Thieno[2,3d]pyrimidine compounds for use in the treatment of cancer

Abstract

It relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where R1, R2, and R3 is selected from the group consisting of H and C1-C3, for use as a medicament. These compounds, by inducing apoptosis, are able to treat different types of cancer in mammals, including humans. It also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound (I), together with one or more pharmaceutically acceptable excipients or carriers.

Description

[0001] THIENO[2,3D]PYRIMIDINE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER

[0002] This application claims the benefit of European Patent Application EP23383243 filed on December 1st, 2024.

[0003] Technical Field

[0004] The present invention relates to compounds used to specific thieno[2,3d]pyrimidine, to be use as a medicament. These compounds, by inducing apoptosis, are able to treat different types of cancer in mammals, including humans.

[0005] Background Art

[0006] Cancer remains one of the leading causes of death globally, posing significant challenges in terms of diagnosis, treatment, and management.

[0007] Virtually all cells of higher metazoans harbour a genetic death program called programmed cell death (PCD) that has evolved to eliminate unwanted and potentially dangerous cells. Apoptosis, the most common form of PCD, is characterized by a conserved sequence of morphological, cytological, and biochemical events that mainly converge in the permeabilization of the mitochondrial membrane and the activation of a family of proteases, known as caspases.

[0008] The permeabilization of the mitochondrial membrane is considered the point of no return of the cell death pathway and is modulated by the BCL-2 protein family. The BCL-2 proteins are classified into three groups based on their functions and structures: the pro- apoptotic "executors" (BOK, BAX, and BAK), the anti-apoptotic proteins (BCL2, BCLXL, BCLW, MCL1, A1 and BCL2L10) that keep the effectors in control and inhibit cell death, and the BH3-only proapoptotic “sensor” proteins (NOXA, BAD, BIM, BMF, BID, and PUMA), initiators of cell death that neutralize pro-survival proteins. A complex network of interactions in the cytosol and on the mitochondrial membrane between members of the BCL-2 protein family controls the permeabilization of the mitochondrial outer membrane (MOM) and in consequence, the initiation of apoptosis.

[0009] Apoptosis evasion is recognized as a common mechanism of tumour development and resistance to anticancer treatments and correlates with the appearance of autoimmune diseases. Amplification and protein overexpression of BCL-2 anti-apoptotic proteins is correlated with bad prognosis and poor response to treatments in several types of tumours.

[0010] Activators of the intrinsic pathway of apoptosis have been developed targeting cytosolic domains of the BCL-2 proteins. BCL-2 targeting drugs are currently in clinical trials, including the pan BCL-2 family inhibitor navitoclax (ABT-263). Venetoclax (ABT-199), a selective inhibitor for BCL2 protein has been already approved for treatment of acute myeloid and chronic lymphocytic leukemia. However, appearance of the first resistances to venetoclax treatment caused by the overexpression of other antiapoptotic proteins (such as MCL1) or by mutations in the drug protein binding site have been observed.

[0011] During apoptosis, most interactions between BCL-2 proteins take place within the membranes of intracellular organelles.

[0012] BCL-2 transmembrane interactions participate in the retro translocation of pro-apoptotic members from the mitochondria to the cytosol, in mitochondrial fusion and fission processes, and more relevantly, the interactions of pro- and anti-apoptotic members of the BCL-2 protein family through their TMDs modulate cell death.

[0013] Analyses of somatic copy-number alterations from thousands of cancer specimens have highlighted MCL1 amplification in 10% of tumours. Remarkably, this value reaches 36% for breast cancers and 54% for lung cancers. MCL1 expression is also highly relevant in residual disease that gives rise to metastases appearance and poor patient survival.

[0014] According to Zhai D et al. “Differential Regulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B and Mcl-1 ”, MCL1 interacts with the pro-apoptotic NOXA, BIM, PUMA, and truncated BID BH3-only proteins and the pro-apoptotic effector BAK through the BH3 domain. Strategies specifically targeting the BH3 binding domain of MCL1 (S63845 / S64315; MIK665) have been developed. However, results are being carefully considered due to some cardiotoxicity adverse effects. Drugs targeting cytosolic MCL1 interactions and inducing BAX / BAK dependent cell death have also shown cardiotoxicity problems.

[0015] Apart from these cytosolic interactions, a new interaction site between the TMDs of the antiapoptotic protein MCL1 and the cell death effector BOK has been recently discovered. Targeting TMD MCL1 I BOK hetero-interaction represents an effective strategy to release BOK and induce cell death in tumour cells. Drugs releasing BOK could also be useful to avoid cardiotoxicity due to the low expression of BOK in human heart as disclosed in Ke F et al.”BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice”. Therefore, from what is known in the art, it is derived that there remains a need to find more effective compounds that can be addressed to cancerous cells, without showing cardiotoxicity problems, and that can, therefore, be used to treat cancer.

[0016] Summary of Invention

[0017] Inventors have identified compounds able to disrupt selectively MCL1-BOK transmembrane (TM) interactions to release BOK, and as a result, induce apoptosis in tumour cells, showing a strong potential in the treatment of cancer, such as for example breast cancer, having the additional advantatge that no apparent toxicity is seen.

[0018] Accordingly, a first apect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where: Ri, R2, and R3 is selected from the group consisting of H and C1-C3, for use as a medicament.

[0019] A second aspect of the present invention relates to a compound as defined above, for use in the treatment of cancer in a mammal, including a human.

[0020] A third aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof as defined above, together with one or more pharmaceutically acceptable excipients or carriers.

[0021] Brief Description of Drawings

[0022] Fig. 1 shows the la induces BOK-dependent apoptosis in colon cancer cells. A) Cytotoxic effect of la on HCT 116 cells. Data represent the percentage of viable cells treated with compound for 72 h at the indicated concentrations (10, 25, 35, 50, 60, 75, 85, 100 and 150 pM). Caspase 3 / 7 activity (B) and mitochondrial membrane potential measurement (C) induced by la (50 pM) in HCT 116 cells after 24 h. DMSO refers to control cells treated with vehicle, STS refers to staurosporine (1 pM) positive control. Error bars represent the mean ± SD, of at least n = 4. One-way ANOVA with Dunnett’s multiple post-test comparison displayed ***P < 0.001 and ****P < 0.0001. D) Western blot of HCT 116 WT and BAX- / - and BAK- / - knockout (DKO) to confirm absence of expression of BAX and BAK proteins. Tubulin is used as loading control. E) Comparison of IC50 for each cell line calculated by measuring mitochondrial activity (MTS assay) at 72 h after la treatment. Error bars represent the mean ± SD of n=3. F) Caspase 3 / 7 activity induced by la in HCT 116 WT and DKO cells after 24 h of la (50 pM) treatment. DMSO refers to control cells treated with vehicle. Error bars represent the mean ± SD, of n = 4. Two-way ANOVA with Tukey’s multiple post-test comparison displayed ***P < 0.001. G) Western blot of HCT 116 depleted of BOK by siRNA transfection. Random siRNA (Randsi) was used as a negative control. Tubulin is used as loading control. H) Comparison of IC50 for control (Randsi) and BOK silenced (Boksi) cell line calculated by measuring mitochondrial activity (MTS assay) at 72 h after treatment. Error bars represent the mean ± SD of n=4. A Student's t-test displayed ***P < 0.001. I) Caspase 3 / 7 activity induced by la in HCT116 control and BOK silenced cells after 24 h of la (50 pM) treatment. Error bars represent the mean ± SD, of n = 6. Paired t-test was performed with a ***P < 0.001 result.

[0023] Fig. 2 shows the la induces BOK-dependent cell death in 3D cancer models. A) Representative image of HCT116 derived spheroids treated with vehicle or la (50 pM) and stained with Hoescht (nuclei) and propidium iodide (PI; dead cells). Scale refers to 100 pm. Area (B) and PI positive cells (C) quantification of 20 spheroids treated as previously indicated. D) MTS activity in 20 spheroids derived from HCT116 WT, DKO and HCT TKO. Error bars represent the mean ± SD, n = 4. One-way ANOVA with Dunnett’s multiple posttest comparison displayed **P < 0.01.

[0024] Fig. 3 shows the la induces BOK-dependent apoptosis in 4T1 breast cancer cell line. A) Cytotoxic effect of la in several breast cancer cell lines. Data represent the IC50 of cells treated with the drug for 72 h. B) Western blot of 4T 1 depleted of BOK by siRNA transfection (Boksi). Random siRNA (Randsi) was used as a negative control. Tubulin is used as loading control. C) Caspase 3 / 7 activity induced by la in 4T1 control and BOK silenced cells after 24 h of la (50 pM) treatment. Error bars represent the mean ± SD, of n = 5. Paired t-test was performed with a ***P < 0.001 result. D) Viability comparison of 4T 1 control (Randsi) and BOK silenced (BOKsi) cells treated with la. Cells were stained with crystal violet, resuspended in DMSO and measured absorbance at A 590 nm. Fig. 4 shows the in vivo antitumor efficacy of la in the orthotopic 4T 1 model of breast cancer. A) Scheme of the experimental procedure. B) Changes in tumour volume from 4T1-engrafted mice treated with vehicle control, la at 75 mg / Kg or MIK665 (25 mg / kg). Image represent tumours at the end of the experimental procedure. Graph data are presented as mean ± SD. **p<0.01 versus vehicle, one way ANOVA and Bonferroni’s post-test. C) Activation of apoptosis in treated tumours. Caspase-3 (green) immunostaining of 4T 1 tumour tissues derived from mice treated or not with la or MIK665 as indicated in A. Nuclei were stained with DAPI (blue). Green fluorescence was quantified using the Image J software (right panel). Scale bar 50 pm. D) Immunohistochemical detection of Ki67 in sections of tumors at the experimental endpoint with and without MBolN treatment. Scale bar 50 pm. E) Lung cells were plated in the presence of 6-thioguanine (TG) for analysis of metastasis. Representative pictures of the clonogenic assays with different treatments and quantification of all the plates are shown.

[0025] Fig. 5 shows the toxicity evaluation of 4T1-TNBC mice treated with la. A) Red blood cells, white blood cells and platelet numbers in blood of 4T1-TNBC mice after treatment with vehicle or la drug (75 mg / Kg). B) Detailed characterization of white blood cells in these animals. Graphs for neutrophile, lymphocyte and monocyte content are shown. Almost no detection was observed in basophile and eosynophyle population. C) Liver, heart and muscle damage was evaluated by detecting changes in creatine phosphokinase (CPK), aspartate aminotransferase (AST / GOT), glutamate pyruvate aminotransferase (GPT) and lactate dehydrogenase (LDH) activity. D) Haematoxylin & eosin staining of heart section of animals treated or not with la.

[0026] Fig. 6 shows the differential cardiotoxicity upon la or MIK665 treatment in AC10 cell line. Viability comparison of 4T 1 and AC10 cells treated with la (25 pM) or MIK665 (25pM). Samples were first stained with crystal violet (A) and then quantified (B). (C) Immunoblot to check BOK expression in AC10 cell line.

[0027] Detailed description of the invention

[0028] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply throughout the description and claims.

[0029] As used herein, the indefinite articles “a” and “an” are synonymous with “at least one” or “one or more.” Unless indicated otherwise, definite articles used herein, such as “the,” also include the plural of the noun.

[0030] The term “pharmaceutically acceptable salts” used herein encompasses any salt formed from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. There is no limitation regarding the salts, except that if used for therapeutic purposes, they must be pharmaceutically or cosmetically acceptable.

[0031] The preparation of pharmaceutically acceptable salts of the compounds of formula (I) can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the base form of these compounds with a stoichiometric amount of the appropriate pharmaceutically acceptable acid in water or in an organic solvent or in a mixture of them.

[0032] The expression "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, compositions, or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition, without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0033] As mentioned above, one aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where: Ri, R2, and R3 is selected from the group consisting of H and C1-C3, for use as a medicament.

[0034] In a particular embodiment, the compound for use as defined above, where R1 is methyl, R2 is isopropyl, and R3 is H. In another particular embodiment, the compound for use as defined above, where Ri and R2, are methyl, and Ra is ethyl.

[0035] The compounds of formula (I) according to the invention have resulted to be effective in adrressing to cancerous cells without showing cardiotoxicity and, therefore, it is also part of the invention a compound (I) as defined above, for use in the treatment of cancer in a mammal, including a human.

[0036] This aspect of the invention can also be formulated as a use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment of cancer in a mammal, including a human. This aspect may also be formulated as a method of treatment of a mammal, including a human, suffering from cancer, said method comprising the administration to said mammal of a therapeutically effective amount of a compound of formula (I) or their pharmaceutical acceptable salts as defined above, together with pharmaceutically acceptable excipients or carriers.

[0037] In a particular embodiment, the compounds for use as defined above, are those where the induction of cell death is conducted by disrupting MCL1-BOK transmembrane interaction.

[0038] In another particular embodiment, the compound for use as defined above, is particularly useful for treating a variety of cancers. Specifically, the cancer types that can be treated using the compound include, but are not limited to, colon cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, pancreatic cancer, and metastatic cancer.

[0039] In ar particular embodiment, the compounds for use as defined above, are those where the cancer is selected from the group consisting of colon cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, pancreatic cancer, and metastatic cancer.

[0040] Cancer cells often evade the body's natural defense mechanisms, allowing them to proliferate uncontrollably and form tumors. One of the hallmark features of cancer cells is their ability to avoid apoptosis, the programmed cell death process that normally ensures damaged or unwanted cells are eliminated. By circumventing this process, cancer cells can survive and multiply, leading to tumor growth and progression. Therefore, strategies that can induce apoptosis in these cells are of paramount importance in the fight against cancer. The compounds described above have been found to effectively induce apoptosis in tumor cells. This mechanism of action not only halts the growth of tumors but also can lead to their regression, offering a potential therapeutic avenue for various cancer types.

[0041] Therefore, in a particular embodiment, the compounds for use as defined above, are those where the treatment comprises inducing apoptosis in tumor cells.

[0042] Cancer's ability to spread from its primary site to other parts of the body, known as metastasis, is a defining characteristic that significantly complicates treatment and often worsens prognosis. Metastatic cancer is particularly challenging to treat because it signifies the disease's advanced stage and its spread to multiple organs or tissues. As such, compounds and strategies that can inhibit or prevent the metastatic process are of immense therapeutic value.

[0043] By targeting specific pathways that cancer cells utilize to metastasize, these compounds offer a promising approach to manage and potentially halt the progression of advanced- stage cancers. Thus, in a particular embodiment, the compound for use as defined above, where the treatment comprises inhibiting cancer metastasis. In another particular embodiment, the compound for use as defined above, where the cancer is a metastatic cancer.

[0044] In another particular embodiment, the compounds for use as defined above, are those where the treatment comprises reversing the epithelial-mesenchymal transition, thus decreasing the metastatic capacity of the tumour.

[0045] In another particualr embodiment, the compound for use as defined above, wherein the compound is administered in combination with at least one other chemotherapeutic agent. Examples of chemotherapeutic agents include, doxorubicin, carboplatin, and staurosporin.

[0046] In another particular embodiment, the compound for use as defined above, wherein the compound is administered in combination with radiation therapy.

[0047] In another particular embodiment, the compound for use as defined above, is that where the patient who is administered the compound or pharmaceutical composition underwent at least one round of prior cancer therapy; wherein, optionally, the cancer was resistant or became resistant to prior therapy. In another particular embodiment, the compound for use as defined above, where the compound is administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound (I), together with one or more pharmaceutically acceptable excipients or carriers.

[0048] In another particular embodiment, the compounds for use as defined above, are those where the pharmaceutical composition is selected from an oral and an injectable pharmaceutical composition.

[0049] It is also part of the invention a pharmaceutical composition comprising a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof, wherein:Ri, R2, and R3 is selected from the group consisting of H and C1-C3, together with one or more pharmaceutically acceptable excipients or carriers.

[0050] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.

[0051] Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

[0052] Examples

[0053] In the experiments detailed herein, the compounds as disclosed in the claims and in the description can be procured from multiple commercial sources.

[0054] Bimolecular Fluorescence Complementation (BiFC) assay is a method used to directly visualize protein-protein interaction in vivo using live-cell imaging or fixed cells.

[0055] The MCL1 and BOK TMDs were cloned at the C-terminal end of the N- and C-terminal fragments of the Venus fluorescent protein (VN and VC, respectively), maintaining their natural topology in full-length proteins. Upon interaction the Venus full-lenght reconstitutes and fluorescence can be recorded. Compounds disrupting interaction cause a decrease in the fluorescence signal. HCT116 cells were seeded in six-well plates and co-transfected with 0.5 pg of VN and VC DNA constructs using TurboFect (Thermo Scientific™) according to manufacturer instructions. For Venus fluorescence measurement, cells were harvested and resuspended in 150 pl phosphate-buffered saline (PBS) after 16 h transfection. Fluorescence emission was measured using 96 well black plates and a Wallac 1420 Workstation (Aexc 510 nm and Aem 535 nm). For image acguisition, a Leica SP8 confocal microscope was used.

[0056] Example 1 - Image based BiFC assay with the compounds of the invention to evaluate its targeting MCL1 / BOK TMD interactions

[0057] Drugs targeting hetero-interaction of the MCL1 / BOK TMDs represent an effective strategy to release BOK and induce cell death in tumours avoiding cardiotoxicity. An image based BiFC assay was established in which HCT 116 human colorectal carcinoma cells expressing the MCL1 TMD and BOK TMD, fused to the N- and C-terminal fragments of the Venus fluorescent protein, were used to perform a high throughput screening (HTS) of the MyriaScreen small molecule library (Sigma-Aldrich). Hits were selected according to their ability to decrease fluorescence obtained by the hetero-interaction of the MCL1 / BOK TMDs.

[0058] After a secondary screening to exclude unspecific drug interactions, a set of molecules with a common aromatic core structure able to disrupt MCL1 and BOK TMD hetero-dimer formation were selected (Table 1). The drug la, showed the highest inhibition activity.

[0059] Table 1 List of the compounds sharing a structural core and their BiFC activity in the HTS assay, la showed the highest inhibitory activity on BiFC assay. is in colon and breast cancer cell lines la induces cell death in colon cancer HCT116 cells with an IC50 of 40 pM (Fig. 1A). Interestingly, decrease in cell viability correlates with the increase of caspase activity (Fig. 1 B) and the decrease of mitochondrial membrane potential (Fig. 1 C), confirming apoptosis induction, la also induces cell death (Fig. 1 E) and activates caspase 3 / 7 (Fig. 1 F) in HCT116 BAX / - and BAK- / - Knockout (DKO; Fig. 1D), suggesting that cell death does not require BAX I BAK presence.

[0060] On the contrary, BOK silencing in HCT116 cells (Fig. 1G) resulted in increased resistance to treatment (Fig. 1 H) and no caspase-3 activity was detected (Fig. 11). These data confirm that la induces BAX / BAK-independent and BOK-dependent cell death.

[0061] In addition, la also triggers cell death in colon cancer spheroids (Fig. 2A-C), reducing mitochondrial activity both in WT and BAX- / -, BAK- / - (DKO) but not in BAX- / -, BAK- / -, BOK - / - (TKO) spheres (Fig. 2D). These results confirm that the drug retains on target activity in 3D colon cancer models.

[0062] The activity of la was also evaluated in a panel of human breast cancer cell lines (Fig 3A) and in the mice triple-negative breast cancer 4T 1 cell line, obtaining different drugsensitivities. The behaviour of MBolN179 in breastcancer cell lines reproduces the cell death by BOK-dependent apoptosis, observed for colon cancer (Fig. 3B-D).

[0063] Example 3 - la reduces tumour size and metastasis in a syngeneic 4T 1 orthotopic in vivo TNBC mouse model.

[0064] The 4T1 mice model is a syngeneic orthotopic breast cancer model, mimicking human stage IV metastatic breast cancer. Balb / cByJ female mice (8 weeks) were injected into the mammary pads with 4T 1 cells to induce tumour formation, and after one week of tumour growth, mice were treated with la intraperitoneally with three dosis (75 mg / kg) every 3 days (Fig. 4A). Interestingly, la treatment reduces tumour size at levels comparable to the MCL1 inhibitor MIK6665 and reduces lung metastasis indeed better (Fig. 4B and E). Both drugs produce apoptotic cell death as demonstrated by the immunofluorescent detection of active caspase 3 in tumour sections (Fig. 4C). In addition, immunohistochemical detection of Ki67 indicated high levels of proliferation in vehicle treated in comparison to la treated tumour sections (Fig. 4D).

[0065] In addition, la treatment shows no acute toxicity in mice at 75 mg / kg dose as demonstrated by both hematological parameters and tissue analysis (Fig. 5).

[0066] More interestingly, human cardiomyocyte toxicity induced by MIK665 was not observed in the case of la, probably due to the low expression of BOK in cardiomyocytes (Fig. 6).

[0067] These findings demonstrate that la inhibits the growth of breast tumours and metastasis without causing harmful side effects in mice model. This drug may be a therapeutic option to treat cancer cells that have inhibited apoptosis. Therefore, la is a new chemical entity that deserves further pre- and clinical development in order to explore therapeutic applications.

[0068] Citation List

[0069] Non Patent Literature

[0070] - Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC. “Differential Regulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B and Mcl-1”; Journal of Biological Chemistry. 2008 April; 283(15): pag. 9580-9586.

[0071] - Ke F, Voss A, Kerr JB, O’Reilly LA, Tai L, Echeverry N, et al. “BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice; Cell Death Differ;

[0072] 2012; June 27;19(6): pag. 915-925.

Claims

Claims1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof,wherein:Ri, R2, and R3 is selected from the group consisting of H and C1-C3, for use as a medicament.

2. The compound for use according to claim 1 , wherein R1 is methyl, R2 is isopropyl, and R3is H.

3. The compound for use according to claim 1 , wherein R1 and R2, are methyl, and Rs is ethyl.

4. A compound as defined in any of the claims 1-3, for use in the treatment of cancer in a mammal, including a human.

5. The compound for use according to claim 4, wherein the treatment comprises inducing apoptosis in tumor cells.

6. The compound for use according to claim 5, wherein the induction of cell death is conducted by disrupting MCL1-BOK transmembrane interaction.

7. The compound for use according to any of the claims 1-6, wherein the cancer is selected from the group consisting of colon cancer, breast cancer, glioblastoma, pancreatic caner, and metastatic cancer.

8. The compound for use according to any of the claims 1-7, wherein the treatment comprises inhibiting cancer metastasis.

9. The compound for use according to any of the claims 1-7, wherein the cancer is a metastatic cancer.

10. The compound for use according to any of the claims 1-9, wherein the compound is administered in combination with at least one other chemotherapeutic agent.

11. The compound for use according to any of te claims 1-9 wherein the compound is administered in combination with radiation therapy.

12. The compound for use according to any of the claims 1-11 , wherein the patient who is administered the compound or pharmaceutical composition underwent at least one round of prior cancer therapy; wherein, optionally, the cancer was resistant or became resistant to prior therapy.

13. The compound for use according to any of the claims 1-12, wherein the compound is administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound (I), together with one or more pharmaceutically acceptable excipients or carriers.

14. The compound for use according to claim 13, wherein the pharmaceutical composition is selected from an oral and an injectable pharmaceutical composition15. A pharmaceutical composition comprising a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof,wherein:Ri, R2, and R3 is selected from the group consisting of H and C1-C3, together with one or more pharmaceutically acceptable excipients or carriers.

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