Cyclic d-peptides, derivatives, compositions and uses thereof

Abstract

The present disclosure relates to cyclic D-peptides, derivatives, compositions and combinations thereof. Specifically, the cyclic peptides, compositions and derivatives thereof are capable of not increasing bilirubin levels. The present disclosure also provides uses of the cyclic peptides, derivatives, compositions and combinations thereof for the treatment and or prevention of proliferative diseases.

Description

[0001] CYCLIC D-PEPTIDES, DERIVATIVES, COMPOSITIONS AND USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to novel cyclic D-peptides and to derivatives, compositions and uses thereof for the treatment of proliferative diseases.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] - [1] WO 2006 / 046239

[0007] - [2] WO 2007 / 122622

[0008] - [3] WO 2007 / 091240

[0009] - [4] WO 2008 / 075349

[0010] [5] Sandler, U. et al., 2010, Recent advances in clinical medicine, ISSN: 1790-5125.

[0011] [6] Sandler, U. et al., 2010, J Experimental Therapeutics and Oncology 8:327-339.

[0012] - [7] WO2015 / 083167

[0013] - [8] WO2017 / 134668

[0014] 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.

[0015] BACKGROUND OF THE INVENTION

[0016] A peptide termed “T101” that is encoded by a cDNA unique for the human thymus was previously identified. This peptide as well as derivatives thereof were implicated, inter alia, for the treatment of cancer via the role of T101 as a stimulator of the immune system (WO 2006 / 046239, [1]). WO 2006 / 046239 demonstrates that T101 is able to stimulate the immune system and to reduce tumor size, suggesting that the peptide affects the proliferation of cancer cells. WO 2006 / 046239 also suggests an immune-based role for T101, for example in protecting patients during the course of standard chemotherapy.

[0017] Treatment of cancer by using T101 was also suggested in WO 2007 / 122622 [2], which demonstrates, inter alia, the effect of T101 on the development of various types of tumors. The peptide T101 was also described in WO 2007 / 091240 [3], relating to treatment of immunological diseases and in WO 2008 / 075349 [4] as well as in the publications by Sandler et al. [5-6], relating to treating or preventing a disease involving a cell having T1 / ST2 receptor.

[0018] In addition, a peptide derivative of T101, termed “Nerofe”, has been reported to decrease the secretion of proteins that are known to be associated with cancer metastasis by cancer cells and to directly inhibit migration of cancer cells in vitro. Moreover, the peptide was shown to affect the serum level of vascular endothelial growth factor (VEGF) in cancer patients (WO2015 / 083167, [7]), and was suggested for use in a method of preventing or treating cancer metastasis.

[0019] Furthermore, the peptide termed “Nerofe” mentioned above was also shown in WO2017 / 134668 [8] to be implicated in the induction of ER stress which contributes to promoting cell death, and was suggested for reducing the administered standard of care doses of anti-cancer agents in treated cancer patients.

[0020] SUMMARY OF THE INVENTION

[0021] In a first aspect the present disclosure provide a cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D- amino acid residues.

[0022] In a further aspect, the present disclosure provides a composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu- Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D- amino acid residues, optionally, said composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0023] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D-amino acid residues, said pharmaceutical composition further comprises and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0024] In an additional aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr- Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues.

[0025] In a yet another aspect, the present disclosure provides a cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of said cyclic peptide.

[0026] In a further aspect, the present disclosure provides a combined composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser- Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues, and at least one anticancer agent or any pharmaceutically acceptable salt thereof.

[0027] In a further aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr- Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues and at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof.

[0028] In another aspect, the present disclosure provides a kit comprising:

[0029] (a) at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof and at least one anti-cancer agent, or pharmaceutically acceptable salt thereof, wherein the amino acid residues of said peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, optionally, in a first dosage form;

[0030] (b) at least one anti-cancer agent, optionally in a second dosage form.

[0031] In a further aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject displaying high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr- Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

[0032] In another aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1, wherein the amino acid residues of said peptide are D-amino acid residues, or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

[0033] BRIEF DESCRIPTION OF THE DRAWINGS

[0034] 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:

[0035] Fig. 1: Percentage of cell viability of SHSY5Y, MDA231 and SKBR3 cells following treatment with Nerofe and its derivatives.

[0036] The cells were treated as follows: no treatment (C), treatment with Nerofe derivative 1 (1), treatment with Nerofe derivative 2 (2), treatment with Nerofe derivative 3 (3), treatment with Nerofe derivative 4 (4), treatment with Nerofe derivative 5 (5), treatment with Nerofe derivative 6 (6), treatment with Nerofe derivative 7 (7), and treatment with the original Nerofe peptide.

[0037] Fig. 2: Fold increase in tumor volume of mice injected with CT26 cells.

[0038] DETAILED DESCRIPTION OF THE INVENTION

[0039] The present disclosure relates for the first time to D-cyclic peptides and several derivatives thereof, exhibiting strong therapeutic effects, specifically on cancer cells.

[0040] In a first aspect the present disclosure provide a cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues.

[0041] As used herein, the term "cyclic peptide" encompasses a peptide molecule comprising the amino acid sequence denoted by SEQ ID NO. 1 (namely the amino acid sequence Trp Trp Thr Phe Phe Leu Pro Ser Thr Leu Trp Glu Arg Lys in an all D conformation) or any derivatives thereof for example comprising the amino acid as denoted by any one of SEQ ID NO: 1 to 10, termed herein "dTCApFs" or "Nerofe" and in which the amino acid sequence forms a ring structure. The cyclic peptide according to the present disclosure also relates to functional derivatives of the amino acid sequence denoted by SEQ ID NO. 1 (e.g. comprising the amino acid as denoted by any one of SEQ ID NO: 2 to 10) or pharmaceutically acceptable salts of said cyclic peptide. Any pharmaceutically acceptable salt of the cyclic peptide as herein defined are encompassed by the present disclosure.

[0042] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 1. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 1.

[0043] In some embodiments, the cyclic peptide of the present disclosure further comprises n polyethylene glycol (PEG) moieties, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) wherein n is the number of PEG moieties and is an integer from 1 to 10.

[0044] In some embodiments, n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 2.

[0045] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 2.

[0046] In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 3.

[0047] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 3. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 3.

[0048] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 4.

[0049] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 4. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 4.

[0050] In some further embodiments, n is an integer from 1 to 100, specifically in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 20, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47, n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99 or n is 100.

[0051] In some embodiments, the cyclic peptide of the present disclosure further comprises n Sarcosine (Sar) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)), wherein n is the number of Sar residues and is an integer from 1 to 10. In some embodiments, n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 5.

[0052] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 5. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 5.

[0053] In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 6.

[0054] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 6. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 6.

[0055] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 7.

[0056] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 7. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 7.

[0057] In some further embodiments, n is an integer from 1 to 100, specifically in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 20, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47, n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99 or n is 100.

[0058] In some embodiments, the cyclic peptide of the present disclosure comprises an amino acid as denoted by SED ID NO: 8.

[0059] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 8. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 8.

[0060] In some embodiments, the cyclic peptide of the present disclosure further comprises n Glycine (Gly) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)), wherein n is the number of Gly residues and is an integer from 1 to 10. In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 9.

[0061] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 9. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 9.

[0062] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 10.

[0063] In some embodiments, the cyclic peptide or a functional derivative thereof comprises an amino acid having at least 70%, or 80%, or 90%, or 95% identity to the corresponding sequence of SEQ ID NO: 10. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 10.

[0064] In some further embodiments, n is an integer from 1 to 100, specifically in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 20, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47, n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99 or n is 100.

[0065] It was surprisingly shown in Example 6 that the cyclic peptides of the present disclosure are safe compounds since they do not increase the levels of bilirubin upon injection to mice.

[0066] In some embodiments, the cyclic peptide of the present disclosure is capable of not increasing the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the present disclosure is capable of maintaining the levels of bilirubin (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the present disclosure is capable of not (altering or modifying) the levels of bilirubin upon administration (e.g. to a subject in need).

[0067] The term “peptide” as herein defined refers to a molecular chain of amino acid residues, which, if required, can be modified at each one of its amino acid residues, for example by manosylation, glycosylation, amidation (for example C-terminal amides), carboxylation or phosphorylation. The peptide may be obtained synthetically, through genetic engineering methods, expression in a host cell, or through any other suitable means. Methods for producing peptides as well as cyclic peptides as mentioned above are well known in the art.

[0068] More specifically, "Amino acid molecule" , "Amino acid sequence" or "peptide sequence" is the order in which amino acid residues connected by peptide bonds, lie in the chain in peptides and proteins. The sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing amide. Amino acid sequence is often called peptide, protein sequence if it represents the primary structure of a protein, however one must discern between the terms "Amino acid sequence" or "peptide sequence" and "protein", since a protein is defined as an amino acid sequence folded into a specific three-dimensional configuration and that had typically undergone post-translational modifications, such as phosphorylation, acetylation, glycosylation, manosylation, amidation, carboxylation, sulfhydryl bond formation, cleavage and the like.

[0069] Amino acids, as used herein refer to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. “Amino acid analogs” refers to compounds that have the same fundamental chemical structure as a naturally occurring amino acid, i.e., an alpha carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. “Amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC- IUB Biochemical Nomenclature Commission.

[0070] The term “amino acid“ as used herein, refers to naturally occurring and synthetic amino acid residues, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y- carboxy glutamate, and O-phosphoserine.

[0071] The term amino acid encompasses L-amino acids and D-amino acids, which are mirror images of L-amino acids, where the chirality at carbon alpha has been inverted. D-amino acids are highly resistant to protease mediated degradation and have a low immunogenic response.

[0072] The terms "amino acid sequence" or "peptide sequence" also relate to the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins. The sequence is generally reported from the N-terminal end containing free amino group to the C- terminal end containing free carboxyl group.

[0073] As indicated above, the present disclosure also encompasses cyclic peptides comprising derivatives of the peptide having the amino acid sequence denoted by SEQ ID NO. 1 (for example comprising the amino acid as denoted by any one of SEQ ID NO: 2 to 10). By the term "derivative” or “derivatives” it is meant to include peptides, which comprise the amino acid sequence denoted by SEQ ID NO: 1 or any one of the amino acid as denoted by any one of SEQ ID NO: 2 to 10, but differ in one or more amino acids in their overall sequence, namely, which have deletions, substitutions (e.g. replacement of at least one amino acid by another amino acid), inversions or additions within the overall sequence of SEQ ID NO: 1 as well as any one of SEQ ID NO: 2 to 10. This term also encompasses the replacement of at least one amino acid residue in the overall sequence by its respective L amino acid residue.

[0074] In particular embodiments, the modified cyclic peptide of the composition of the present disclosure or invention has at least 70%, or 80%, or 90%, or 95%, or in particular 99% identity to the corresponding sequence of SEQ ID NO: 1 as well as any one of SEQ ID NO: 2 to 10.

[0075] In some embodiments, the cyclic peptide comprising the amino acid sequence denoted by SEQ ID NO. 1 or any one of SEQ ID NO: 2 to 10 may comprise one or more amino acid residues is replaced by conservative substitution without significantly affecting the biological characteristics of the modified peptide as compared to the unmodified peptide having the amino acid sequence of SEQ ID NO: 1 or any one of SEQ ID NO: 2 to 10.

[0076] Amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, i.e., conservative amino acid replacements. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the residues involved. For example, each of the following eight groups contains amino acids that are conservative substitutions for one another:

[0077] 1) Alanine (A), Glycine (G);

[0078] 2) Aspartic acid (D), Glutamic acid (E);

[0079] 3) Asparagine (N), Glutamine (Q);

[0080] 4) Arginine (R), Lysine (K);

[0081] 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);

[0082] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);

[0083] 7) Serine (S), Threonine (T); and

[0084] 8) Cysteine (C), Methionine (M).

[0085] It is appreciated that these peptide derivatives must not alter the biological activity of the original peptide. The term "functional" means to denote that the modified peptide (namely the derivative) retains a biological activity qualitatively similar to that of the unmodified peptide. The biological activity of the derivative may be determined as herein described, namely by monitoring the effect of said derivative upon administration to an animal model, as known in the art.

[0086] In particular embodiments, the present disclosure relates to a functional derivative thereof or functional fragment of the cyclic polypeptide comprising amino acid sequence denoted by SEQ ID NO. 1 or any one of SEQ ID NO: 2 to 10, wherein said functional derivative thereof or functional fragment has an amino acid sequence that is at least about 70%, 75%, 80%, 85%, 90%, or 95%, in particular 99% identical to the amino acid sequence of the unmodified isolated polypeptide of the invention, namely to the amino acid sequence denoted by SEQ ID NO: 1 or any one of SEQ ID NO: 2 to 10 and retains a biological activity qualitatively similar to that of the unmodified peptide.

[0087] In some specific embodiments, the cyclic peptide consists of the amino acid sequence of SEQ ID NO: 1 or any one of SEQ ID NO: 2 to 10.

[0088] Several types of derivatives may be used to modify therapeutic peptides for improved stability, bioavailability, and pharmacokinetic properties for example, PEGylation, addition of N- methyl amino acids (e.g. Sarcosine), addition of Glycine residues, as well as addition of fatty acid chain (acylation), acylation, glycosylation, phosphorylation, introduction of a sulfur-containing group into the peptide backbone (Thioether derivatives), etc.

[0089] In some embodiments, the cyclic peptide derivative of the invention comprises at least PEG moieties. PEG (polyethylene glycol) is a synthetic polymer that can be attached to therapeutic peptides as a "PEG moiety" or "PEGylation" to modify their physicochemical and pharmacokinetic properties. PEGylation involves covalently attaching PEG to the peptide molecule, typically at the N- or C-terminus or on specific amino acid residues. This modification can offer several advantages to the peptides which can affect their pharmacokinetics, biodistribution, and therapeutic outcomes such as increased half-life, improved solubility and stability, enhanced bioavailability, reduced toxicity: By decreasing immunogenicity and nonspecific binding to tissues, PEGylation can contribute to a reduced toxicity profile of peptides as well as providing tunablee properties to the peptides (such as their size, charge, and hydrophobicity) .

[0090] In some embodiments, the cyclic peptide derivative of the invention comprises addition of at least one Glycine residue. Adding glycine residues to therapeutic peptides enables to improve their pharmacokinetic properties. Glycine is the smallest amino acid and is highly flexible, which means it can introduce flexibility and conformational variability to the peptide structure. This can be beneficial for several reasons since it may improve solubility, reduce immunogenicity, increase half-lifeand may enhance receptor selectivity.

[0091] In some embodiments, the cyclic peptide derivative of the invention comprises addition of at least one Sarcosine residue or N-methyl glycine. Sarcosine is a non-proteinogenic amino acid that can be added to therapeutic peptides to modify their properties. The addition of sarcosine can improve the pharmacokinetic profile of the peptide by offering several benefits such as increased stability, improved solubility, reduced immunogenicity, enhanced receptor selectivity and reduced toxicity.

[0092] In some further embodiments, the cyclic peptide of the present disclosure may further comprise one or more targeting moieties selected from the group consisting of antibodies, antibody fragments, aptamers, and small molecules. In some embodiments, the targeting moiety may be directly or indirectly attached or conjugated to the cyclic peptide.

[0093] In some further embodiments, the peptide is directly or indirectly attached or conjugated to at least one therapeutic compound.

[0094] In some embodiments, the at least one therapeutic compound in accordance with the present disclosure may be an anti-cancer agent. In some embodiments the anti-cancer agent according to the present disclosure is a chemotherapeutic agent, an immunotherapy agent (e.g. an antibody, an antibody fragment or a monoclonal antibody that down-regulates inhibitory immune receptors) or an immune-stimulatory agent, a Bcl2 inhibitor, a tyrosine kinase inhibitor, a hormonal agent, a biological agent, a differentiation factor, an anti-angiogenic factor or an antiautophagy agent.

[0095] In some specific embodiments, the at least one therapeutic agent may be doxorubicin. In some specific embodiments, the at least one therapeutic agent may be a BCL2 inhibitor. In some further alternative embodiments, the at least one therapeutic agent may be an anti-cancer immunotherapeutic agent e.g. an anti-PDl antibody or an anti PDL1 antibody.

[0096] In a further aspect, the present disclosure provides a composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu- Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D-amino acid residues, optionally, said composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0097] In some embodiments, the at least one cyclic peptide of the composition of the present disclosure is as defined in the previous aspect of the present disclosure detailed above.

[0098] In some embodiments, the composition of the present disclosure is for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

[0099] In some embodiments, the composition is a pharmaceutical composition.

[0100] In some embodiments, the cyclic peptide of the composition of the present disclosure is capable of not increasing the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the composition of the present disclosure is capable of maintaining the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the composition of the present disclosure is capable of not (altering or modifying) the levels of bilirubin upon administration (e.g. to a subject in need).

[0101] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D-amino acid residues, said pharmaceutical composition further comprises and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive. In some embodiments, the at least one cyclic peptide of the pharmaceutical composition of the present disclosure is as defined in the previous aspects of the present disclosure detailed above.

[0102] In some embodiments, the pharmaceutical composition of the present disclosure is for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

[0103] In some embodiments, the proliferative disorder relevant to the above compositions of the invention may be at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS- mutated cancer, mCRC mtKRAS cancer and / or melanoma. Additional proliferative disorders relevant to the above compositions of the invention are defined in the subsequent aspects of the present disclosure defined below.

[0104] In some embodiments, the cyclic peptide of the pharmaceutical composition of the present disclosure is capable of not increasing the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the pharmaceutical composition of the present disclosure is capable of maintaining the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the pharmaceutical composition of the present disclosure is capable of not (altering or modifying) the levels of bilirubin upon administration (e.g. to a subject in need).

[0105] The term "pharmaceutical compositions " as herein defined refers to the cyclic peptide of the invention or any derivatives thereof and optionally at least one pharmaceutically acceptable excipient or carrier as known in the art. As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Pharmaceutical compositions used to treat subjects in need thereof according to the present disclosure optionally also comprise a buffering agent, an agent who adjusts the osmolarity thereof, and optionally, one or more pharmaceutically acceptable additives as known in the art. Pharmaceutical compositions used to treat subjects in need thereof according to the invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry, for example as detailed in the Examples below. It should be understood that in addition to the ingredients particularly mentioned herein, the compositions according to the present disclosure may also include other agents conventional in the art having regard to the type of formulation in question. In an additional aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr- Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues.

[0106] In some embodiments, the cyclic peptide of the methods of the present disclosure further comprises n PEG moieties, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) wherein n is the number of PEG moieties and is an integer from 1 to 10.

[0107] In some embodiments, the cyclic peptide of the methods of the present disclosure comprises an amino acid sequence as denoted by SEQ ID NO: 2.

[0108] In some embodiments, the cyclic peptide of the methods of the present disclosure comprises an amino acid sequence as denoted by SEQ ID NO: 3.

[0109] In some embodiments, the cyclic peptide of the methods of the present disclosure comprises an amino acid sequence as denoted by SEQ ID NO: 4.

[0110] In some embodiments, the cyclic peptide of the methods of the present disclosure further comprises n Sarcosine residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)), wherein n is the number of Sar residues Sar and is an integer from 1 to 10.

[0111] In some embodiments, n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 5.

[0112] In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 6.

[0113] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 7.

[0114] In some embodiments, the cyclic peptide of the methods of the present disclosure comprises an amino acid as denoted by SED ID NO: 8.

[0115] In some embodiments, the cyclic peptide of the methods of the present disclosure further comprises n Glycine (Gly) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)), wherein n is the number of Gly residues and is an integer from 1 to 10. In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 9.

[0116] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 10.

[0117] In some embodiments, the peptide of the methods of the present disclosure is directly or indirectly attached or conjugated to at least one therapeutic compound.

[0118] In some embodiments, the at least one cyclic peptide of the methods of the present disclosure is as defined in the previous aspects of the present disclosure detailed above.

[0119] As used herein, "proliferative disorder" is a disorder displaying hyper proliferation. This term means cell division and growth that is not part of normal cellular turnover, metabolism, growth, or propagation of the whole organism. Unwanted proliferation of cells is seen in tumors and other pathological proliferation of cells, does not serve normal function, and for the most part will continue unbridled at a growth rate exceeding that of cells of a normal tissue in the absence of outside intervention. A pathological state that ensues because of the unwanted proliferation of cells is referred herein as a "hyper proliferative disease" or "hyper proliferative disorder." It should be noted that the term “proliferative disorder”, “cancer”, “tumor” and “malignancy” all relate equivalently to a hyperplasia of a tissue or organ. In general, the compositions and methods of the present invention may be used in the treatment of non-solid and solid tumors.

[0120] In some embodiments, the proliferative disorder may refer to malignancy. Malignancy, as contemplated in the present invention may be any one of lymphomas, leukemias, carcinomas, melanomas, myeloma and sarcomas.

[0121] In some embodiments, the proliferative disorder may refer to lymphoma. 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. Non limiting examples for lymphoma include Hodgkin's disease, nonHodgkin's lymphomas and Burkitt's lymphoma.

[0122] In some embodiments, the proliferative disorder may refer to leukemia. 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). In some embodiments, the proliferative disorder may refer to carcinoma. 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.

[0123] In some embodiments, the proliferative disorder may refer to melanoma. 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.

[0124] In some embodiments, the proliferative disorder may refer to sarcoma. 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.

[0125] In some embodiments, the proliferative disorder may refer to myeloma. 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.

[0126] In some embodiments, the proliferative disorder may refer to at least one of hematological malignancies (including lymphoma, leukemia and myeloproliferative disorders), hypoplastic and aplastic anemia (both virally induced and idiopathic), myelodysplastic syndromes, all types of paraneoplastic syndromes (both immune mediated and idiopathic) and solid tumors (including GI tract, colon, lung, liver, breast, prostate, pancreas and Kaposi's sarcoma. In some embodiments, the malignant disorder may be lymphoma.

[0127] In some embodiments, the proliferative disorder may refer to at least one of hematopoietic malignancies such as all types of lymphomas, leukemia, e.g. acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), mutated KRAS tumors, chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), mast cell leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, Burkitt's lymphoma and / or multiple myeloma. In some embodiments, the methods of the present disclosure may be relevant to the treatment or inhibition of at least one 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, extrahepatic 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 / or Kaposi's sarcoma.

[0128] In some particular embodiments, the proliferative disorder may refer to mutated KRAS tumors. In some particular embodiments, the cyclic peptides, compositions or methods of the invention are for treating, preventing, ameliorating, reducing or delaying the onset of mutated KRAS tumors. Mutated KRAS tumors or KRAS-driven tumors relate to a type of cancer tumors in which the Kirsten rat sarcoma viral oncogene (KRAS) is mutated. The KRAS oncogene has the highest mutation rate among all cancers and is associated with a series of highly fatal cancers, such as pancreatic ductal adenocarcinoma (PDAC), nonsmall-cell lung cancer (NSCLC), and colorectal cancer (CRC).

[0129] In some embodiments, the proliferative disorder is at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS-mutated cancer, mCRC mtKRAS cancer and / or melanoma.

[0130] The above described definitions and embodiments relevant to the proliferative disorder are applicable to any suitable additional aspects of the present disclosure.

[0131] In some embodiments, the methods of the present disclosure comprises administering a composition comprising at least one cyclic peptide as defined in the previous aspects of the present disclosure detailed above.

[0132] In some embodiments, the composition is a pharmaceutical composition, optionally wherein said composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0133] In some embodiments, the methods of the present disclosure further comprises administering to said subject at least one additional anti-cancer agent. In some specific embodiments, the at least one additional anti-cancer agent may be at least one of doxorubicin, taxol, cisplastin, a BCL2 inhibitor, and / or an anti-cancer immunotherapeutic agent (e.g. an anti-PDl antibody or an anti PDL1 antibody).

[0134] The term "anti-cancer agent" also known as "anticancer drug" or "antineoplastic drug" is used in its broader sense and encompasses any drug or agent that is effective in the treatment of malignant or cancerous disease. There are several classes of anticancer drugs as further detailed below.

[0135] In some embodiments, the anti-cancer agent according to the present disclosure is a chemotherapeutic agent, an immunotherapy agent (e.g. an antibody, an antibody fragment or a monoclonal antibody that down-regulates inhibitory immune receptors) or an immune-stimulatory agent, a Bcl2 inhibitor, a tyrosine kinase inhibitor, a hormonal agent, a biological agent, a differentiation factor, an anti-angiogenic factor or an anti-autophagy agent.

[0136] In some embodiments the anti-cancer agent according to the present disclosure is a chemotherapeutic agent. A "chemotherapeutic agent" as known in the art is a drug that targets cells at different phases of the process of forming new cells and is used to treat cancer by killing or inhibiting the growth of cancer cells. These drugs can be administered orally, intravenously, or through injection. Non limiting examples of chemotherapeutic agents are Anthracycline agents which work by inhibiting an enzyme called topoisomerase II involved in DNA replication and repair, leading to the death of cancer cells, e.g. doxorubicin-, mitotic inhibitors: these drugs interfere with the mitotic spindle fibers of the cell, which are required for cell division and causes the cancer cells to die, e.g. paclitaxel (Taxol), vinblastine, and docetaxel; alkylating agents: these drugs work by damaging the DNA of cancer cells, preventing them from dividing and growing, e.g. cyclophosphamide, cisplatin, and carmustine; antimetabolites: these drugs are similar in structure to natural substances that are required for DNA / RNA synthesis and interfere with the cancer cell's ability to grow and divide, e.g. methotrexate, 5-fluorouracil, and gemcitabine; topoisomerase inhibitors: these drugs prevent the unwinding of DNA during replication, causing DNA damage and preventing cell growth, e.g. etoposide, irinotecan, and topotecan; hormonal agents: these drugs target cancer cells that are driven by hormones, such as breast and prostate cancer and work by blocking the hormones or the receptors that the cancer cells use to grow, e.g. tamoxifen, letrozole, and bicalutamide; immunomodulators: these drugs work by enhancing the immune system's ability to detect and destroy cancer cells, e.g. interferon-alpha and interleukin-2.

[0137] In some embodiments the anti-cancer agent according to the present disclosure is doxorubicin. Doxorubicin (also referred to e.g. as Adriamycin or Doxil) having a systematic (IUPAC) name (7S,9S)-7-[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,ll- trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5, 12-dione is an antineoplastic antibiotic obtained from Streptomyces peucetius. Doxorubicin is an Anthracycline Topoisomerase Inhibitor that intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis. Additionally, doxorubicin inhibits topoisomerase II which results in an increased and stabilized cleavable enzyme-DNA linked complex during DNA replication and subsequently prevents the ligation of the nucleotide strand after double-strand breakage. Doxorubicin also forms oxygen free radicals (ROS) resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids. Any derivatives of doxorubicin are encompassed by the present disclosure.

[0138] In some embodiments the anti-cancer agent according to the present disclosure is cisplastin. Cisplatin, cisplatinum or cis-diamminedichloroplatinum(II) (ChHe^Pt ), having a systematic (IUPAC) name (SP-4-2)-diamminedichloridoplatinum(II), is a platinum-based chemotherapy drug used to treat various types of cancers, it was the first member of its class, which now also includes carboplatin and oxaliplatin. Cisplatin functions by forming intrastrand and interstrand crosslinks within DNA, leading to the inhibition of DNA replication and transcription. These crosslinks interfere with cellular processes, ultimately inducing apoptosis in cancer cells. Furthermore, cisplatin exhibits its cytotoxic effects by activating cellular pathways involved in apoptosis and inhibiting DNA repair mechanisms. Any analogs, derivatives, or formulations of cisplatin falling within the scope of the claims are encompassed by this patent disclosure.

[0139] In some embodiments the anti-cancer agent according to the present disclosure is taxol. Taxol (also known as paclitaxel) having a systematic (IUPAC) name (2a,4a,5p,7p,10p,13a)-4,10- Bis(acetyloxy)-13-{ [(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-l,7- dihydroxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate, is a chemotherapeutic agent derived from the bark of the Pacific yew tree (Taxus brevifolia). Taxol is classified as a member of the taxane family. It functions as a microtubule stabilizer by binding to the P-subunit of tubulin within the microtubule, promoting polymerization and inhibiting depolymerization. This mechanism disrupts the dynamic equilibrium of microtubule assembly and disassembly, leading to mitotic arrest during cell division. Additionally, taxol induces apoptosis by activating intracellular signaling pathways. Taxol's antineoplastic activity primarily targets rapidly dividing cells, making it effective against various solid tumors, including ovarian, breast, and lung cancers. Any derivatives or analogs of taxol fall within the scope of this description.

[0140] In some embodiments the anti-cancer agent according to the present disclosure is an immune therapy agent. The terms "an immunotherapy agent" or "immune-stimulatory agent" in the context of the present disclosure refers to cancer immunotherapy, which attempts to stimulate the immune system to destroy tumours. Immunotherapy is a type of cancer treatment that harnesses the body's immune system to fight cancer cells. There are several types of immunotherapy agents, such as monoclonal antibodies, checkpoint inhibitors, CAR T-cell therapy and oncolytic viruses.

[0141] In some embodiments the anti-cancer agent according to the present disclosure is a monoclonal antibody. Monoclonal antibodies help the immune system to recognize and attack cancer cells more effectively, e.g. nivolumab, pembrolizumab or spartalizumab against programmed cell death protein 1 (PD-1), atezolizumab, durvalumab or avelumab against programmed cell death receptor ligand 1 (PD-L1), trastuzumab (Herceptin) for HER2 -positive breast cancer and rituximab (Rituxan) for certain types of lymphoma.

[0142] In some embodiments the anti-cancer agent according to the present disclosure is a checkpoint inhibitor. Checkpoint inhibitors are drugs that block proteins on immune cells called checkpoints, which cancer cells can use to evade the immune system. By blocking these checkpoints, checkpoint inhibitors can help the immune system recognize and attack cancer cells. Non limiting examples of checkpoint inhibitors used in cancer immunotherapy include pembrolizumab (Keytruda) and nivolumab (Opdivo).

[0143] In some embodiments the anti-cancer agent according to the present disclosure refers to CAR T-cell therapy. CAR T-cell therapy is a type of immunotherapy that involves genetically modifying a patient's T-cells (a type of immune cell) to better recognize and attack cancer cells. CAR T-cell therapy has shown promise in treating certain types of blood cancers, such as leukemia and lymphoma.

[0144] In some embodiments the anti-cancer agent according to the present disclosure is a oncolytic virus. Oncolytic viruses are viruses that have been modified to infect and kill cancer cells, while leaving healthy cells unharmed. Oncolytic viruses can also help stimulate the immune system to attack cancer cells. Non limiting examples of oncolytic viruses used in cancer immunotherapy include talimogene laherparepvec (T-VEC) for melanoma.

[0145] In some embodiments the anti-cancer agent according to the present disclosure is an anti- PDL1 agent. As used herein, an anti-PDLl agent, also known as a programmed death-ligand 1 inhibitor, is a therapeutic compound utilized in the treatment of various cancers. It functions by obstructing the interaction between programmed death-ligand 1 (PDL1) and its receptor, programmed cell death protein 1 (PD1), thereby impeding the suppression of the immune response against cancer cells. This inhibition ultimately amplifies the activity of cytotoxic T lymphocytes and other immune cells, leading to the eradication of tumor cells. Anti-PDLl agents encompass monoclonal antibodies, small molecules, fusion proteins, and other pharmacologically active compounds specifically designed to target the PDL1 / PD1 pathway. Any compounds, compositions, or formulations capable of modulating the PDL1 / PD1 interaction for therapeutic purposes, are encompassed within the scope of the present disclosure.

[0146] In some specific embodiments, an anti-PDLl agent may be a monoclonal antibody. In some further specific embodiments, the anti-PDLl antibody may be any one of Atezolizumab (brand name: Tecentriq), Durvalumab (brand name: Imfinzi) and Avelumab (brand name: Bavencio).

[0147] In some embodiments the anti-cancer agent according to the present disclosure is an anti- PD1 agent. As used herein, an anti-PDl agent, also known as a programmed cell death protein 1 inhibitor, is a therapeutic compound utilized in the treatment of various cancers. These agents bind to PD1 receptors on T cells, thereby blocking the interaction between PD1 and its ligands, including PDL1 and programmed death-ligand 2 (PDL2), which are expressed on tumor cells and antigen-presenting cells. By releasing the inhibition on T cells, anti-PDl agents unleash the immune system ability to recognize and attack cancer cells, offering a broad spectrum of efficacy across various cancer types regardless of PDL1 expression levels. Anti-PDl agents encompass monoclonal antibodies, small molecules, fusion proteins, and other pharmacologically active compounds specifically designed to target the PD1 pathway. Any compounds, compositions, or formulations capable of modulating the PD1 pathway for therapeutic purposes, are encompassed within the scope of the present disclosure.

[0148] In some specific embodiments, an anti-PDl agent may be a monoclonal antibody. In some further specific embodiments, the anti-PDl antibody may be any one of Pembrolizumab (brand name: Keytruda), Nivolumab (brand name: Opdivo), and Cemiplimab (brand name: Libtayo).

[0149] In some embodiments the anti-cancer agent according to the present disclosure is a Bcl2 inhibitor. Bcl-2 inhibitors” are a class of drugs that target the B-cell lymphoma 2 (Bcl-2) protein family. Bcl-2 is a group of proteins that play a key role in regulating apoptosis, or programmed cell death. Overexpression of Bcl-2 proteins can lead to the survival of cancer cells, making them resistant to chemotherapy and radiation therapy. Therefore, Bcl-2 inhibitors are designed to bind to Bcl-2 proteins and prevent them from inhibiting apoptosis, leading to cell death and the inhibition of tumor growth. Bcl-2 inhibitors are being studied as potential treatments for a variety of cancers, including lymphomas, leukemias, and solid tumors.

[0150] In some embodiments, a Bcl2 inhibitor may bind and antagonize any one of the human Bcl-2 pro-survival proteins, Mcl-1, Bcl-w, Bcl2Al and Bcl-B / Bcl2L10 as denoted by accession number: NP_068779.1, AAB09055, NP_004040.1 and NP_001293097.1, respectively. In some other embodiments, the at least one inhibitor of a Bcl2 prosurvival protein is at least one Bcl-2 homology 3 (BH3) mimetic compound. BH3-mimetics are a class of anticancer drug that mimic the actions of BH3-only proteins in that they bind to prosurvival proteins like BCL2 in the same way and inhibit BCL2’s ability to bind BAX or BAK.

[0151] In some specific embodiments, the anti-cancer agent according to the present disclosure may a BH3 mimetic compound. In some embodiments, the BH3 mimetic compound is at least one of 4- { 4- [(4'-Chloro[ 1 , 1 '-biphenyl] -2-yl)methyl]piperazin- 1 -yl } -N-(4- { [(2R)-4-(dimethylamino)- 1 -(phenylsulfanyl)butan-2-yl]ami-no } -3-nitrobenzene- 1 -sulfonyl)benzamide (ABT-737), 4-(4- { [2-(4-Chlorophenyl)-4,4-dimethyl- 1 -cyclohexen- 1 -yl]methyl } - 1 -piperazinyl)-N-({ 3-nitro-4- [(tetrahydro-2H-pyran-4-ylmethyl)-amino]phenyl}sulfonyl)-2-(lH-pyrrolo[2,3-b]-pyridin-5- yloxy)benzamide (venetoclax or ABT-199), 4-(4-{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-l- en- 1 -yl] methyl } piper azin- 1 -yl)-N-(4- { [(2R)-4-(morpholin-4-yl)- 1 -(phe-nylsulfanyl)butan-2- yl]amino}-3-(trifluoromethanesulfonyl)benzene-l-sulfonyl)-benzamide (navitoclax or ABT- 263), 2-(2-((3,5-Dimethyl-lH-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-lH-indole (obatoclax or GX15-070), or 3-[l-(l-adamantylmethyl)-5-methylpyrazol-4-yl]-6-[8-(l,3- benzothiazol-2-ylcarbamoyl)-3,4-dihydro-lH-isoquinolin-2-yl]pyridine-2-carboxylic acid (A- 1331852), or any combinations thereof.

[0152] In some further embodiments, the at least one inhibitor of a Bcl2 prosurvival protein or BH3 mimetic compound is 4-{4-[(4'-Chloro[l,T-biphenyl]-2-yl)methyl]piperazin-l-yl}-N-(4- { [(2R)-4-(dimethylamino)- 1 -(phenylsulf anyl)butan-2-yl] ami-no } -3-nitrobenzene- 1 -sulfonylbenzamide (ABT-737), or any a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof.

[0153] In some specific embodiments, the anti-cancer agent according to the present disclosure is ABT-737. ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. ABT-737 is not bioavailable after oral administration, leading to the development of navitoclax (ABT-263) as an orally-available derivative with similar activity on small cell lung cancer (SCLC) cell lines. The systematic (IUPAC) name of ABT-737 is 4-{4-[(4'-Chloro[l,T-biphenyl]-2- yl)methyl]piperazin- 1 -yl } -N-(4- { [(2R)-4-(dimethylamino)- 1 -(phenylsulfanyl)butan-2-yl] amino} -3-nitrobenzene- 1 -sulf onyl)benzamide (C42H45CIN6O5S2; CAS number: 852808-04-9). The molecular weight of ABT-737 is 813.43 g / mol.

[0154] In some further embodiments, the at least one inhibitor of a Bcl2 prosurvival protein or BH3 mimetic compound is 4-(4-{ [2-(4-Chlorophenyl)-4,4-dimethyl-l -cyclohexen- l-yl]methyl}- l-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-amino]phenyl} sulfonyl)-2-(lH- pyrrolo[2,3-b]-pyridin-5-yloxy)benzamide (ABT-199), or any a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof.

[0155] In some specific embodiments, the anti-cancer agent according to the present disclosure is ABT-199. ABT-199 or venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML). Venetoclax attaches to the Bcl-2 protein which is present in high amounts in CLL cancer cells, where it helps the cells survive for longer in the body and makes them resistant to cancer medicines. By attaching to Bcl-2 and blocking its actions, venetoclax causes the death of cancer cells and thereby slows down progression of the disease. Venetoclax is the first selective BCL2 inhibitor, to be approved for routine clinical practice, specifically in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). The systematic (IUPAC) name of ABT-199 is 4-(4-{ [2-(4-Chlorophenyl)-4,4-dimethyl-l- cyclohexen- 1 -yl]methyl } - 1 -piperazinyl)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)- amino]phenyl}sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (C45H50C1N7O7S; CAS number: 1257044-40-8). The molecular weight of ABT-199 is 868.45 g / mol.

[0156] In some further embodiments, the at least one inhibitor of a Bcl2 prosurvival protein or BH3 mimetic compound is 4-(4-{ [2-(4-Chlorophenyl)-5,5-dimethylcyclohex-l-en-l- yl] methyl } pi pci azin- 1 -yl)-N-(4- { [(2R)-4-(morpholin-4-yl)- 1 -(phe-nylsulfanyl)butan-2- yl]amino}-3-(trifluoromethanesulfonyl)benzene-l-sulfonyl)-benzamide (ABT-263), or any a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof.

[0157] In some specific embodiments, the anti-cancer agent according to the present disclosure is ABT-263. The systematic (IUPAC) name of ABT-263 is 4-(4-{[2-(4-Chlorophenyl)-5,5- dimethylcyclohex- 1 -en- 1 -yl]methyl } pipcrazin- l-yl)-N-(4- { [(2R)-4-(morpholin-4-yl)- 1 -(phe- nylsulfanyl)butan-2-yl] amino } -3-(trifluoromethanesulfonyl)benzene- 1 -sulfonyl)benzamide (C47H55CIF3N5O6S3; CAS number: 923564-51-6). The molecular weight of ABT-263 is 974.61 g / mol.

[0158] In some further embodiments, the at least one inhibitor of a Bcl2 prosurvival protein or BH3 mimetic compound is 2-(2-((3,5-Dimethyl-lH-pyrrol-2-yl)methylene)-3-methoxy-2H- pyrrol-5-yl)-lH-indole (GX15-070), or any a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof.

[0159] In some specific embodiments, the anti-cancer agent according to the present disclosure is GX15-070 or obatoclax. GX15-070 or obatoclax is a drug for the treatment of various types of cancer. Obatoclax is an inhibitor of the Bcl-2 family of proteins. This inhibition induces apoptosis in cancer cells, preventing tumor growth. The systematic (IUPAC) name of GX15-070 is 2-(2- ((3,5-Dimethyl-lH-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-lH-indole (C20H19N3O;

[0160] CAS number: 803712-7-6). The molecular weight of GX15-070 is 317.392 g / mol.

[0161] In some further embodiments, the at least one inhibitor of a Bcl2 prosurvival protein or BH3 mimetic compound is 3-[l-(l-adamantylmethyl)-5-methylpyrazol-4-yl]-6-[8-(l,3- benzothiazol-2-ylcarbamoyl)-3,4-dihydro-lH-isoquinolin-2-yl]pyridine-2-carboxylic acid (A- 1331852), or any a pharmaceutically acceptable salt or hydrate thereof or any stereoisomer or salt thereof.

[0162] In some specific embodiments, the anti-cancer agent according to the present disclosure is A- 1331852. A-1331852 is a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. The systematic (IUPAC) name of A-1331852 is 3-[l-(l-adamantylmethyl)-5-methylpyrazol-4-yl]-6-[8-(l,3-benzothiazol-2- ylcarbamoyl)-3,4-dihydro-lH-isoquino-lin-2-yl]pyridine-2-carboxylic acid (C isH isNeChS; CAS number: 1430844-80-6). The molecular weight of A-1331852 is 658.27 g / mol.

[0163] In some embodiments the anti-cancer agent according to the present disclosure is an antiautophagy agent. The term "anti-autophagy agent" as known in the art refers to a drug that interferes with the process autophagy, namely the regulated, destructive mechanism of the cell that disassembles unnecessary or dysfunctional components. In contrast, anti-autophagy agents are compounds that interfere with or inhibit the process of autophagy, which can have therapeutic implications in certain diseases. Non limiting examples of anti-autophagy agents are chloroquine and hydroxychloroquine, bafilomycin Al, spautin-1, wortmannin, doxorubicin or bleomycin.

[0164] In some embodiments the anti-cancer agent according to the present disclosure is a biological agent. The term "biological agent" in the context of cancer treatment as known in the art (sometimes referred to as "immune therapy") involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body’s immune system to act against cancer cells. Biological therapies that interfere with specific molecules involved in tumour growth and progression are also referred to as targeted therapies.

[0165] In some embodiments the anti-cancer agent according to the present disclosure is an anti- angiogenic agent. The term "anti-angiogenic factor" as known in the art refers to an agent that interferes with angiogenesis, the process of creation of new blood vessels. Anti-angiogenesis agents are types of targeted therapy that use drugs or other substances to stop tumours from making the new blood vessels they need to keep growing. In some embodiments the anti-cancer agent according to the present disclosure is a tyrosine kinase inhibitor. The term "tyrosine kinase inhibitor" as known in the art refers to a drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that tyrosine kinase inhibitors inhibit.

[0166] In some embodiments, the at least one cyclic peptide of the method of the present disclosure does not increase the levels of bilirubin in said subject.

[0167] In some specific embodiments, the at least one cyclic peptide of the method of the present disclosure does not increase the levels of bilirubin in the blood of said subject.

[0168] In some specific embodiments, the cyclic peptide of the method of the present disclosure maintains the levels of bilirubin in said subject. In some specific embodiments, the cyclic peptide of the method of the present disclosure does not alter (or does not modify) the levels of bilirubin in said subject.

[0169] In some specific embodiments, the cyclic peptide of the method of the present disclosure maintains the levels of bilirubin in the blood of said subject.

[0170] In some specific embodiments, the cyclic peptide of the method of the present disclosure does not alter (or does not modify) the levels of bilirubin in the blood of said subject.

[0171] The cyclic peptide comprising for example the amino acid sequence denoted by SEQ ID NO. 1 (or any one of SEQ ID NO: 2-10) or any derivatives thereof defined herein may be administered by any route of administration known to a person skilled in the art, for example intravenously (iv) or any suitable additional route including intraperitoneal, subcutaneous, transcutaneous, topical, intramuscular, intraarticular, subconjunctival, or mucosal, e.g. oral, intranasal, or intraocular administration.

[0172] The cyclic peptide or any derivative thereof as herein defined may be administered at an “effective amount” such that necessary to achieve the desired therapeutic result. The "effective amount" is determined by the severity of the disease in conjunction with the therapeutic objectives, the route of administration and the patient's general condition (age, sex, weight and other considerations known to the attending physician). Amounts effective for this use generally range from 0.001 to 1000 mg / Kg.

[0173] In some embodiments, an effective amount or an effective dose of the cyclic peptide of the invention may refer to a dose of 1 mg / m2to 500 mg / m2. In some specific embodiments, the dose may refer to 10 mg / m2, or 12 mg / m2, or 24 mg / m2or 48 mg / m2or 96 mg / m2or 100 mg / m2or 110 mg / m2or 120 mg / m2or 130 mg / m2or 140 mg / m2or 150 mg / m2or 160 mg / m2or 170 mg / m2or 180 mg / m2 or 190 mg / m2or 192 mg / m2or 194 mg / m2or 196 mg / m2or 198 mg / m2or 200 mg / m2or 300 mg / m2or 400 mg / m2or 500 mg / m2.

[0174] In some embodiments, the effective dose is administered once or twice or three times or four times or five times or six times or seven times or eight times or nine times or ten times a week to the patient or subject in need.

[0175] In some specific embodiments, the effective dose of the cyclic peptide of the present disclosure is 192 mg / m2. In some further embodiments, the effective dose of the cyclic peptide of the present disclosure is 192 mg / m2and is administered three times a week to a patient or subject in need. In some other embodiments, the effective dose of the cyclic peptide of the present disclosure is 192 mg / m2and is administered two times a week to a patient or subject in need. In some other embodiments, the effective dose of the cyclic peptide of the present disclosure is 192 mg / m2and is administered once a week to a patient or subject in need.

[0176] In a yet another aspect, the present disclosure provides a cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of said cyclic peptide.

[0177] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises n PEG moieties, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) wherein n is the number of PEG moieties and is an integer from 1 to 10.

[0178] In some embodiments, n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 2.

[0179] In some embodiments, is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 3.

[0180] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 4.

[0181] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises n Sarcosine residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)), wherein n is the number of Sar residues Sar and is an integer from 1 to 10. In some embodiments, n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 5.

[0182] In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 6.

[0183] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 7.

[0184] In some embodiments, the cyclic peptide for use according to the present disclosure comprises an amino acid as denoted by SED ID NO: 8.

[0185] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises n Glycine (Gly) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe- Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)), wherein n is the number of Gly residues and is an integer from 1 to 10.

[0186] In some embodiments, n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 9.

[0187] In some embodiments, n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 10.

[0188] In some embodiments, the peptide of the present disclosure is directly or indirectly attached or conjugated to at least one therapeutic compound.

[0189] In some embodiments, the at least one cyclic peptide for use according to the present disclosure is as defined in the previous aspects detailed above.

[0190] In some embodiments, the cyclic peptide for use according to the present disclosure comprises administering a composition comprising at least one cyclic peptide as defined in the previous aspects detailed above.

[0191] In some embodiments, said composition is a pharmaceutical composition, optionally wherein said composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0192] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises administering to said subject at least one additional anti-cancer agent.

[0193] In some embodiments, the proliferative disorder is at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS-mutated cancer, mCRC mtKRAS cancer and / or melanoma. Additional proliferative disorders relevant to the cyclic peptide for use according to the present disclosure are defined in the previous aspects above.

[0194] In some embodiments, the cyclic peptide for use according to the present disclosure does not increase the levels of bilirubin in said subject. In some specific embodiments, the cyclic peptide for use according to the present disclosure does not increase the levels of bilirubin in the blood of said subject.

[0195] In some specific embodiments, the cyclic peptide for use according to the present disclosure maintains the levels of bilirubin in said subject. In some specific embodiments, the cyclic peptide of the method of the present disclosure does not alter (or does not modify) the levels of bilirubin in said subject.

[0196] In some specific embodiments, the cyclic peptide for use according to the present disclosure maintains the levels of bilirubin in the blood of said subject.

[0197] In some specific embodiments, the cyclic peptide for use according to the present disclosure does not alter (or does not modify) the levels of bilirubin in the blood of said subject. In a further aspect, the present disclosure provides a combined composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr- Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues, and at least one anti-cancer agent or any pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the combined composition optionally comprises at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0199] In some embodiments, the at least one cyclic peptide of the combined composition of the present disclosure is as defined in the previous aspects detailed above.

[0200] In some embodiments, the at least one anti-cancer agent may be at least one of doxorubicin, taxol, cisplatin, Bcl2 inhibitor, anti PDL1 and / or anti-PDl. Additional relevant anti-cancer agents are as defined in the previous aspects of the present disclosure.

[0201] In some embodiments, the cyclic peptide of the combined composition of the present disclosure is capable of not increasing the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the combined composition of the present disclosure is capable of maintaining the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the combined composition of the present disclosure is capable of not (altering or modifying) the levels of bilirubin upon administration (e.g. to a subject in need).

[0202] In some embodiments, the combined composition of the present disclosure is for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

[0203] In a further aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr- Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues and at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof.

[0204] In some embodiments, the at least one cyclic peptide of the method of the present disclosure is as defined in the previous aspects above.

[0205] In some embodiments, the at least one anti-cancer agent may be at least one of doxorubicin, taxol, cisplatin, Bcl2 inhibitor, anti PDL1 and / or anti-PDl. Additional relevant anti-cancer agents are as defined in the previous aspects of the present disclosure.

[0206] In some embodiments, the at least one cyclic peptide of the method of the present disclosure does not increase the levels of bilirubin in said subject.

[0207] In some specific embodiments, the at least one cyclic peptide of the method of the present disclosure does not increase the levels of bilirubin in the blood of said subject.

[0208] In some specific embodiments, the cyclic peptide of the method of the present disclosure maintains the levels of bilirubin in said subject. In some specific embodiments, the cyclic peptide of the method of the present disclosure does not alter (or does not modify) the levels of bilirubin in said subject.

[0209] In some specific embodiments, the cyclic peptide of the method of the present disclosure maintains the levels of bilirubin in the blood of said subject.

[0210] In some specific embodiments, the cyclic peptide of the method of the present disclosure does not alter (or does not modify) the levels of bilirubin in the blood of said subject.

[0211] In another aspect, the present disclosure provides a kit comprising:

[0212] (a) at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof and at least one anti-cancer agent, or pharmaceutically acceptable salt thereof, wherein the amino acid residues of said peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, optionally, in a first dosage form;

[0213] (b) at least one anti-cancer agent, optionally in a second dosage form.

[0214] In some embodiments, the at least one anti-cancer agent may be at least one of doxorubicin, taxol, cisplatin, Bcl2 inhibitor, anti PDL1 and / or anti-PDl. Additional relevant anti-cancer agents are as defined in the previous aspects of the present disclosure. In some embodiments, the at least one cyclic peptide of the kit of the present disclosure is as defined in the previous aspects above.

[0215] In some embodiments, the cyclic peptide of the kit of the present disclosure is capable of not increasing the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the kit of the present disclosure is capable of maintaining the levels of bilirubin upon administration (e.g. to a subject in need). In some specific embodiments, the cyclic peptide of the kit of the present disclosure is capable of not (altering or modifying) the levels of bilirubin upon administration (e.g. to a subject in need).

[0216] In some embodiments, the kit of the present disclosure is for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof.

[0217] In a further aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject displaying high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr- Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

[0218] In some embodiments, said subject displaying high levels of bilirubin is affected by at least one disease and / or condition associated with high bilirubin levels.

[0219] In another aspect, the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1, wherein the amino acid residues of said peptide are D-amino acid residues, or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

[0220] In some embodiments, said at least one agent is for treating at least one disease or condition associated with high bilirubin levels.

[0221] Bilirubin is a yellowish substance that forms during the normal breakdown of red blood cells in the liver. It is a waste product produced when hemoglobin, the oxygen-carrying molecule in red blood cells, is broken down. Bilirubin is then released into the bloodstream and eventually excreted from the body through bile, a fluid produced by the liver that aids in digestion. In safety tests, bilirubin levels in the blood are often measured as part of liver function tests or a comprehensive metabolic panel. Elevated levels of bilirubin in the blood, a condition known as hyperbilirubinemia, can indicate liver disease, such as hepatitis or cirrhosis, or other conditions that affect the liver's ability to process bilirubin effectively. It can also be a sign of red blood cell disorders or blockage of bile ducts.

[0222] Normal range for bilirubin levels in humans can vary slightly depending on the laboratory and the method used for measurement. However, in general, the normal total bilirubin levels in adults typically range from 0.2 to 1.2 milligrams per deciliter (mg / dL) or 3.4 to 20.5 micromoles per liter (pmol / L).

[0223] Bilirubin levels can be further divided into two main types specifically unconjugated (Indirect) Bilirubin and Conjugated (Direct) Bilirubin. Unconjugated (Indirect) Bilirubin is a form of bilirubin is not water-soluble and is bound to albumin in the bloodstream. Normal levels of unconjugated bilirubin typically range from 0.2 to 0.8 mg / dL. Conjugated (Direct) Bilirubin is a form of bilirubin has been processed by the liver and is water-soluble. Normal levels of conjugated bilirubin are usually less than 0.3 mg / dL.

[0224] In some embodiments, bilirubin levels refer to bilirubin levels in a human subject. In some embodiments, bilirubin levels in a human subject (e.g. in a blood of a human subject) may refer to total bilirubin levels. In some embodiments, high total bilirubin levels (e.g. in a blood of a human subject) may be above 1 mg / dL. In some further embodiments, high bilirubin levels in a human subject (e.g. in a blood of a human subject) may be above 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8 or 10.0 mg / dL. In some specific embodiments, high total bilirubin levels in a human subject (e.g. in a blood of a human subject) may be above 1.2 mg / dL.

[0225] In some embodiments, high total bilirubin levels in a human subject (e.g. in a blood of a human subject) may be above 20 micromoles per liter (pmol / L). In some further embodiments, high total bilirubin levels in a human subject (e.g. in a blood of a human subject) may be above 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 or 180 pmol / L. In some specific embodiments, high total bilirubin levels in a human subject (e.g. in a blood of a human subject) may be above 20.5 pmol / L.

[0226] In some embodiments, bilirubin levels in a human subject (e.g. in a blood of a human subject) may refer to unconjugated (Indirect) Bilirubin. In some embodiments, high unconjugated (Indirect) Bilirubin in a human subject (e.g. in a blood of a human subject) may be above 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0,

[0227] 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,

[0228] 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,

[0229] 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,

[0230] 9.7, 9.8, 9.9 or 10.0 mg / dL. In some specific embodiments, high unconjugated (Indirect) Bilirubin in a human subject (e.g. in a blood of a human subject) may be above 0.8 mg / dL.

[0231] In some other embodiments, bilirubin levels in a human subject (e.g. in a blood of a human subject) may refer to Conjugated (Direct) Bilirubin. In some specific embodiments, high Conjugated (Direct) Bilirubin in a human subject (e.g. in a blood of a human subject) may be above 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,

[0232] 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,

[0233] 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 mg / dL. In some embodiments, high Conjugated (Direct) Bilirubin in a human subject (e.g. in a blood of a human subject) may be above 0.3 mg / dL.

[0234] In some embodiments, said at least one cyclic peptide of the methods of the present disclosure is as defined the previous aspects above.

[0235] In some embodiments, said subject is affected with at least one disease and / or condition associated with high bilirubin levels.

[0236] In some embodiments, said at least one disease and / or condition associated with high bilirubin levels is at least one of an hepatic disease, a blood disease, a bile duct disorder and / or a genetic disorder.

[0237] In some further embodiments, the disease and / or condition associated with high bilirubin levels may be at least one of jaundice, an hepatic disease, hemolytic anemia, a bile duct disorder and / or a genetic disorder.

[0238] In some embodiments, the disease and / or condition associated with high bilirubin levels may be jaundice. Jaundice is a condition characterized by yellowing of the skin and the whites of the eyes due to high levels of bilirubin in the blood. It can occur as a result of various underlying conditions, including liver diseases, such as hepatitis, cirrhosis, or liver cancer, as well as conditions affecting the bile ducts, such as gallstones or bile duct obstruction.

[0239] In some embodiments, the disease and / or condition associated with high bilirubin levels may be an hepatic disease (or liver disease). Various liver diseases can cause impaired bilirubin metabolism and clearance, leading to elevated levels of bilirubin in the blood. In some embodiments, said hepatic disease may be at least one of hepatitis (inflammation of the liver), cirrhosis (scarring of the liver), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and / or liver cancer. In some embodiments, the disease and / or condition associated with high bilirubin levels may be Hemolytic Anemia. In hemolytic anemia, there is an accelerated breakdown of red blood cells, leading to an increase in bilirubin levels. Conditions that can cause hemolytic anemia include autoimmune disorders, such as autoimmune hemolytic anemia, infections, medications, and inherited disorders like sickle cell anemia or thalassemia.

[0240] In some embodiments, the disease and / or condition associated with high bilirubin levels may be a bile duct disorder. Bile duct disorders refers to conditions that obstruct or impair the flow of bile from the liver to the intestines can cause bilirubin levels to rise. This can include bile duct obstruction due to gallstones, tumors, or strictures (narrowing of the bile ducts). In some embodiments, the bile disorder may be at least one of Bile duct obstruction, Primary sclerosing cholangitis (PSC), Biliary atresia, Choledochal cyst(s), Choledochal cyst(s), Bile duct stricture(s).

[0241] In some embodiments, the disease and / or condition associated with high bilirubin levels may be a genetic disorder. In some embodiments, the genetic disorder may be Gilbert's Syndrome. Gilbert's syndrome is a relatively common genetic disorder characterized by mild elevations in bilirubin levels, particularly unconjugated bilirubin. It is usually benign and does not cause any significant health problems, although it can lead to intermittent jaundice.

[0242] In some embodiments, the genetic disorder may be Dubin-Johnson Syndrome. In some embodiments, the genetic disorder may be Rotor Syndrome. Dubin-Johnson Syndrome and Rotor Syndrome are rare genetic disorders that affect bilirubin metabolism and excretion, leading to elevated bilirubin levels in the blood. Dubin-Johnson syndrome is characterized by chronic jaundice and liver pigment accumulation, while Rotor syndrome presents with similar symptoms but without liver pigment accumulation.

[0243] In some embodiments, the genetic disorder may be Crigler-Najjar Syndrome. Crigler- Najjar Syndrome is a hereditary disorder characterized by the absence or deficiency of an enzyme called uridine diphosphate glucuronosyl transferase (UGT). This enzyme plays a crucial role in the liver's ability to process bilirubin, a waste product of red blood cells. In individuals with Crigler-Najjar Syndrome, the lack of functional UGT enzyme leads to the accumulation of unconjugated bilirubin in the blood, resulting in jaundice and potential neurological complications. In some embodiments, said high bilirubin levels are caused by at least one of a medication, an infection and / or a physiological factor.

[0244] In some embodiments, a medication that may cause high bilirubin levels may be at least one of an antibiotic (e.g., erythromycin, rifampin), an antifungal agent (e.g., ketoconazole), an antiviral drug (e.g., indinavir), and / or a chemotherapy drug. In some embodiments, an infection that may cause high bilirubin levels may be at least one of a viral hepatitis (e.g. hepatitis A, B, C or the like), a bacterial infection affecting the liver or bacterial hepatitis (e.g. caused by Salmonella, Leptospira, or brucellosis bacteria) and / or an inflammatory condition (e.g. cholangitis).

[0245] In some embodiments, an physiological factor that may cause high bilirubin levels may be at least one of newborn jaundice, fasting, dehydration and / or intense physical exercise.

[0246] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) is at least one Ursodeoxycholic Acid (UDCA) or ursodiol, Rifampicin, Phenobarbital and / or Cholestyramine.

[0247] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be Ursodeoxycholic Acid (UDCA).Ursodeoxycholic Acid (UDCA) or ursodiol is a bile acid that is naturally produced in the body and is also available as a medication. It is commonly used in the treatment of various liver diseases and conditions, as the one mentioned above.

[0248] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be Rifampicin. Rifampicin is an antibiotic that also has bile acid sequestrant properties. Rifampicin is sometimes used off- label for specific conditions related to elevated bilirubin levels, particularly Crigler-Najjar Syndrome and Gilbert's Syndrome.

[0249] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be Phenobarbital. Phenobarbital is a barbiturate medication that has been used to treat certain liver conditions associated with elevated bilirubin levels, particularly unconjugated hyperbilirubinemia. It works by increasing the activity of hepatic enzymes involved in bilirubin metabolism and excretion. Phenobarbital may be used in conditions such as Gilbert's syndrome or Crigler-Najjar syndrome type II to reduce bilirubin levels and alleviate symptoms of jaundice.

[0250] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be Cholestyramine. Cholestyramine is a bile acid sequestrant that binds bile acids in the intestine, preventing their reabsorption and promoting their excretion in the feces. It is sometimes used in the treatment of certain cholestatic liver diseases, such as primary biliary cholangitis (PBC) or intrahepatic cholestasis of pregnancy (ICP), to improve bile flow and reduce pruritus (itching) associated with elevated bilirubin levels. In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be N-acetylcysteine (NAC). N-acetylcysteine is a medication commonly used as a mucolytic agent and antidote for acetaminophen overdose. It has also been investigated for its potential hepatoprotective effects and its ability to improve liver function in various liver diseases. While not a direct treatment for high bilirubin levels, NAC may help mitigate liver injury and inflammation, which can contribute to elevated bilirubin levels in certain conditions.

[0251] A further aspect of the present disclosure provides a combined composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser- Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues and at least one agent for treating at least one disease and / or condition associated with high bilirubin levels, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0252] In some embodiments, said combined composition is for use in treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject displaying high bilirubin levels.

[0253] Another further aspect of the present disclosure provides a kit comprising:

[0254] (a) at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof and at least one anti-cancer agent, or pharmaceutically acceptable salt thereof, wherein the amino acid residues of said peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, optionally, in a first dosage form;

[0255] (b) at least one agent for treating at least one disease and / or condition associated with high bilirubin levels, optionally in a second dosage form.

[0256] In some embodiments, said kit is for use in treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject displaying high bilirubin levels.

[0257] In some embodiments, said at least one cyclic peptide of the combined composition or kit mentioned herein is as defined in the previous aspects of the present disclosure.

[0258] In some embodiments, said at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) is at least one Ursodeoxycholic Acid (UDCA) or ursodiol, Rifampicin, Phenobarbital and / or Cholestyramine. In some embodiments, said combined composition or kit is for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof.

[0259] A further aspect of the invention relates to a conjugate comprising a peptide comprising an amino acid sequence as denoted by SEQ ID NO: 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues, and doxorubicin, having the formula:

[0260] An additional aspect of the invention relates to a pharmaceutical composition comprising the conjugate and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0261] In some embodiments, said pharmaceutical composition for use in a method of in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

[0262] A further aspect of the present disclosure provides a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of the conjugate.

[0263] In some embodiments, the conjugate for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of said conjugate.

[0264] The term “treatment or prevention” refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, reduction of, alleviation of, and relief from, proliferative disorder symptoms or undesired side effects of such proliferative disorder related disorders. More specifically, treatment or prevention includes 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. As used herein, “disease”, “disorder”, “condition” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms.

[0265] 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 affected by the above- mentioned conditions, and to whom the treatment methods herein described are 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 methods and compositions of the invention are intended for 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 gavage and directly into the digestive tract of subjects 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 selfadministration and administration to the patient by another person.

[0266] It should be noted that all the embodiments recited for one of the aspect of the present disclosure may be applicable to any other suitable aspects of the present disclosure.

[0267] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0268] The term "about" as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. In some embodiments, the term "about" refers to ± 10 %.

[0269] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0270] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0271] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of’ “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0272] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0273] Throughout this specification and the Examples and claims which follow, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Specifically, it should understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures. More specifically, the terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to". The term “consisting of means “including and limited to”. The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0274] It should be noted that various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging / ranges between" a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals there between.

[0275] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0276] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0277] Various embodiments and aspects of the present invention as delineated herein above and as claimed in the claims section below find experimental support in the following examples.

[0278] Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps, and compositions disclosed herein as such methods steps and compositions may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

[0279] The following examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.

[0280] EXAMPLES

[0281] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the claimed invention in any way.

[0282] Materials:

[0283] Clear bottom black 96 well cell culture plates (Greiner 60-65590)

[0284] Cell Culture Media: o 10% FBS (Biological industries, cat# 04-121-1 A) o DMEM (Gibco cat# 41965) o 1 mM sodium pyruvate (Biological Industries) o 100 u / ml penicillin and 100 pg / ml streptomycin (Biological Industries) o 250 ng / ml Amphotericin B (Biological Industries) o 100 pg / ml Normocin (ant-nr-2 Invivogen)

[0285] Cell Treatment Media 1 : Cell Culture media + 5% Mannitol (Filter after Mannitol addition) Cell Treatment Media 2: Cell Culture media without phenol red and with 2% FBS (instead of 10% FBS) + 5% Mannitol (Filter after Mannitol addition)

[0286] Cell media for MTT: Cell culture media without phenol red and without FBS.

[0287] MTT Assay Kit (Cell Proliferation) (ab211091)

[0288] - Cell line: SH-SY5Y (ATCC® CRL-2266™), MDA-MB-231 (ATCC® HTB-26™) For Treatment: o Nerofe stock solution: Diluted at 3mg / ml 5% mannitol in DW o Nerofe derivatives 1-10 stock solutions: diluted in DMSO at a concentration of at least 6mg / ml

[0289] Summary of Treatment regimen:

[0290] Cells were treated either untreated or treated with 25 or 50pg / ml Nerofe or Nerofe derivatives on the 2ndday and the 4thday after seeding. On the 5thday the MTT assay is performed

[0291] Procedure

[0292] 1. The cells were collected by trypsinization and seeded them at 3000 cells / well in a black 96 well plate with clear bottom in lOOpl growing media. All unused wells were always filled with 100 pl media. Blank cells were left, without seeded wells. Incubation was for 24hrs.

[0293] 2. The media was removed. In untreated wells only 100 pl of treatment media 1 was added, in treated wells 100 pl of 25 or 50 pg / ml of Nerofe or Nerofe derivatives 1-10 was added in a total of 100 pl treatment media 1. Incubation was for 48hrs.

[0294] 3. The media was removed. In untreated wells only 100 pl of treatment media 2 was added, in treated wells 100 pl of 25 or 50 pg / ml of Nerofe or Nerofe derivatives 1-10 was added in a total of 100 pl treatment media 2. Incubation was for 24hrs.

[0295] 4. The media was removed. An amount of 50 pl MTT and 50 pl cell media for MTT was added. Incubation was for 3hrs in the incubator.

[0296] 5. Wells were emptied and 150 pl solvent was added. Shaking was for 15min. Reading was performed with a microplate reader at 590OD. Preparation of the dTCApFs peptide or NEROFE™ and its derivatives

[0297] The peptide dTCApFs or NEROFE™ (both terms are used herein interchangeably and refer to the same peptide as indicated above) is a 14 amino acid residues long peptide, in which all of the amino acid residues are at their D configuration, having the amino acid sequence of Trp Trp Thr Phe Phe Leu Pro Ser Thr Leu Trp Glu Arg Lys (or WWTFFLPSTLWERK in a single letter code, as denoted by SEQ ID NO: 1). The derivatives of Nerofe are described in Table 1 below.

[0298] The Nerofe derivatives described in Table 1 below were obtained by covalently binding doxorubicin (Peptide 1), or PEG moieties (Peptides 2, 3 and 4), or Sarcosine residues (Peptides 5, 6 and 7) or Glycine residues (Peptides 9 or 10) to D-Trp (at the N terminal) and to D-Lys (at the C terminal) to close the cycle. An additional Nerofe derivative (Peptide 8) was obtained by cyclization of the Nerofe peptide without any addition.

[0299] EXAMPLE 1

[0300] Preparation of several derivatives of the Nerofe D peptide

[0301] Several derivatives of the D-peptide termed “Nerofe” were prepared and are described in Table 1 below. The Nerofe derivative 1 (Compound ID 1) was obtained by covalently linking the compound doxorubicin to the N-terminal of Nerofe. The Nerofe derivative 2 (Compound ID 2 as denoted by SEQ ID NO: 2) was obtained by adding one polyethylene glycol (PEG) moiety (PEGylation) to the Lysine residue of Nerofe and cyclization. The Nerofe derivative 3 (Compound ID 3 as denoted by SEQ ID NO: 3) was obtained by adding three PEG units to the Lysine residue of Nerofe and cyclization. The Nerofe derivative 4 (Compound ID 4 as denoted by SEQ ID NO: 4) was obtained by adding five PEG units to the Lysine residue of Nerofe and cyclization. The Nerofe derivative 5 (Compound ID 5 as denoted by SEQ ID NO: 5) was obtained by adding one Sarcosine residue to the Lysine residue of Nerofe and cyclization. The Nerofe derivative 6 (Compound ID 6 as denoted by SEQ ID NO: 6) was obtained by adding three Sarcosine residues to the Lysine residue of Nerofe and cyclization. The Nerofe derivative 7 (Compound ID 7 as denoted by SEQ ID NO: 7) was obtained by adding five Sarcosine residues to the Lysine residue of Nerofe and cyclization. The Nerofe derivative peptide 8 (Compound ID 8 as denoted by SEQ ID NO: 8) was obtained by cyclization of Nerofe. The Nerofe derivative peptide 9 as denoted by SEQ ID NO: 9 was obtained by adding three Glycine residues to the Lysine residue of Nerofe and cyclization. The Nerofe derivative peptide 10 as denoted by SEQ ID NO: 10 was obtained by adding five Glycine residues to the Lysine residue of Nerofe and cyclization.

[0302] The cyclization of Nerofe derivatives coupled to PEG residue(s) was performed as follows: Head-to-Tail Lactam Ring Formation was employed. Briefly, CTC resin (Chlorotrityl Chloride) was used for the synthesis and Fmoc (9-fluorenylmethyloxycarbonyl)-PEG(n) was coupled first on resin (c-terminus). The solid phase synthesis was continued. The peptide was then cleaved from the resin using HFIP (hexafluoroisopropanol) / DCM (dichloromethane) and the Head-to-Tail Lactam Ring between PEG(n) and D-Trp was created. Finally, cleavage was performed using strong acid to de-protect the side chain of amino acid.

[0303] Glycol). Sar is for Sarcosine or N-methylglycine.

[0304] EXAMPLE 2

[0305] Effect ofNerofe and its derivatives in inducing cell death of SHSY5Y cells

[0306] The effect of Nerofe and its above described derivatives on percentage of cell viability of SHSY5Y cells (human neuroblastoma cell line) was examined. As shown in Figure 1, while the covalent linking of doxorubicin to Nerofe (Nerofe derivative 1) was not effective on the induction of cell death, the more PEG units in the cyclic peptide were added to Nerofe, the more important was the effect on the induction of cell death (Nerofe derivatives 2, 3 and 4). The addition of Sarcosine residue(s) provides similar effect on the induction of cell death as the original Nerofe peptide.

[0307] EXAMPLE 3

[0308] Effect of Nerofe and its derivatives in inducing cell death of MDA231 cells

[0309] The effect of Nerofe and its above described derivatives on percentage of cell viability of MDA231 cells (epithelial human breast cancer cell line) was examined. As shown in Figure 1, while the covalent linking of doxorubicin to Nerofe (Nerofe derivative 1) was not effective on the induction of cell death, the more PEG units in the cyclic peptide were added to Nerofe, the more important was the effect on the induction of cell death (Nerofe derivatives 2, 3 and 4) and their effect was even greater than the original Nerofe. Similarly, the more Sarcosine (N-methyl-glycine) residues in the cyclic peptide were added to Nerofe, the more important was the effect on the induction of cell death (Nerofe derivatives 5, 6 and 7) while the addition of three and five Sarcosine residues leads to better effect than the original Nerofe peptide.

[0310] EXAMPLE 4

[0311] Effect of Nerofe and its derivatives in inducing cell death of SKBR3 cells

[0312] The effect of Nerofe and its above described derivatives on percentage of cell viability of SKBR3 cells (human breast cancer cell line) was examined. As shown in Figure 1, while the covalent linking of doxorubicin to Nerofe (Nerofe derivative 1) was not effective on the induction of cell death, the addition of one to five PEG units in the cyclic peptide provides a greater effect than the original Nerofe peptide (Nerofe derivatives 2, 3 and 4). Addition of one Sarcosine residue to the cyclic peptide was not effective (Nerofe derivative 5) while the addition of three or five Sarcosine residues provides a greater effect than the original Nerofe peptide (Nerofe derivatives 6 and 7).

[0313] EXAMPLE 5

[0314] Effects of Nerofe and its derivatives on tumor volume of mice injected with CT26 cells

[0315] Balc / C mice (age: 5 weeks; weight: 20 g) were acquired from Harlan Laboratories Ltd. (Israel). Mice were subcutaneously injected with 100,000 CT26 cells (metastatic colorectal cancer, KRAS-mutated; mCRC mtKRAS). Regular Nerofe and the cyclic Nerofe derivative 3 (Compound ID 3 as denoted by SEQ ID NO: 3) treatments commenced after the tumor size reached 50 mm3at its largest dimension (7-10 d after injection). Mice were divided into four different groups of 7 mice: Group 1-untreated group, injected with 5% Mannitol IP once a week; Group 2-treated with regular Nerofe (15 mg / kg, 3 times a week); Group 3-treated with cyclic Nerofe derivative 3 (15 mg / kg, 3 times a week).

[0316] As shown in Figure 2, the fold increase in the tumor volume of the mice was reduced following treatment with Nerofe. However, the fold increase in the tumor volume of the mice was even more reduced following treatment with cyclic Nerofe derivative 3. It therefore appears that cyclic Nerofe derivative 3 seems more efficient that regular Nerofe.

[0317] The effects of the additional Nerofe derivatives described in Table 1 on tumor volume of mice injected with CT26 cells is also evaluated.

[0318] EXAMPLE 6

[0319] Effects of Nerofe and its derivatives on total bilirubin levels of mice

[0320] Total bilirubin (mg / dl) levels in Balb / c mice injected IP 3 times a week with regular Nerofe (lOmg / kg) or cyclic Nerofe derivative 3 (lOmg / kg) was evaluated. Total bilirubin levels (mg / dl) were measured at end of 6 injections after 2 weeks. Control group was injected with 5% mannitol solution. As shown in Table 2 below, it appears that while the bilirubin levels were increased in mice treated with regular Nerofe, in mice treated with cyclic Nerofe derivative 3, the bilirubin levels remain unchanged.

[0321] The total bilirubin (mg / dl) levels in Balb / c mice injected IP 3 times a week with the additional Nerofe derivatives described in Table 1 is also evaluated.

[0322] Table 2: Total bilirubin levels in mice treated with regular Nerofe or Cyclic Nerofe derivative 3.

[0323] EXAMPLE 7

[0324] Effect of a combination of Nerofe and its derivatives with Bcl2 inhibitors in a mouse model

[0325] Balc / C mice (age: 5 weeks; weight: 20 g) are acquired from Harlan Laboratories Ltd. (Israel). Mice are subcutaneously injected with 100,000 CT26 cells (metastatic colorectal cancer, KRAS-mutated; mCRC mtKRAS). Treatment commenced after the tumor size reached 50 mm3at its largest dimension (7-10 d after injection). Mice were divided into the following different groups of mice:

[0326] - Group A - Control

[0327] - Group B - Nerofe (15mg / kg intraperitoneally (IP) 3 times a week

[0328] - Group C - Cyclic Nerofe derivative 3 (15 mg / kg, 3 times a week)

[0329] - Group D - ABT-737 IP 3 times a week

[0330] - Group E - ABT- 199 (venetoclax) IP 3 times a week

[0331] - Group F - ABT-263 (navitoclax) IP 3 times a week IP 3 times a week

[0332] - Group G - GX15-070 (obatoclax) IP 3 times a week IP 3 times a week

[0333] - Group H - A- 1331852 IP 3 times a week IP 3 times a week

[0334] - Group I - Nerofe IP 3 times a week + ABT-737 IP 3 times a week

[0335] - Group J - Nerofe IP 3 times a week + ABT- 199 (venetoclax) IP 3 times a week

[0336] - Group K - Nerofe IP 3 times a week + ABT-263 (navitoclax) IP 3 times a week

[0337] - Group L - Nerofe IP 3 times a week + GX15-070 (obatoclax) IP 3 times a week

[0338] - Group M - Nerofe IP 3 times a week + A- 1331852 (obatoclax) IP 3 times a week.

[0339] - Group N - Cyclic Nerofe derivative 3 IP 3 times a week + ABT-737 IP 3 times a week

[0340] - Group 0 - Cyclic Nerofe derivative 3IP 3 times a week + ABT- 199 (venetoclax) IP 3 times a week

[0341] - Group P - Cyclic Nerofe derivative 3IP 3 times a week + ABT-263 (navitoclax) IP 3 times a week

[0342] - Group Q - Cyclic Nerofe derivative 3IP 3 times a week + GX15-070 (obatoclax) IP 3 times a week

[0343] - Group R - Cyclic Nerofe derivative 3IP 3 times a week + A- 1331852 (obatoclax) IP 3 times a week.

[0344] Weight of mice is measured twice a week and tumor volume is also measured twice a week.

[0345] The effects of the additional Nerofe derivatives detailed in Table 1 in combination with the above described Bcl2 inhibitors on tumor volume of mice injected with CT26 cells is also evaluated. EXAMPLE 8

[0346] Combination of Nerofe and its derivatives with chemotherapeutic agents such as doxorubicin and / or cisplastin

[0347] Balc / C mice (age: 5 weeks; weight: 20 g) are acquired from Harlan Laboratories Ltd. (Israel). Mice are subcutaneously injected with 100,000 CT26 cells (metastatic colorectal cancer, KRAS-mutated; mCRC mtKRAS). Treatment commenced after the tumor size reached 50 mm3at its largest dimension (7-10 d after injection). Mice were divided into the following different groups of mice:

[0348] - Group A - Control

[0349] - Group B - Nerofe (15mg / kg intraperitoneally (IP) 3 times a week

[0350] - Group C - Cyclic Nerofe derivative 3 (15 mg / kg, 3 times a week)

[0351] - Group D - Doxorubicin IP once a week (2 mg / kg)

[0352] - Group E - Cisplastin IP 20mg / kg once a week IP 3 times a week

[0353] - Group F - Nerofe IP 3 times a week + Doxorubicin IP once a week (2 mg / kg)

[0354] - Group G - Nerofe IP 3 times a week + Cisplastin IP 20mg / kg once times a week

[0355] - Group H - Cyclic Nerofe derivative 3 IP 3 times a week + Doxorubicin IP once a week (3 mg / kg)

[0356] - Group I - Cyclic Nerofe derivative 3 IP 3 times a week + Cisplastin IP 20mg / kg once a week

[0357] Weight of mice is measured twice a week and tumor volume is also measured twice a week.

[0358] The effects of the additional Nerofe derivatives detailed in Table 1 in combination with the above described chemotherapeutic agents on tumor volume of mice injected with CT26 cells is also evaluated.

[0359] EXAMPLE 9

[0360] Combination of Nerofe and its derivatives with immune checkpoint inhibitors such as anti- PDL1 and / or anti-PDl monoclonal antibodies

[0361] The effects of Regular Nerofe or the cyclic Nerofe derivatives (as described in Table 1) in combination with an anti-PD-Ll antibody or an anti-PDl antibody are explored in a mice model for antibody melanoma, as detailed below.

[0362] C57B16 mice are inoculated SC with 0.2 million B 16 cells per mouse. When tumors exceed a volume of 50 mm3, mice are divided randomly into several groups, as follows: the “Control” group is treated with 5% mannitol; the “anti PDL1 antibody” group is treated with an anti-PDLl antibody (BXcell); the “anti-PDLl antibody + Nerofe” group is treated with Nerofe and an anti- PDLl antibody; the “anti-PDLl antibody + Cyclic Nerofe derivative 3”; the “anti PD1 antibody” group is treated with an anti-PDl antibody; the “anti-PDl antibody + Nerofe” group is treated with Nerofe and an anti-PDl antibody; the “anti-PDl antibody + Cyclic Nerofe derivative 3”. Nerofe and Cyclic Nerofe derivative 3 are administered three times per week, at 1 mg / kg; the anti- PDLl antibody is administered twice a week, at 20 mg / kg and the anti-PDl antibody is administered once every two weeks, at 1 mg / kg.

[0363] Tumor volume changes in mice are then evaluated.

[0364] The effects of the additional Nerofe derivatives detailed in Table 1 in combination with the above described anti-PDLl and anti-PDl antibodies on tumor volume changes of mice injected with B16 cells is also evaluated.

Claims

CLAIMS:

1. A cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser- Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues.

2. The cyclic peptide of claim 1 , further comprising n polyethylene glycol (PEG) moieties, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg- Lys-n(PEG)) wherein n is the number of PEG moieties and is an integer from 1 to 10.

3. The cyclic peptide of claim 2, wherein n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 2.

4. The cyclic peptide of claim 2, wherein n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 3.

5. The cyclic peptide of claim 2, wherein n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 4.

6. The cyclic peptide of claim 1, further comprising n Sarcosine (Sar) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys- n(Sar)), wherein n is the number of Sar residues and is an integer from 1 to 10.

7. The cyclic peptide of claim 6, wherein n is 1 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 5.

8. The cyclic peptide of claim 6, wherein n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 6.

9. The cyclic peptide of claim 6, wherein n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 7.

10. The cyclic peptide of claim 1, comprising an amino acid as denoted by SED ID NO: 8.

11. The cyclic peptide of claim 1, further comprising n Glycine (Gly) residues, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys- n(Gly)), wherein n is the number of Gly residues and is an integer from 1 to 10.

12. The cyclic peptide of claim 11, wherein n is 3 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 9.

13. The cyclic peptide of claim 11, wherein n is 5 and said cyclic peptide comprises an amino acid sequence as denoted by SEQ ID NO: 10.

14. The cyclic peptide of any one of claims 1 to 13, wherein said peptide is directly or indirectly attached or conjugated to at least one therapeutic compound.

15. A composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 orany functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D-amino acid residues, optionally, said composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

16. The composition of claim 15, wherein said at least one cyclic peptide is as defined by any one of claims 2 to 14.

17. The composition of claim 15 or 16, wherein the composition is a pharmaceutical composition.

18. A pharmaceutical composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, wherein the amino acid residues of said peptide are D-amino acid residues, said pharmaceutical composition further comprises and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

19. The pharmaceutical composition of claim 18, wherein said at least one cyclic peptide is as defined in any one of claim 2 to 14.

20. The pharmaceutical composition of claim 18 or 19, for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

21. A method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues.

22. The method of claim 21, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

23. The method of claim 21 or 22, comprising administering a composition comprising at least one cyclic peptide of any one of claims 2 to 14.

24. The method of any one of claims 21 to 23, further comprising administering to said subject at least one additional anti-cancer agent.

25. The method of any one of claims 21 to 24, wherein said at least one cyclic peptide does not increase the levels of bilirubin in said subject.

26. A cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser- Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or any vehicle, matrix, nano- or micro-particle thereof, or any composition comprising the same, wherein the amino acid residues of said peptide are D-amino acid residues for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of said cyclic peptide.

27. The cyclic peptide for use of claim 26, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

28. The cyclic peptide for use of claim 26 or 27, comprising administering a composition comprising at least one cyclic peptide of any one of claims 2 to 14.

29. The cyclic peptide for use of any one of claims 26 to 28, further comprising administering to said subject at least one additional anti-cancer agent.

30. The cyclic peptide for use of any one of claims 26 to 29, wherein said at least one cyclic peptide does not increase the levels of bilirubin in said subject.

31. A combined composition comprising at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D- amino acid residues, and at least one anti-cancer agent or any pharmaceutically acceptable salt thereof.

32. The combined composition of claim 31, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

33. The combined composition of claim 31 or 32, for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder.

34. A method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, wherein the amino acid residues of said peptide are D-amino acid residues and at least one anti-cancer agent, or a pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof.

35. The method of claim 34, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

36. The method of claim 34 or 35, wherein said at least one cyclic peptide does not increase the levels of bilirubin in said subject.

37. A kit comprising:(a) at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro- Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof and at least one anti-cancer agent, or pharmaceutically acceptable salt thereof, wherein the amino acid residues of said peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, optionally, in a first dosage form;(b) at least one anti-cancer agent, optionally in a second dosage form.

38. The kit of claim 37, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

39. The kit of claim 37 or 38 for use in a method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject in need thereof.

40. A method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject displaying high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

41. A method of treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, the method comprising the step of administering a therapeutically effective amount of at least one cyclic peptide comprising an amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser- Thr-Leu-Trp-Glu-Arg-Lys as denoted by SEQ ID NO. 1 , wherein the amino acid residues of said peptide are D-amino acid residues, or any functional derivative thereof, or pharmaceutically acceptable salt thereof, or any compositions, kits or combinations thereof, to said subject.

42. The method of claim 40 or 41, wherein said at least one cyclic peptide is as defined in any one of claims 2 to 14.

43. The method of any one of claims 40 to 42, wherein said subject is affected with at least one disease and / or condition associated with high bilirubin levels.

44. The method of claim 43, wherein said at least one disease associated with high bilirubin levels is at least one of an hepatic disease, a blood disease, a bile duct disorder and / or a genetic disorder.

45. The method of any one of claims 40 to 44, wherein said high bilirubin levels are caused by at least one of a medication, an infection and / or a physiological factor.

46. The method of any one of claims 40 to 45, wherein said at least one agent for treating high bilirubin levels is at least one Ursodeoxycholic Acid (UDCA) or ursodiol, Rifampicin, Phenobarbital, Cholestyramine and / or N- acetylcysteine (NAC).

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