Use of somatostatin agonists in the treatment of SSTR3-expressing tumors

Abstract

The present invention relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof in the treatment of SSTR3-expressing tumors selected from nonfunctioning pituitary adenomas (NFPAs) or other neuroendocrine-related malignancies selected from pancreatic tumors, pheochromocytoma, paraganglioma, lung carcinoid or breast cancer. More specifically, the present invention provides for the use of a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof, and at least one physiologically acceptable excipient, in the treatment of patients suffering from a SSTR3-expressing tumor selected from a non-functioning pituitary adenoma (NFPA) or other neuroendocrine-related malignancy selected from pancreatic tumor, pheochromocytoma, paraganglioma, lung carcinoid or breast cancer.

Description

[Technical field]

[0001] The present invention relates to the use of a compound of formula (I), or a pharma- ceutically acceptable salt and / or solvate thereof, in the treatment of SSTR3-expressing tumours. [Background technology]

[0002] Nonfunctioning pituitary adenomas (NFPAs) are benign anterior pituitary tumors not associated with clinical evidence of hormone hypersecretion. NFPAs are predominantly gonadotrophic pituitary adenomas and account for approximately 35% (14-54%) of all pituitary tumors. The prevalence is 7-41.3 / 100,000 with a standardized incidence of 0.65-2.34 / 100,000. The peak incidence is in the 30s to 70s. 1、2 .

[0003] NFPA is often diagnosed when "mass effect" signs and symptoms occur, such as headaches, visual disturbances, and / or cranial nerve disorders caused by compression and lesions extending into the cavernous sinus and soleus sellae. 3 Additionally, in some cases, the diagnosis is incidental on imaging studies performed for other purposes. Hypopituitarism and hyperprolactinemia may be present due to compression of the normal anterior pituitary gland and a displaced pituitary stalk, respectively.

[0004] Currently, the standard first-line treatment for most NFPAs is endoscopic or microsurgical transsphenoidal and transcranial surgery, with second-line treatments being primarily used for suprasellar tumors. 4 .

[0005] NFPA after surgical treatment often progresses, with regrowth rates ranging from 15% to 66% in patients with NFPA treated with surgery alone and 2% to 28% in patients who have surgery followed by radiation therapy. 5、6 Furthermore, the systematic use of radiation therapy is limited by its side effects.

[0006] Therefore, adjunctive and / or alternative terminoma therapy is a relevant medical need. However, despite their frequency, no standard medical therapy is currently recommended for NFPA or GPA (gonadotropic pituitary adenomas). 7、8 .

[0007] Three oncologic classes of peptides have been tested for the treatment of NFPA: dopamine receptor 2 (DR2) agonists, somatostatin agonists (SSAs) and gonadotropin-releasing hormone (GnRH) analogues. In addition, some centers have introduced the use of temozolomide as treatment for advanced tumors.

[0008] The efficacy of DR2 agonists (cabergoline and bromocriptine) correlates with receptor expression, and some studies have shown efficacy only when the agents are administered immediately after surgery.

[0009] No evidence of efficacy of GnRH analogues has been shown. Furthermore, in some cases, when GnRH agonists were used as treatment for metastatic prostate cancer in patients with gonadotroph adenomas, they increased gonadotropic hormone secretion or induced pituitary apoplexy without altering tumor growth. 9 .

[0010] SSAs such as octreotide and lanreotide, which bind to somatostatin receptor SSTR2 and to a lesser extent SSTR5 and SSTR3, are effective in treating secretory pituitary adenomas. 10~12 However, NFPA has little effect 13 .

[0011] Similarly, pasireotide, a pan-agonist that binds to SSTR1, 2, 3, and 5, showed modest efficacy in a recent Phase II clinical trial (NCT01283542 - Evaluate the Efficacy and Safety of Pasireotide LAR (Long Acting Release) on the Treatment of Patients With Clinically Non-Functioning Pituitary Adenoma - Passion I), with only 16.7% of patients experiencing at least a 20% reduction in tumor size. 8、14 . [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Patent Application WO2009 / 071460A2 (WO2009 / 071460A2) [Non-patent literature]

[0013] [Non-Patent Document 1] NCT01283542 - Evaluate the Efficacy and Safety of Pasireotide LAR (Long Acting Release) on the Treatment of Patients With Clinically Non-Functioning Pituitary Adenoma - Passion I [Non-Patent Document 2] Handbook of Pharmaceutical Excipients, sixth edition(2009) [Non-Patent Document 3] Ntali,G.; Wass, JA Epidemiology, Clinical Presentation and Diagnosis of Non-Functioning Pituitary Adenomas. Pituitary 2018, 21(2), 111–118.

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Summary of the Invention

Problems to be Solved by the Invention

[0014] Therefore, there is a need for new and effective drug therapies that can be used effectively with low side effects in patients suffering from NFPA or other neuroendocrine-related malignancies. [Brief description of the drawings]

[0015] [Figure 1A] Figure 1 shows the structures of ITF2984, pasireotide, and octreotide. The structures of the somatostatin analogs (SSAs) evaluated in this study are shown: (A) ITF2984, (B) pasireotide, and (C) octreotide. [Figure 1B] Figure 1 shows the structures of ITF2984, pasireotide, and octreotide. The structures of the somatostatin analogs (SSAs) evaluated in this study are shown: (A) ITF2984, (B) pasireotide, and (C) octreotide. [Figure 1C] Figure 1 shows the structures of ITF2984, pasireotide, and octreotide. The structures of the somatostatin analogs (SSAs) evaluated in this study are shown: (A) ITF2984, (B) pasireotide, and (C) octreotide. [Diagram 2] Figure 2 shows the best ZDOCK scoring pose of SRIF-14 (blue tube) and the superposition of the "active" conformers of SSTR3 and SSTR2. The EL4 5-loop reduces the channel entrance in SSTR2 (red ribbon) but does not interfere in SSTR3. The top and bottom pictures are front and top views, respectively. Top right: ligand Trp8 side chain pocket (top right side), bottom right: Lys8 in the inner space: ζ nitrogen atom is near the tertiary amine of the k-opioid agonist MP1104. [Diagram 3] Figure 3 shows a detailed best-scoring pose of the Phe-Trp-Lys-Thr motif in SRIF-14, as well as a general sketch summarizing the reference backbone torsions of the I, I', II, and II' β-turns. The measured dihedral angles Φ, Ψ of the Trp-.Lys dyad are in qualitative agreement with the ideal β-turn II' type. [Figure 4]Figure 4 shows the inhibition of GHRH-stimulated GH release in vitro using primary cultures of rat anterior pituitary cells. The graph shows the inhibition of GHRH-stimulated GH release in vitro induced by octreotide, pasireotide and ITF2984 using primary cultures of rat anterior pituitary cells. Results are expressed as the mean ± SD of three experiments. [Diagram 5] Figure 5: Internalization of SSTR3 induced by ITF2984 in HEK293 cells (A, B). HEK293 cells stably expressing wild-type hSSTR3 were treated with 1 μM or 10 μM SST14, octreotide, pasireotide or ITF2984 for 30 min. Cells were then fixed, stained with anti-HA antibody and observed by confocal microscopy. Shown are representative images from at least three independent experiments performed in duplicate. [Figure 6] FIG. 6: Internalization of SSTR3 after treatment with SST28, pasireotide, ITF2984 and octreotide in U2OS cells. FIG. 6 shows internalization of SSTR3 after treatment with SST28, pasireotide, ITF2984 and octreotide (mean internalized fluorescence in Arbitrary Units (AU)). [Figure 7]Figure 7: ITF2984-selective SSTR3 phosphorylation (phosphorylation) in HEK293 transfected cells. (A) Schematic diagram of the human SSTR3 receptor showing all potential phosphate acceptor sites in the carboxyl-terminal tail. Epitopes for phospho-specific antibodies are marked with (-P). (B, C) HEK293 cells stably expressing wild-type hSSTR3 were not exposed or exposed to 10 μM SST14, octreotide, pasireotide or ITF2984 at concentrations ranging from 10-12 to 10-5 M for 10 min at 37 °C (B); exposed to 10 μM SST14, octreotide, ITF2984 or pasireotide at concentrations ranging from 10-12 to 10-5 M (C). The levels of phosphorylated SST3 receptor were then measured using phosphosite-specific anti-pS337 / pT341 or anti-pT348. [Figure 8] Figure 8: Agonist-selective SSTR2 phosphorylation in HEK293 transfected cells. (A) Schematic diagram of the human SSTR2 receptor showing all potential phospho-acceptor sites within the carboxyl-terminal tail. Phospho-specific antibody epitopes are marked with (-P). (B, C) HEK293 cells stably expressing wild-type hSSTR2 were not exposed or exposed to SST14 (=SS14), octreotide, pasireotide, or ITF2984 at concentrations of 10 μM or 1 μM for 10 min at 37 °C. The levels of phosphorylated SSTR2 receptor were then measured using phosphorylation site-specific anti-pS341 / pS343, pT353 / T354, pT356 / T359 antibodies. Blots were then stripped and reprobed with UMB1 antibody to ensure equal gel loading. Pasireotide and ITF2984 induce selective phosphorylation of S341 / S343. In contrast, SST14 and octreotide induce complete phosphorylation of SSTR2. The blots shown are representative of three independent experiments. The positions of molecular weight markers are indicated on the left (units are kDa). [Figure 9]Figure 9: Agonist-selective SSTR5 phosphorylation in HEK293 transfected cells. (A) Schematic diagram of the human SSTR5 receptor showing all potential phospho-acceptor sites in the carboxyl-terminal tail. Epitopes for phosphorylase-specific antibodies are indicated with (-P). (B) HEK293 cells stably expressing wild-type hSSTR5 were not exposed or were exposed to SS14, octreotide, pasireotide, ITF2984 for 10 min at 37 °C. The ability of SST14, octreotide, pasireotide and ITF2984 to induce phosphorylation of SSTR5 was tested by Western blot using a phosphorylation site-specific anti-pT333 antibody. ITF2984 induced partial phosphorylation of SSTR5. Pasireotide was more potent than ITF2984 and octreotide. (C) Blots were subsequently stripped and reprobed with anti-HA antibody to confirm equal gel loading. The blots shown are representative of three independent experiments. The positions of molecular weight markers are indicated on the left (units are kDa). [Figure 10] Figure 10: Agonist-mediated G protein signaling of SSTR3 in HEK293 transfected cells. The ability of SST14, octreotide, pasireotide, and ITF2984 to activate the GIRK2 channel via SSTR3 was tested using a fluorescent membrane potential assay. The concentrations used are indicated. ITF2984 induced a strong G protein signal in SSTR3, approximately 5-fold more potent than octreotide or pasireotide. Data points represent the mean ± SEM. [Figure 11]Figure 11: Analysis of G protein-signalling in mouse AtT-20 cells using a fluorescence-based membrane potential assay. (A) The ability of octreotide to activate endogenous GIRK channels through endogenously expressed SSTR2 and SSTR5 receptors (black) or exogenously expressed human SSTR3 receptor (gray) in wild-type AtT-20 cells was tested. (B) The ability of ITF2984 to activate endogenous GIRK channels through endogenously expressed SSTR2 and SSTR5 receptors (black) or exogenously expressed human SSTR3 receptor (gray) in wild-type AtT-20 cells was tested. Expression of SSTR3 resulted in a leftward shift of the dose-response curve. [Figure 12] Figure 12: Changes in tumor volume in rats treated with ITF2984 or placebo. MENX-affected rats at 5.5 months of age were injected with ITF2984 at the indicated dose (12.5 mg / kg body weight) once every 14 days. MRI was performed every 14 days and tumor volumes were normalized to the volume on day 0. Tumors from male and female rats are shown separately. Data are means ± SEM. # is not significant; * is p-value < 0.05; ** is p-value < 0.001. [Figure 13] Figure 13: Growth of NFPA in rats treated with ITF2984 or placebo. (A, B) The number of Ki67 positive cells per 100.000 μm2 in the tumors of rats was assigned to two groups (ITF2984-treated group, control group) and to males and females. Shown are the mean ± SEM. * indicates p-value < 0.05; ** indicates p-value < 0.001. [Figure 14] Figure 14: Expression of Sstr genes in male and female rats with NFPA treated with ITF2984 or placebo. (A) Absolute quantification of mRNA copy number / cell for SSTR1,2,3,5 genes in both male and female placebo-treated control rats. (B) Relative expression of Sstr1,2,3,5 genes in ITF2984-treated group compared to the control group, arbitrarily set to 100%. Shown as mean ± SEM. * indicates p-value < 0.05. [Figure 15]Figure 15: Cytotoxic effect of increasing concentrations of ITF2984 (20-2560 nM) on NT-3 cell line spheroids treated for 18 days. Pictures were always taken from the same well on days 0, 4, 7, 11, 14 and 18. Day 0 corresponds to the first day of treatment. [Figure 16] Figure 16: Cytotoxic effect of increasing concentrations of octreotide (20-2560 nM) on NT-3 cell line spheroids treated for 18 days. Pictures were always taken from the same well on days 0, 4, 7, 11, 14 and 18. Day 0 corresponds to the first day of treatment. [Figure 17] Figure 17: Cytotoxic effect of increasing concentrations of pasireotide (20-2560 nM) on NT-3 cell line spheroids treated for 18 days. Pictures were always taken from the same well on days 0, 4, 7, 11, 14 and 18. Day 0 corresponds to the first day of treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] definition Unless otherwise defined, all terms, expressions and other scientific terms used herein are intended to have the meaning commonly understood by those skilled in the art to which this disclosure pertains.In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference.Therefore, the inclusion of such definitions herein should not be interpreted as representing substantial differences beyond what is commonly understood in the art.

[0017] As used herein, the term "physiologically acceptable excipient" refers to a substance that does not have any pharmacological effect by itself and does not cause any adverse reaction when administered to a mammal, preferably a human. Physiologically acceptable excipients are well known in the art and are described, for example, in Handbook of Pharmaceutical Excipients, sixth edition (2009), which is incorporated herein by reference.

[0018] As used herein, the term "salts and / or pharma- ceutically acceptable derivatives" refers to salts or derivatives that have the biological effectiveness and properties of the salt or derivative compound and do not produce adverse reactions when administered to a mammal, preferably a human. Pharmaceutically acceptable salts may be inorganic or organic salts, and examples of pharma- ceutically acceptable salts include, but are not limited to, carbonates, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, citrates, maleates, fumarates, trifluoroacetates, 2-naphthalenesulfonates, paratoluenesulfonates, and the like. More detailed information on pharma- ceutically acceptable salts can be found in the Handbook of pharmaceutical salts. 15 (Non-Patent Document 17). Pharmaceutically acceptable derivatives include esters, ethers and N-oxides.

[0019] As used herein, the term "concurrent, separate, or sequential use" refers to simultaneous administration of a first and a second compound, or administration in such a manner that the two compounds act simultaneously in the patient's body, or administration of one compound after the other to produce a therapeutic effect. In some embodiments, the compound is taken with a meal. In other embodiments, the compound is taken after a meal, for example, 30 minutes or 60 minutes after a meal. In some embodiments, the compound is administered to the patient for a period of time, followed by administration of the other compound.

[0020] The terms "comprising," "having," "including," and "containing" should be understood as "open" terms (i.e., meaning "including, but not limited to") and should be considered to support terms such as "consist essentially of," "consisting essentially of," "consist of," or "consisting of."

[0021] The abbreviation "NFPA" in the present invention means "nonfunctioning pituitary adenoma."

[0022] The term "SSA" in the present invention refers to somatostatin analogues.

[0023] The term "PAN-agonist" in the present invention means an agonist of the somatostatin receptors (SSTR1, 2, 3 and 5).

[0024] A "pulmonary carcinoid tumor" is a type of cancerous tumor made up of neuroendocrine cells. These cells are found throughout the body, including the lungs. They are considered endocrine cells because they produce and secrete hormones or hormone-like substances.

[0025] A "pheochromocytoma" is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as brown cells. When a tumor composed of the same cells as a pheochromocytoma occurs outside the adrenal gland, it is called a "paraganglioma." These neuroendocrine tumors have the ability to produce and release large amounts of catecholamines, metanephrines, or methoxytyramine, resulting in the most common symptoms of hypertension (high blood pressure), tachycardia (fast heart rate), and diaphoresis (sweatiness). However, not all of these tumors secrete catecholamines. Those that do not are called biochemically silent and are mainly located in the head and neck.

[0026] Description of the invention As disclosed in detail in the Experimental Section, the inventors have surprisingly found that ITF2984, a novel cyclic SSA pan-agonist hexapeptide with high binding affinity to SSTR3 and improved properties over first generation SSAs, is effective in treating NFPA in the MENX (homozygous mutant) NFPA rat model, which closely resembles its human counterpart. 16、17 .

[0027] During the course of molecular characterization of ITF2984, we found that while structurally similar to other pan-agonists such as pasireotide and octreotide, ITF2984 has a higher affinity for SSTR3 compared to known molecules. Molecular modeling revealed that a higher probability of β-II' turn in ITF2984 correlates with a higher SSTR3 affinity, providing a structural basis for the unique selectivity pattern of this molecule.

[0028] In particular, the obtained in vitro results surprisingly show that ITF2984 induces SSTR3 internalization and phosphorylation more effectively than pasireotide or octreotide in two different cell lines, and further induces GIRK activation in a pharmacologically relevant concentration range. These data suggest that ITF2984 is a full agonist of the SSTR3 receptor and promotes receptor internalization.

[0029] Several studies have shown that SSTR3 is frequently and strongly expressed in gonadotroph adenomas, whereas SSTR2 is expressed only in a minority of patients and SSTR5 only occasionally. 3、8、18、19 .

[0030] Furthermore, recent studies have shown that in addition to pituitary adenomas, pancreatic tumors 20 , pheochromocytoma, paraganglioma 21 , pulmonary carcinoid 22 and breast cancer 23 Increased SSTR3 expression has been suggested in a variety of neuroendocrine-related malignant tumors, such as:

[0031] Nonfunctioning pituitary adenomas (NFPAs) and other neuroendocrine-related malignancies, such as pancreatic tumors 20 , pheochromocytoma, paraganglioma 21 , pulmonary carcinoid 22 and breast cancer 23Neuroendocrine-related malignancies such as are considered SSTR3-expressing tumors.

[0032] Activation of SSTR3 by somatostatin (SST) and SSA induces cytostatic and cytotoxic effects by disrupting mitogenic pathways through activation of protein tyrosine phosphatases and subsequent inactivation of Raf1 and MAPK. Furthermore, engagement of SSTR3 has been proposed to induce apoptosis through activation of p53 and caspases. Targeting SSTR3 also inhibits endothelial cell proliferation and consequently angiogenesis. 10、24~26 .

[0033] Therefore, the development of new SSAs that recognize and activate SSTR3 is based on the following facts: 1) NFPA primarily express SSTR3, which persists even after radiation therapy. 3 ,and, 2) The response of pituitary adenomas to SSAs depends on the expression of specific SSTR subtypes, such as SSTR2 in GH-secreting adenomas. 27 , is a potentially promising strategy for the treatment of NFPA.

[0034] This was confirmed by the results obtained in the in vivo studies reported in the experimental section, which clearly show that ITF2984 effectively inhibits tumor growth in mice and induces a strong reduction in the proliferation of NFPA cells.

[0035] ITF2984 demonstrated selective antitumor activity, consistent with the observed receptor affinity profile and data obtained in vitro.

[0036] This antitumor activity was consistent with a decreased proliferation index (KI67 positive) in ITF2984-treated tumors. Furthermore, ITF2984 selectively induced SSTR3 mRNA expression in female rats, suggesting a compensatory upregulation.

[0037] Thus, the data obtained are consistent with in vivo SSTR3 involvement and primarily SSTR3-driven antitumor activity of ITF2984 in this model and provide in vivo proof of concept for the clinical use of ITF2984 in NFPA and other SSTR3-driven diseases such as SSTR3-expressing tumors (i.e., pancreatic tumors, pheochromocytoma, paraganglioma, lung cancer and breast cancer) and ciliopathies.

[0038] Recently, the activity of pasireotide and octreotide in the MENX model has been reported. 28 , we compared those data with the results of ITF2984 reported here. The published report showed that pasireotide had greater antitumor activity than octreotide, which was evident in both male and female rats, although females tended to show greater activity. This greater activity was due to the involvement of the SSTR3 receptor.

[0039] We note that these data are different from our observations with ITF2984. Indeed, ITF2984 showed a significant radiation tumor response and compensatory upregulation of SSTR3 mRNA only in female rats, whereas no significant antitumor effect was observed in male rats with low SSTR3 levels. We interpret these data in terms of a more selective activity of ITF2984 that is mediated primarily, if not exclusively, by SSTR3 involvement under the experimental conditions tested.

[0040] It has also been observed that treated animals show no signs of discomfort at the end of treatment. The safety of ITF2984 has been confirmed in preclinical safety studies, two Phase I clinical trials in healthy volunteers, and a Phase II clinical trial in patients with acromegaly, demonstrating efficacy at tolerated doses. (39、40) .

[0041] Thus, one embodiment of the present invention relates to the use of a compound of formula (I) in the treatment of SSTR3-expressing tumors:

[0042] [ka]

[0043] or a pharma- ceutically acceptable salt and / or solvate thereof.

[0044] According to a preferred embodiment, said SSTR3-expressing tumor is a non-functioning pituitary adenoma (NFPA) or a neuroendocrine-related malignant tumor selected from pancreatic tumor, pheochromocytoma, paraganglioma, lung carcinoid or breast cancer.

[0045] Preferably, the pharma- ceutically acceptable salts and / or solvates are pamoates, diacetates or trifluoroacetates.

[0046] The IUPAC name of the compound of formula (I) is (3S,6R,9S,12S,15S,19R,20aS)-9-(4-aminobutyl)-15-benzyl-12-(4-(benzyloxy)benzyl)-6-((3,8-dimethoxynaphthalen-2-yl)methyl)-3-(4-hydroxybenzyl)-1,4,7,10,13,16-hexaoxoicosahydropyrrolo[1, 2-a][1,4,7,10,13,16]hexaazacyclooctadecin-19-yl(2-aminoethyl)carbamate or cyclo[4(R)-[N-(2-aminoethyl)carbamoyloxy]-L-prolyl-L-tyrosyl-D-3,8-dimethoxynaphthylalanyl-L-lysyl-(4-O-benzyl)-L-tyrosyl-L-phenylalanyl].

[0047] The compound of formula (I), also referred to herein as ITF2984, has been previously disclosed in International Patent Application WO2009 / 071460A2 (WO2009 / 071460A2).

[0048] According to a preferred embodiment of the invention, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the patient daily.

[0049] Preferably, the patient is a human.

[0050] According to a further preferred embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the patient in an amount ranging from 0.5 to 5 mg / die, preferably from 0.2 to 2.5 mg / die, more preferably from 0.1 to 2 mg / die.

[0051] Preferably, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the patient in an amount of 0.1 mg twice daily, preferably 0.5 mg twice daily, more preferably 5 mg once daily.

[0052] Preferably, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered by oral, sublingual, rectal, intravascular, intravenous or subcutaneous route, preferably by oral route.

[0053] According to a further preferred embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the patient in the form of a pharmaceutical composition containing it together with at least one physiologically acceptable excipient.

[0054] Preferably, the pharmaceutical composition is administered by oral, sublingual, rectal, intravascular, intravenous or subcutaneous route, preferably by intravenous route.

[0055] Preferably, the pharmaceutical composition is in solid or liquid form.

[0056] More preferably, said solid forms are selected from powders, tablets, granules, agglomerates, compressed or coated pills, hard capsules or gelatin capsules; said liquid forms are suspensions, syrups or injectable solutions.

[0057] According to a preferred embodiment of the invention, the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is administered to the patient in combination with at least one active principle.

[0058] Preferably, the at least one active ingredient is selected from a secretagogue of the insulin, a promoter of the insulin secretion, an insulin sensitizer, a low insulin dose agent, an agent having dopamine receptor 2 agonism, an agent having antiangiogenic activity or a chemotherapeutic agent.

[0059] Preferably, said drug with insulin sensitizing activity is metformin, which reduces hepatic gluconeogenesis.

[0060] Preferably, the insulin secretagogue is a sulfonylurea or an incretin-based drug selected from vindagliptin and nataglinide.

[0061] Preferably, the insulin secretion enhancer is a GLP-1 agonist, more preferably, the agent is liraglutide or exenatide.

[0062] Preferably, said agents having dopamine receptor 2 agonism are cabergoline and bromocriptine.

[0063] Preferably, the chemotherapeutic agent is temozolomide.

[0064] According to a further preferred embodiment, the compound of formula (I) or its pharma- ceutically acceptable salts and / or solvates is administered simultaneously, separately or sequentially with at least one active ingredient.

[0065] The invention is described in further detail in the experimental section below. The following examples are not intended to limit the invention. EXAMPLES

[0066] Experimental Section Structure of ITF2984 The novel SST pan-agonist, cyclic hexapeptide ITF2984 (formula reported in Figure 1, panel A), was discovered in a medicinal chemistry program aimed at identifying pan-agonists with improved properties over first-generation SSAs. The compound exhibits high binding affinity for SSTR1, 2, 3 and 5 with respect to other known somatostatin analogues such as pasireotide and octreotide, and has IC in the nanomolar range for all receptors. 50 had a value of IC 50 Values ​​are from one representative experiment. Confidence intervals from three independent experiments (Table 1).

[0067] Compared with octreotide, ITF2984 showed high affinity for SSTR1, SSTR3 and SSTR5 and low affinity for SSTR2, but compared with pasireotide, it showed high affinity for human SSTR1, SSTR2 and SSTR3 (Table 1).

[0068] Table 1 shows the activity profile of ITF2984 compared to pasireotide and octreotide.

[0069] Table 1. Profile of ITF2984, first-generation (octreotide) and second-generation (pasireotide) SSAs emerged in this study. Qualitative description by color code: excellent (very light gray), good / fair (light gray), fair (dark gray), negligible (very dark gray), poor (especially dark gray).

[0070] [Table 1]

[0071] In particular, the IC of ITF2984 against SSTR3 50 were approximately one order of magnitude lower than those obtained with octreotide or pasireotide.

[0072] To rationalize the structural basis of the high affinity of ITF2984 for SSTR3, we used a molecular modeling approach. To this end, we used the GPCRdb, an open access repository of G-coupled protein receptor structures. 28 The SSTR structures of the opioid receptors were used. The models of receptors SSTR1-4 are mainly based on the kappa-opioid receptor (or KOP, sequence similarity 60-66%, pdb codes 6B73 and 6VI4 for active and inactive conformers respectively), whereas SSTR5 is more similar to the delta-opioid receptor. The validity of using opioid receptors to perform this modeling was experimentally confirmed by single dose binding assays of ITF2984 and pasireotide for this particular GPCR family, where both hexapeptides were administered at 10 -5 M can completely replace the agonist (Table 2).

[0073] Table 2:10 -5 Inhibition of several G protein-coupled receptors induced by ITF2984 and pasireotide in M ​​(light grey = 25–50% inhibition; dark grey = >50% inhibition).

[0074] [Table 2-1]

[0075] [Table 2-2]

[0076] [Table 2-3]

[0077] To explain the different behavior of ITF2984 and pasireotide at SSTR2 and SSTR3, we first explored the interaction of somatostatin with the receptor using the SST14 conformer obtained from an NMR study of SST14 in 5% D-mannitol solution (first of 10 conformers, PDB code 2MI1). SST14 docks well to SSTR3, and the pose with the highest ZDOCK score interacts with transmembrane helices TM5, TM6, and TM7, with Phe7 likely located near the extracellular loop (EL4-5) connecting TM4 and TM5. Unfortunately, comparable docking calculations could not be performed for SRIF-14 and SSTR2, due to the presence of a long extracellular loop between TM4 and TM5: this loop conformation obstructs the entrance to the internal space delimited by the transmembrane helices of SSTR2 (Figure 2).

[0078] The binding geometry of SST14 in the SSTR3 model has a series of interesting features: i) Lys9 is fixed to Asp123, and the ζ-nitrogen atom is fixed to the NH4 of the KOP agonist MP1104 when the active form of κ-opioid (PDB code 6B73) is superimposed on the optimal docking pose complex of SSTR3-SST14. + It occupies the same region as the base. ii) Trp8 fits into a hydrophobic pocket bounded by Leu100, Val299, Tyr295 and Phe273 and is buried in a local non-covalent network. iii) The ligand residues Phe7-Trp8-Lys9-Thr10 generate a distorted β-II' turn.

[0079] The distorted β-II' turn found in the most likely SRIF-14-bound conformer suggests that peptide agonists exhibiting high stability of such secondary structure motifs may be preferred. NMR studies of pasireotide and L-363, 301 29indicates a high flexibility of this conformer compared to other cyclic hexapeptides, and this greater degree of freedom is believed to be the reason for pasireotide's ability to better fit all receptor binding sites.

[0080] A similar experiment with ITF2984 (Figure 3) shows a higher probability of β-II'-turn for ITF2984 compared to pasireotide, due to the higher number of molecular dynamics snapshots detected by trajectory analysis (30% instead of 12%). The β-II'-turn probability of compound ITF2842 is even higher (58%). Comparing the binding results for SSTR1-3 and SSTR5 for all three molecules (Table 3), we can see a correlation between β-turn stability and potency (and selectivity) versus SSTR3. The higher the β-turn stability, the higher the selectivity for SSTR3.

[0081] The inventors conclude that there is a plausible structural hypothesis that explains the increased affinity of ITF2984 for SSTR3.

[0082] [Table 3]

[0083] We further characterized the biological activity of ITF2984: this molecule potently inhibited GH release from primary rat anterior pituitary cell cultures, but was not statistically different from pasireotide (Figure 4). ITF2984 further inhibited pentobarbital-induced GH release in rats and reduced IGF1 levels in rats and dogs.

[0084] To clarify the mechanistic differences between ITF2984 and other SSTR agonists, we investigated the internalization of SSTRs using two different experimental models: HEK293 cells transfected with human SSTRs and U2OS cells transfected with human GFP-tagged receptors (SSTR2-tGFP, SSTR3-tGFP, SSTR5-tGFP). SST14 and SST28 were included as reference compounds in the first and second experiments, respectively.

[0085] In transfected HEK293 cells, ITF2984 induced a strong internalization of SSTR3 that was similar to that induced by SST14 and significantly higher than that induced by octreotide or pasireotide (Figures 5A, 5B). In contrast, only partial internalization of SSTR2 and SSTR5 was observed.

[0086] In U2OS cells, all compounds increased internalization of SSTR2-tGFP in a dose-dependent manner compared to untreated controls, with octreotide being the most potent internalization inducer, followed by pasireotide and ITF2984. In cells transfected with SSTR5-tGFP, the increase in receptor internalization by treatment with SSA was similar to that of SST, although the effect of SST was less (approximately 50% of that of SST28) (Table 4, Figure 6).

[0087] [Table 4]

[0088] Finally, in cells transfected with SSTR3-tGFP, ITF2984 was the most potent inducer of receptor internalization, showing an increase comparable to that of SST28 at 1 μM, whereas octreotide and pasireotide were significantly less effective at the same concentration.

[0089] We conclude that ITF2984 induces internalization of SSTR3 more effectively than pasireotide or octreotide in two different cell lines.

[0090] Assessment of SSA-induced activation of human SSTR2, SSTR3, and SSTR5 receptors using phosphorylation site-specific antibodies Next, SSA-induced activation of human SSTRs was examined by Western blot using phosphosite-specific antibodies against the following residues: for SSTR2: S341 / pS343, T353 / T354, T356 / T359; for SSTR3: S337 / T341, T358; for SSTR5: T333. 30 SSTR3 induced full phosphorylation in a dose-dependent manner and in the pharmacologically relevant nanomolar dose range (Fig. 7B,C), whereas pasireotide induced only a weak effect in the pharmacologically relevant micromolar dose range. In SSTR2, both cyclohexapeptides induced selective phosphorylation of S341 / S343, whereas SST14 and octreotide led to full phosphorylation of SSTR2 at all sites investigated (Fig. 8B,C). Finally, the pT333 phosphorylation site of SSTR5 was only partially affected by all tested compounds, with pasireotide showing the most pronounced effect (Fig. 9B,C).

[0091] Agonist-mediated G protein signaling of SSTR3 in HEK293 and AtT20 SSTR3-transfected cells.

[0092] Somatostatin receptor signaling is known to activate G protein-coupled inwardly rectifying potassium (GIRK) channels. 30 .

[0093] Therefore, we studied G protein signaling mediated by SSTR agonists using a GIRK-based fluorescent membrane potential assay in both hSSTR3-transfected HEK293 cells and AtT20 wild-type, as well as hSSTR3-transfected cells.

[0094] When HEK293 cells stably expressing human SSTR3 receptor were stimulated with SST14, octreotide, pasireotide and ITF2984, the fluorescent signal of FMP dye was dose-dependently decreased, with ITF2984 being more potent than octreotide or pasireotide (Figure 10). To better characterize ITF2984, activation of GIRK channels was also applied to SSTR2 and SSTR5. In HEK293-GIRK2-GFP-HA-hSST2, the most potent agonist was octreotide, followed by pasireotide and ITF2984, whereas in HEK293-GIRK2-GFP-HA-hSST5, the highest activation was induced by pasireotide. The results of agonist-mediated G protein signaling of SSTR2, SSTR3 and SSTR5 in HEK293 cells are summarized in Table 5.

[0095] Results are expressed as the mean ± SEM calculated from duplicate determinations from three independent experiments.

[0096] [Table 5]

[0097] Furthermore, G protein signaling mediated by octreotide and ITF2984 was analyzed in mouse cortical tumor AtT-20 cells that endogenously express GIRK1 / 2 channels and SSTR2 and SSTR5 receptors. Exogenous expression of the SSTR3 receptor led to a leftward shift in the dose-response curve mediated by ITF2984, but not by octreotide under these conditions. These data are consistent with those obtained in a hSSTR3-transfected HEK293 cell line.

[0098] Efficacy of ITF2984 against endogenous NFPA in vivo Encouraged by the results of the in vitro studies, we decided to study the in vitro antitumor activity of ITF2984 in the MENX (homozygous mutant) rat model, the only spontaneous endogenous model in which NFPA develops with full penetrance, closely resembling human NFPA. 16、17 NFPAs developing in this model also recapitulated the SSTR expression pattern of their human counterparts, displaying high SSTR3 expression. Interestingly, SSTR3 levels in MEX rat pituitary tumors were sex specific, with higher expression observed in females; this pattern may extend to human NFPAs. Rats of both sexes were treated with ITF2984 or placebo for 56 days, and tumor growth was monitored longitudinally using high-resolution MRI.

[0099] A rapid increase in relative tumor volume was observed in male rats treated with ITF2984 and in members of the control group (Figure 12), with logarithmic values ​​best fitted to a linear mixed-effects model (LME) with a quadratic time effect. In contrast, female rats treated with ITF2984 showed only a slight increase in tumor volume during treatment, instead showing linear growth. The difference in time slope between male and female rats treated with ITF2984 was significant (p-value = 0.0251). This indicates that female mutant rats responded significantly better to ITF2984 compared to males. Unexpectedly, although two female rats already had relatively large tumors at the start of the study, ITF2984 continued to suppress tumor growth, and these two showed no signs of discomfort at the end of treatment. When both sexes were combined, the overall reduction in tumor growth in rats treated with ITF2984 (used as a proxy for drug response) was modest relative to the reduction in tumor growth in control rats, as assessed by best-fit LME. However, when sexes were analyzed separately, drug-treated female rats showed suppression of tumor growth compared with placebo-treated female rats, indicating that the former group responded to ITF2984.

[0100] Effect of ITF2984 on the growth rate of NFPA At the end of treatment, pituitary tissue was harvested for ex vivo analysis. Ki67 staining was performed on all tumors from placebo- or ITF2984-treated rats at 100.000 μm 2 The number of Ki67 positive cells per area was counted. Placebo-treated (control) NFPAs showed, on average, 375 (males) and 312 (females) Ki67 positive cells per area, as reported (Figure 13). Not surprisingly, in the control group, there was a positive trend between Ki67 positive cell count and absolute tumor volume in males and females. In tumors from rats treated with ITF2984, the number of Ki-67 positive cells was reduced, on average, to 250 (-33.5%) in male rats and 134 (-57%) in female rats (Figure 13). The difference in Ki67 positive cell count between placebo and ITF2984-treated female rats was significant (p=0.031). Changes in tumor cell proliferation correlated with changes in tumor volume determined by MRI: ITF2984 inhibited tumor growth more effectively in females than in males, and this was accompanied by a stronger reduction in NFPA cell proliferation in the former.

[0101] Expression of SSTRs in rat NFPA The expression levels of the various Sstr genes were assessed in rat tumors at the end of treatment by measuring the copy number (absolute quantification) of each transcript by quantitative RT-PCR. Tumors from the two animal groups were also stained by immunohistochemistry (IHC) with antibodies against SSTR1, 2, 3 and 5, and the results were confirmed by high expression of SSTR3 in female rats. 31 Administration of ITF2984 downregulated the expression of SSTR5 and increased the mRNA of SSTR3 in both males and females (Figure 14). This high expression of SSTR3 in female rats explains the greater effect of ITF2984 in females.

[0102] In human females, SSTR3 expression has not been shown to be statistically significantly higher.

[0103] Activity of ITF2984 in T-3 cell line spheroids compared with octreotide and pasireotide Methods – Generation and processing of NT-3 cell line spheroids NT-3 well-differentiated pancreatic neuroendocrine (PanNET) cell line (32) is an in vitro model of pancreatic tumors.

[0104] The cells were cultured in RPMI1640 medium GlutaMAX™ containing 10% FBS, 1% penicillin / streptomycin, 20 ng / ml EGF (AF-100-15, Peprotech), and 10 ng / ml FGF (100-18B, Peprotech).

[0105] 3D spheroids were generated by seeding 2000 cells / well in 96-well ULA plates (Corning). Four replicates were seeded for each condition.

[0106] Spheroid formation was allowed for 4 days before treatment began.

[0107] Stock solutions of ITF2984, pasireotide, and octreotide were prepared in 100% DMSO, and working solutions of 2560, 1280, 640, 320, 160, 80, 40, and 20 nM were prepared in complete growth medium containing 0.5% DMSO.

[0108] 50% of the medium (to avoid removal of spheroids) was replaced with fresh medium containing twice the desired drug concentration, and treatments were repeated every 3 days.

[0109] Spheroid morphology was monitored daily during treatment and photographed at days 0, 4, 7, 11, 14, and 18. Day 0 corresponds to the first day of treatment. Photographs were taken from the same wells at each time point.

[0110] Results - Cytotoxic activity of ITF2984 on NT-3 spheroids The recently developed NT-3 cell line is a well-differentiated PanNET that expresses high levels of SSTRs, especially SSTR3 (32) .

[0111] ITF2984 was tested in parallel with octreotide and pasireotide in a dose-response manner for cytotoxic activity on NT-3 spheroids. Spheroid growth / survival was followed for 18 days.

[0112] As shown in Figure 15, ITF2984 reduced the volume of spheroids, starting from day 7 at concentrations ≥ 640 nM. At 2.56 μM, spheroids were completely destroyed. The same phenomenon was less evident for octreotide and pasireotide treated spheroids, which still maintained their morphology even at the highest concentrations (Figures 16 and 17).

[0113] Therefore, considering that the cytotoxic activity observed in NT-3 spheroids corresponds to antitumor activity, the results may indicate that ITF2984 can be used as a more effective drug for the treatment of pancreatic cancer.

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Claims

1. 1. A compound of formula (I) for use in the treatment of SSTR3-expressing tumors: 【Chemistry 1】 or a pharmaceutically acceptable salt and / or solvate thereof.

2. 10. The compound of claim 1 or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of non-functioning pituitary adenomas, and neuroendocrine-related malignancies selected from pancreatic tumors, pheochromocytoma, paraganglioma, lung carcinoid, or breast cancer.

3. 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1, characterized in that it is administered to a patient daily.

4. 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1, characterized in that it is administered to humans.

5. 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1, characterized in that it is administered to a patient in an amount ranging from 0.5 to 5 mg / die, preferably from 0.2 to 2.5 mg / die, more preferably from 0.1 to 2 mg / die.

6. 2. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1, characterized in that it is administered to a patient in the form of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 together with at least one physiologically acceptable excipient.

7. 7. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 6, characterized in that the pharmaceutical composition is administered by oral, sublingual, rectal, intravascular, intravenous, subcutaneous route, preferably by intravenous route.

8. 7. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 6, characterized in that the pharmaceutical composition is in solid or liquid form.

9. 9. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 8, characterized in that the solid form is selected from powders, tablets, granules, agglomerates, compressed or coated pills, hard capsules or gelatin capsules.

10. 9. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 8, characterized in that said liquid form is a suspension, a syrup or an injectable liquid.

11. 2. A compound for use according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, characterized in that it is administered to a patient in combination with at least one active ingredient.

12. 12. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 11, characterized in that the at least one active ingredient is selected from the group consisting of insulin secretagogues, promoters of insulin secretion, insulin sensitizers, low insulin dosage agents, drugs with dopamine receptor 2 agonism, drugs with anti-angiogenic activity or chemotherapeutic agents.

13. 13. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 12, wherein the drug having insulin sensitizing activity is metformin, the insulin secretagogue is a sulfonylurea or an incretin-based drug selected from vindagliptin and nataglinide, the drug that promotes insulin secretion is a GLP-1 agonist, preferably said drug is liraglutide or exenatide, the drug having dopamine receptor 2 agonism is cabergoline or bromocriptine, and the chemotherapeutic agent is temozolomide.

14. 12. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 11, characterized in that it is administered simultaneously, separately or sequentially with at least one active ingredient.

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