising a therapeutically effective amount of N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide having a structure: (denoted herein as #33)

[0455] In some other embodiments, the pharmaceutical composition for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition, comprising a therapeutically effective amount of 1-(2,6-dimethylpiperidin-1-yl)-2-[[5-(quinolin-8-yloxymethyl)-1,3,4-oxadiazol-2-yl]sulfanyl]ethanone having a structure (denoted herein as SMC#34).

[0456] In some further embodiments, the pharmaceutical composition for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition, comprising a therapeutically effective amount is ethyl 4-[[3-(4-acetylpiperazin-1-yl)sulfonylbenzoyl]amino]benzoate having a structure (denoted herein as SMC #23). (not part of the claims)

[0457] In yet some other embodiments, the pharmaceutical composition for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of an innate or acquired immune-related disorder or condition, comprising a therapeutically effective amount of 10-(3-Chloro-benzyl)-8-(4-methyl-piperazine-1-carbonyl)-5,5-dioxo-5,10-dihydro-5λ6-dibenzo[b,f][1,4]thiazepin-11-one having a structure (denoted herein as SMC #26). (not part of the claims)

[0458] It should be appreciated that the small molecule compounds (SMCs) of the invention are referred to either by their formula or by their numbers, for example, compound #34 may be referred to herein as SMC 34, SMC#34 or #34.

[0459] In some specific embodiments, the compositions of the invention may be used for treating hereditary disorder associated with WASp dysfunction. In more specific embodiments, such disorders may be at least one of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT), or any condition or disorder associated therewith.

[0460] In some specific embodiments, condition or disorder associated with WAS and / or XLT, may be also defined as an acquired disorder related to WASp dysfunction. Such conditions or disorders may include at least one of autoimmune disorders, inflammatory disorders and atopic eczema.

[0461] It should be appreciated that in some embodiments, the composition of the invention may be used for any immune-related disorders, in some embodiments, any innate or acquired immunodeficiency as detailed in connection with other aspects of the invention. Specifically, any primary (e.g., WAS, XLT and associated conditions) or secondary immunodeficiency (e.g., caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof).

[0462] It should be appreciated that the SMC modulators used by the methods of the invention may be formulated in any vehicle, matrix, nano- or micro-particle, or composition. Of particular relevance are formulations of the SMC modulators of the invention adapted for use as a nano- or micro-particles. Nanoscale drug delivery systems using micellar formu...

Claims

1. An effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for modulating the degradation of Wiskott-Aldrich Syndrome protein (WASp) in a cell of a subject in need thereof, said modulator having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R1 and R2 are each independently from each other selected from H, straight C1-C12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl or R1 and R2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C1-C5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH2-(CH2-C(O)-N)-(CH2)2, -(CH2)-S-, -(CH2)- ,-(CH2)-O-, -NH-(CH2)-, and each optionally substituted with C1-C5 alkyl, a ring system containing five to twelve atoms optionally substituted with C1-C5 alkyl; R3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C1-C5 alkyl, (=O), (=S) or R5, R5 is a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl.

2. The SMC modulator for use according to claim 1, having the general formula (XII): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R1 and R2 are each independently from each other selected from H, straight C1-C12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl; or R1 and R2 together with the nitrogen atom they are connected to form a five to seven membered unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C1-C5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -(CH2)-, (CH2)-S-,-(CH2)-O-,and may be optionally substituted with C1-C5 alkyl, R3 is a ring system containing five atoms, optionally substituted with at least one straight C1-C5 alkyl, or R5, R5 is a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl, R4 is absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight C1-C5 alkyl.

3. The SMC modulator for use according to claim 1 or 2, being one of: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); and 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

4. The SMC modulator for use according to any one of claims 1 to 3, wherein said modulator attenuates WASp ubiquitylation thereby reducing ubiquitin proteasome-mediated degradation of WASp in said cell, preferably, wherein said reduced degradation of WASp restores, enhances or extends at least one of WASp levels and function in said cell, preferably, wherein said cell is a non-erythroid hematopoietic cell, preferably, wherein said non-erythroid hematopoietic cell is at least one of a lymphocyte, platelet, megakaryocyte, granulocyte and monocyte.

5. The SMC modulator for use according to claim 4, wherein said WASp function in a cell is at least one of cell activation, cell proliferation, cell migration, cell homing, cell spreading, cell aggregation, elevation in intracellular calcium concentration, cell adhesion, phagocytosis, and cytolytic activity, preferably, wherein said cell is of a subject suffering from an innate or acquired immune-related disorder or condition.

6. The SMC modulator for use according to claim 5, wherein said immune-related disorder or condition is a primary or a secondary immunodeficiency, wherein: (a) said primary immunodeficiency is a hereditary or acquired disorder associated with WASp dysfunction, preferably, wherein said hereditary disorder associated with WASp dysfunction is at least one of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT), or any condition or disorder associated therewith; or (b) said secondary immunodeficiency is caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

7. The SMC modulator for use according to claim 5, wherein; (a) said immune-related disorder or condition is a pathologic condition caused by at least one pathogen; or (b) said immune-related disorder or condition is thrombocytopenia; or (c) said immune-related disorder or condition is cancer.

8. An effective amount of at least one small molecule compound (SMC) modulator or any vehicle, matrix, nano- or micro-particle comprising the same, for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a an innate or acquired immune-related disorder or condition in a subject in need thereof, wherein said at least one SMC modulator of WASp is having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R1 and R2 are each independently from each other selected from H, straight C1-C12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl or R1 and R2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C1-C5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH2-(CH2-C(O)-N)-(CH2)2, -(CH2)-S-, -(CH2)- ,-(CH2)-O-, -NH-(CH2)-, and each optionally substituted with C1-C5 alkyl, a ring system containing five to twelve atoms optionally substituted with C1-C5 alkyl; R3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C1-C5 alkyl, (=O), (=S) or R5, R5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl.

9. The SMC modulator for use according to claim 8, wherein said SMC modulator is one of: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7); or 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); and 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13).

10. The SMC modulator for use according to any one of claims 8 to 9, wherein said immune-related disorder or condition is a primary or a secondary immunodeficiency, preferably, wherein: (a) said primary immunodeficiency is a hereditary or acquired disorder associated with WASp dysfunction, preferably, wherein said hereditary disorder associated with WASp dysfunction is at least one of WAS and XLT, or any condition or disorder associated therewith; or (b) said secondary immunodeficiency is caused by at least one of chemotherapy, radiotherapy, biological therapy, bone marrow transplantation, gene therapy, adoptive cell transfer or any combinations thereof.

11. The SMC modulator for use according to any one of claims 8 to 9, wherein: (a) said immune-related disorder or condition is a pathologic condition caused by at least one pathogen; or (b) said immune-related disorder or condition is thrombocytopenia; or (c) said immune-related disorder or condition is cancer, preferably, wherein said subject undergoes at least one of chemotherapy, radiotherapy, biological therapy, or any combinations thereof, and wherein said method further comprises the step of administering to said subject before, simultaneously with, after or any combination thereof, the administration of said SMC modulator, at least one agent that induces differentiation of hematopoietic progenitor cells.

12. A SMC modulator of WASp degradation or any pharmaceutical composition thereof, wherein said SMC modulator is having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R1 and R2 are each independently from each other selected from H, straight C1-C12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl or R1 and R2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C1-C5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH2-(CH2-C(O)-N)-(CH2)2, -(CH2)-S-, -(CH2)- ,-(CH2)-O-, -NH-(CH2)-, and each optionally substituted with C1-C5 alkyl, a ring system containing five to twelve atoms optionally substituted with C1-C5 alkyl; R3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C1-C5 alkyl, (=O), (=S) or R5, R5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl.

13. A SMC modulator of WASp degradation or any pharmaceutical composition thereof, wherein said SMC modulator is one of: 1-(2,6-Dimethyl-piperidin-1-yl)-2-[5-(quinolin-8-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-ethanone (designated herein as SMC 34); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-m-tolyloxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.1); 2-(5-Methyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-piperidin-1-yl-ethanone (SMC 34.3); N-Cyclohexyl-2-[5-(naphthalen-2-yloxymethyl)-[1,3,4]oxadiazol-2-ylsulfanyl]-acetamide (SMC 34.4); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.5); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(5-pyridin-3-yl-[1,3,4]oxadiazol-2-ylsulfanyl)-ethanone (SMC 34.6); 1-(2,6-Dimethyl-piperidin-1-yl)-2-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (designated herein as SMC 34.7); 2-(5-Phenoxymethyl-[1,3,4]oxadiazol-2-ylsulfanyl)-1-pyrrolidin-1-yl-ethanone (SMC 34.8); 2-(Quinolin-8-yloxymethyl)-oxazole-4-carboxylic acid (tetrahydro-pyran-2-ylmethyl)-amide (SMC 34.10); 2-[4-Phenyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone (SMC 34.11); 1-Piperidin-1-yl-2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethanone (SMC 34.12); 2-[4-Methyl-5-(quinolin-8-yloxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetamide (SMC 34.13); or N'-[2-(benzylamino)-2-oxoethyl]-N'-(2-methylphenyl)-N-(1,3-thiazol-2-yl)butanediamide (Designated herein as SMC#33); or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.

14. A kit comprising: (a) at least one SMC modulator of WASp having the general formula (XI): or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein R1 and R2 are each independently from each other selected from H, straight C1-C12 alkyl, a saturated ring system containing five to seven atoms, each optionally substituted by at least one ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl or R1 and R2 together with the nitrogen atom they are connected to form a five to seven membered saturated or unsaturated ring optionally include at least one of N, O and optionally substituted with at least one of straight C1-C5 alkyl, L1 and L2 are each independently from each other selected to be absent or from -CH2-(CH2-C(O)-N)-(CH2)2, -(CH2)-S-, -(CH2)- ,-(CH2)-O-, -NH-(CH2)-, and each optionally substituted with C1-C5 alkyl, a ring system containing five to twelve atoms optionally substituted with C1-C5 alkyl; R3 and R4 are each independently from each other absent or selected from a ring system containing five to 12 atoms, each optionally substituted with at least one of straight or branched C1-C5 alkyl, (=O), (=S) or R5, R5 is an a ring system containing five to seven atoms optionally substituted by at least one halide or straight C1-C5 alkyl; and at least one of: (b) at least one chemotherapeutic agent; (c) at least one biological therapy agent; and (d) at least one agent that induces differentiation of hematopoietic progenitor cells.