Thieno[2,3-d]pyrimidines for the treatment of cancer

Abstract

This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are selected from the group consisting of H and C1-C3, and is used as a drug. These compounds are capable of treating different types of cancer in mammals, including humans, by inducing apoptosis. The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) and one or more pharmaceutically acceptable excipients or carriers. (I)

Description

[0001] This application claims priority to European patent application EP23383243, filed on December 1, 2024. Technical Field

[0002] This invention relates to specific thiophene[2,3d]pyrimidine compounds used as pharmaceuticals. These compounds are able to treat different types of cancer in mammals, including humans, by inducing apoptosis. Background Technology

[0003] Cancer remains one of the leading causes of death worldwide, posing significant challenges in its diagnosis, treatment, and management.

[0004] In fact, all cells in higher metazoans possess a genetic death program called programmed cell death (PCD), which has evolved to eliminate unwanted and potentially dangerous cells. Apoptosis is the most common form of PCD, characterized by a conserved sequence of morphological, cytological, and biochemical events, primarily focused on the permeability of the mitochondrial membrane and the activation of a family of proteases called caspases.

[0005] Mitochondrial membrane permeability is considered an irreversible node in the cell death pathway, regulated by the Bcl-2 protein family. Based on their function and structure, BCL-2 proteins are divided into three classes: pro-apoptotic "executive proteins" (BOK, BAX, and BAK); anti-apoptotic proteins responsible for regulating effector molecules and inhibiting cell death (BCL2, BCLX1, BCLW, MCL1, A1, and BCL2L10); and pro-apoptotic "sensor" proteins containing only the BH3 domain (NOXA, BAD, BIM, BMF, BID, and PUMA). These are initiators of cell death and can neutralize pro-survival proteins. A complex network of interactions between BCL-2 protein family members on the cytoplasm and outer mitochondrial membrane regulates the permeability of the outer mitochondrial membrane (MOM), thereby initiating the apoptosis process.

[0006] Apoptosis escape is considered a common mechanism in tumor development and resistance to anticancer therapies, and is associated with the occurrence of autoimmune diseases. Amplification and overexpression of BCL-2 anti-apoptotic proteins are closely related to poor prognosis and treatment response in various types of tumors.

[0007] Endogenous apoptosis pathway activators targeting the cytoplasmic domain of the BCL-2 protein have been developed. Drugs targeting BCL-2 are currently in clinical trials, including the pan-BCL-2 family inhibitor navitoclax (ABT-263). The selective BCL2 protein inhibitor venetoclax (ABT-199) has been approved for the treatment of acute myeloid leukemia and chronic lymphocytic leukemia. However, first-time resistance to venetoclax treatment has been observed due to overexpression of other anti-apoptotic proteins (such as MCL1) or mutations in the drug's protein binding site.

[0008] During apoptosis, the interactions between members of the BCL-2 protein family mostly occur on intracellular membrane structures such as mitochondria.

[0009] The transmembrane interactions of BCL-2 proteins are involved in the retrograde transport of pro-apoptotic proteins (a total of 15 members) from mitochondria to the cytoplasm, as well as mitochondrial fusion and division. More importantly, the pro-apoptotic and anti-apoptotic members of the BCL-2 protein family jointly regulate cell death through the interaction of their transmembrane domains (TMDs).

[0010] Somatic copy number variation analysis of thousands of cancer samples revealed MCL1 amplification in 10% of tumors. Notably, this proportion reached 36% in breast cancer and 54% in lung cancer. Furthermore, MCL1 expression is highly associated with residual lesions leading to metastasis and poor patient survival.

[0011] 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 pro-apoptotic proteins NOXA, BIM, PUMA, truncated BID (proteins containing only the BH3 domain), and the pro-apoptotic effector protein BAK through its BH3 domain. Specific strategies targeting the BH3 binding domain of MCL1 have been developed (S63845 / S64315; MIK665). However, these results are under careful evaluation due to observed cardiotoxicity. Drugs targeting cytoplasmic MCL1 interactions and inducing BAX / BAK-dependent cell death have also shown cardiotoxicity issues.

[0012] In addition to these cytoplasmic interactions, a novel interaction site has recently been discovered between the anti-apoptotic protein MCL1 and the transmembrane domains (TMDs) of the cell death effector protein BOK. Targeting the heterologous interaction of the MCL1 / BOK transmembrane domains represents an effective strategy for releasing BOK and inducing tumor cell death. According to the paper "BCL-2 family member BOK is widely expressed but its loss has only minimal impact in the heart" published by Ke F et al., BOK is expressed at low levels in the human heart; therefore, drugs that release BOK may also help avoid cardiotoxicity.

[0013] Therefore, based on existing knowledge in the field, there is still a need to develop more effective compounds that can target cancer cells without causing cardiotoxicity problems, and thus be used to treat cancer. Summary of the Invention

[0014] The inventors have identified compounds that can selectively disrupt the MCL1-BOK transmembrane (TM) interaction to release BOK, thereby inducing tumor cell apoptosis. These compounds show great potential in treating cancers such as breast cancer, with the added advantage of no apparent toxicity.

[0015] Therefore, a first aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are selected from the group consisting of H and C1-C3, and is used as a drug.

[0016]

[0017] (I) A second aspect of the invention relates to compounds as defined above for the treatment of cancers in mammals, including humans.

[0018] A third aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers. Attached Figure Description

[0019] Figure 1The study showed that LA induced BOK-dependent apoptosis in colon cancer cells. (A) Cytotoxic effects of LA on HCT116 cells. Data represent the percentage of viable cells after 72 hours of treatment with the compound at specified concentrations (10, 25, 35, 50, 60, 75, 85, 100, and 150 μM). Caspase 3 / 7 activity (B) and mitochondrial membrane potential assays (C) induced after 24 hours of LA (50 µM) treatment in HCT116 cells. DMSO refers to control cells treated with the solvent, and STS refers to the astrocytocin (1 µM) positive control. Error bars represent the mean ± SD for at least n=4. One-way ANOVA using Dunnett's multiple comparison test showed ***P < 0.001 and ****P < 0.0001. (D) Western blot analysis of wild-type (WT) HCT116 cells and BAX- / - and BAK- / - double knockout (DKO) cells, confirming the absence of BAX and BAK protein expression. Tubulin was used as a loading control. (E) The half-maximal inhibitory concentration (IC50) of each cell line was calculated and compared by measuring mitochondrial activity 72 hours after la treatment (MTS method). Error bars represent the mean ± SD for n=3. (F) Caspase 3 / 7 activity induced after 24 hours of la (50 µM) treatment of HCT116 wild-type (WT) and double knockout (DKO) cells. DMSO refers to control cells treated with solvent. Error bars represent the mean ± SD for n=4. Two-way ANOVA using Tukey's multiple comparison test showed ***P < 0.001. (G) Western blot experiment of knocking down BOK expression in HCT116 cells using siRNA transfection technology. Random siRNA (Randsi) was used as a negative control. Tubulin was used as a loading control. (H) The IC50 of the control (Randsi) and BOK silencing (Boksi) cell lines was calculated and compared by measuring mitochondrial activity 72 hours after treatment (MTS method). Error bars represent the mean ± SD for n=4. Student's t-test showed *P<0.001. (I) Caspase 3 / 7 activity induced after 24 hours of treatment of HCT116 control and BOK-silenced cells with LA (50 µM). Error bars represent the mean ± SD for n=6. Paired t-test results showed *P<0.001.

[0020] Figure 2The study shows that la induces BOK-dependent cell death in a 3D cancer model. (A) Representative images of HCT116-derived tumor spheroids treated with solvent control or la (50 μM) and stained with Hoescht (nuclei) and propidium iodide (PI; dead cell staining). Scale bar: 100 µm. Quantitative analysis of region area (B) and PI-positive cells (C) of 20 spheroids treated as described above. (D) MTS activity in 20 spheroids derived from HCT116WT, DKO, and HCT TKO. Error bars represent mean ± SD, n = 4. One-way ANOVA using Dunnett's multiple comparison test showed ** P < 0.01.

[0021] Figure 3 The study shows that *la* induces BOK-dependent apoptosis in the 4T1 breast cancer cell line. (A) Cytotoxicity of *la* in various breast cancer cell lines. Data represent the half-maximal inhibitory concentration (IC50) of cells after 72 hours of drug treatment. (B) Immunoblotting results of 4T1 (Boksi) protein with BOK gene knockdown transfected with siRNA. Random siRNA (Randsi) was used as a negative control. Tubulin was used as a loading control. (C) Detection of caspase 3 / 7 activity induced by *la* in 4T1 control cells and BOK-silenced cells after 24 hours of *la* (50 μM) treatment. Error bars represent mean ± SD, n=5. Paired t-test results showed ***P<0.001. (D) Comparison of viability of *la*-treated 4T1 control (Randsi) and BOK-silenced (BOKsi) cells. Cells were stained with crystal violet, resuspended in DMSO, and absorbance was measured at λ=590 nm.

[0022] Figure 4This demonstrates the in vivo antitumor efficacy of la in an orthotopic 4T1 model of breast cancer. (A) Schematic diagram of the experimental procedure. B) Tumor volume changes in 4T1 tumor-bearing mice treated with solvent control, la (75 mg / kg), or MIK665 (25 mg / kg). Images are tumors collected at the end of the experiment. Data are expressed as mean ± SD. **p < 0.01 relative to the solvent group, one-way ANOVA and Bonferroni post-hoc test. (C) Activation of apoptosis in treated tumors. As shown in A, 4T1 tumor tissues from mice treated with or without la or MIK665 were immunostained with caspase-3 (green). Cell nuclei were stained with DAPI (blue). Quantification of green fluorescence was performed using ImageJ software (right panel). Scale bar 50 μm. (D) Immunohistochemical detection of Ki67 in tumor sections treated with or without MPoIN at the experimental endpoint. Scale bar 50 μm. (E) Lung cells were cultured in a medium containing 6-thioguanine (TG) to analyze metastasis. Representative images of colony formation experiments under different treatments and quantitative results from all culture plates are shown.

[0023] Figure 5 Toxicity assessment of 4T1-TNBC mice treated with LA. (A) Red blood cell, white blood cell, and platelet counts in the blood of 4T1-TNBC mice after treatment with the solvent or LA (75 mg / kg). (B) Detailed characterization of white blood cells in these animals. Neutrophil, lymphocyte, and monocyte counts are shown. Basophils and eosinophils were barely detected in the populations. (C) Liver, heart, and muscle injury was assessed by detecting changes in the activities of creatine phosphokinase (CPK), aspartate aminotransferase (AST / GOT), glutamate pyruvate aminotransferase (GPT), and lactate dehydrogenase (LDH). (D) Hematoxylin & eosin staining of heart sections from animals treated with or without LA.

[0024] Figure 6 Differential cardiotoxicity was shown in the AC10 cell line after treatment with LA or MIK665. Viability comparison of 4T1 and AC10 cells treated with LA (25 μM) or MIK665 (25 μM). Samples were first stained with crystal violet (A) and then quantified (B). (C) Immunoblot assay for BOK expression in the AC10 cell line. Detailed Implementation

[0025] Unless otherwise stated, all terms used in this application should be understood to have their ordinary meaning as known in the art. Further more specific definitions of certain terms used in this application are set forth below and are intended to apply throughout the specification and claims.

[0026] As used herein, the indefinite articles “a” and “an” are synonymous with “at least one” or “one or more”. Unless otherwise stated, the definite articles used herein, such as “the”, also include plural nouns.

[0027] As used herein, the term "pharmaceutically acceptable salt" includes any salt formed from pharmaceutically acceptable non-toxic acids (including inorganic or organic acids). There are no restrictions on these salts, but if used for therapeutic purposes, they must be pharmaceutically or cosmetically acceptable.

[0028] Pharmaceutically acceptable salts of the compounds shown in formula (I) can be prepared by methods known in the art. For example, they can be prepared by conventional chemical methods from a parent compound containing a basic moiety. Typically, such salts are prepared, for example, by reacting the basic form of these compounds with a stoichiometric amount of an appropriate pharmaceutically acceptable acid in water, in an organic solvent, or in a mixture thereof.

[0029] The phrase "pharmaceuticalally acceptable excipient or carrier" refers to a pharmaceutically acceptable material, composition, or medium. Each component must be pharmaceutically acceptable in the sense of compatibility with the other components of the pharmaceutical composition, without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0030] As described above, one aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are selected from the group consisting of H and C1-C3, and is used as a drug.

[0031]

[0032] (I) In one specific embodiment, the compound is used as defined above, wherein R1 is methyl, R2 is isopropyl, and R3 is H.

[0033] In another specific embodiment, the compound is used as defined above, wherein R1 and R2 are methyl and R3 is ethyl.

[0034] The compounds represented by formula (I) according to the present invention have been shown to effectively target cancer cells without exhibiting cardiotoxicity; therefore, the use of the compounds represented by formula (I) as defined above for the treatment of cancers in mammals, including humans, is also part of the present invention.

[0035] This aspect of the invention can also be described as the use of a compound of formula (I) as defined above in the preparation of a medicament for treating cancers in mammals, including humans. This aspect can also be described as a method for treating a mammal, including humans, suffering from cancer, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0036] In one specific implementation, compounds used as defined above are compounds that induce cell death by disrupting MCL1-BOK transmembrane interactions.

[0037] In another specific embodiment, the compound used as defined above is particularly suitable for treating a variety of cancers. Specifically, the types of cancer that can be treated with this compound include, but are not limited to, colon cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, pancreatic cancer, and metastatic cancer.

[0038] In one specific embodiment, the compound is used as defined above, wherein the cancer is selected from the group consisting of: colon cancer, breast cancer, lung cancer, prostate cancer, glioblastoma, pancreatic cancer, and metastatic cancer.

[0039] Cancer cells frequently evade the body's natural defense mechanisms, allowing them to proliferate uncontrollably and form tumors. One of the hallmark characteristics of cancer cells is their ability to avoid apoptosis, a programmed cell death process that normally ensures the elimination of damaged or unwanted cells. By circumventing this process, cancer cells can survive and multiply, leading to tumor growth and progression. Therefore, strategies capable of inducing these apoptosis processes are crucial in the fight against cancer.

[0040] The aforementioned compounds have been found to effectively induce tumor cell apoptosis. This mechanism of action not only inhibits tumor growth but also leads to tumor regression, providing a potential therapeutic approach for various cancer types.

[0041] Therefore, in one specific embodiment, the compound as defined above is used, wherein the treatment comprises inducing tumor cell apoptosis.

[0042] The ability of cancer to spread from its primary site to other parts of the body (i.e., metastasis) is a key characteristic that greatly increases the difficulty of treatment and usually means a poor prognosis. Metastatic cancer is particularly difficult to treat because it signifies that the disease has progressed to an advanced stage and spread to multiple organs or tissues. Therefore, compounds and strategies that can inhibit or stop the metastatic process have enormous therapeutic value.

[0043] By targeting specific pathways used by cancer cells for metastasis, these compounds offer a promising approach to controlling and potentially halting the progression of advanced cancer. Therefore, in one specific embodiment, the compounds are used as defined above, wherein the treatment comprises inhibiting cancer metastasis. In another specific embodiment, the compounds are used as defined above, wherein the cancer is metastatic.

[0044] In another specific embodiment, the compound as defined above is used, wherein the treatment comprises reversing epithelial-mesenchymal transition, thereby reducing the metastatic potential of the tumor.

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

[0046] In another specific embodiment, the compound is used as defined above, wherein the compound is administered in combination with radiotherapy.

[0047] In another specific embodiment, the compound is used as defined above, wherein the patient to whom the compound or pharmaceutical composition is administered has previously received at least one round of cancer treatment; wherein, optionally, the cancer is resistant to or has developed resistance to the previous therapy.

[0048] In another specific embodiment, the compound is used as defined above, wherein the compound is administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula (I) and one or more pharmaceutically acceptable excipients or carriers.

[0049] In another specific embodiment, the compound is used as defined above, wherein the pharmaceutical composition is selected from oral and injectable pharmaceutical compositions.

[0050] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R1, R2 and R3 are selected from the group consisting of H and C1-C3, and one or more pharmaceutically acceptable excipients or carriers.

[0051] Throughout the specification and claims, the word "comprising" and its various variations are not intended to exclude other technical features, additives, components, or steps.

[0052] Furthermore, the word "comprising" covers cases where it means "consisting of...". Other objects, advantages, and features of the invention will become apparent to those skilled in the art upon review of the specification or by practice of the invention. The accompanying embodiments and drawings are for illustrative purposes and are not intended to limit the invention. Reference numerals placed in parentheses in the claims related to the drawings are intended only to improve the understanding of the claims and should not be construed as limiting the scope of the claims. Moreover, the invention covers all possible combinations of the specific and preferred embodiments described herein.

[0053] Example In the experiments detailed herein, the compounds disclosed in the claims and specification were available from a variety of commercial sources.

[0054] Bimolecular fluorescence complementarity (BiFC) detection is a method that uses live-cell imaging or fixed cells to visualize protein-protein interactions directly in vivo.

[0055] MCL1 and BOK TMDs were cloned into the C-terminus of the N-terminal and C-terminal fragments (VN and VC, respectively) of the Venus fluorescent protein, preserving their native topology in the full-length protein. When these two interact, the complete Venus protein is reconstructed, allowing for fluorescence signal recording. Compounds disrupting the interaction result in attenuated fluorescence. HCT116 cells were seeded in six-well plates and co-transfected with 0.5 μg of VN and VC DNA constructs using a TurboFect (ThermoScientific™) according to the manufacturer's instructions. Sixteen hours after transfection, cells were collected and resuspended in 150 µl of phosphate-buffered saline (PBS) for Venus fluorescence assays. Fluorescence emission was measured using a 96-well black plate and a Wallac 1420 workstation (Exc 510 nm and Em 535 nm). Image acquisition was performed using a Leica SP8 confocal microscope.

[0056] Example 1 - Image-based BiFC experiment used to evaluate the interaction between the compounds of the present invention targeting MCL1 / BOK TMD. use Drugs targeting the heterologous interaction of MCL1 / BOK TMDs represent an effective strategy for releasing BOK and inducing tumor cell death while avoiding cardiotoxicity. An image-based BiFC detection method was developed, using HCT116 human colorectal cancer cells expressing MCL1 TMDs and BOK TMDs fused with N-terminal and C-terminal fragments of Venus fluorescent protein for high-throughput screening (HTS) of the MyriaScreen small molecule library (Sigma-Aldrich). Positive compounds were selected based on their ability to reduce fluorescence generated by the heterologous interaction of MCL1 / BOK TMDs.

[0057] After a second screening process to exclude non-specific drug interactions, a group of molecules with a common aromatic core structure were identified that could disrupt the formation of MCL1 and BOK TMD heterodimers (Table 1). Among them, compound 1a showed the highest inhibitory activity.

[0058]

[0059] Table 1: List of compounds with the same parent structure and their activities in high-throughput screening (HTS) BiFC assays. la showed the highest inhibitory activity in the BiFC assay.

[0060] Example 2- l a promotes BOK-dependent apoptosis in colon and breast cancer cell lines. la induced cell death in HCT116 colon cancer cells, with an IC50 of 40 μM ( Figure 1 A). Interestingly, decreased cell viability was associated with increased caspase activity ( Figure 1 B) and the decrease in mitochondrial membrane potential ( Figure 1 C) Related to this, confirming the induction of apoptosis. la also showed similar results in HCT 116 BAX / - and BAK- / - knockout (DKO; Figure 1 D) Induces cell death in cells ( Figure 1 E) and activate caspase 3 / 7 ( Figure 1 F) indicates that cell death does not require the presence of BAX / BAK.

[0061] Conversely, silencing BOK expression in HCT116 cells ( Figure 1 G) leads to cell resistance to treatment ( Figure 1 H), and caspase-3 activity was not detected (H), Figure 1 I). These data confirm that Ia induces BOX / BAK-independent but BOK-dependent cell death.

[0062] In addition, la can also induce apoptosis in colon tumor spheres ( Figure 2 AC reduces mitochondrial activity in WT and BAX- / -, BAK- / - (DKO) tumor spheres, but does not reduce mitochondrial activity in BAX- / -, BAK- / -, BOK- / - (TKO) tumor spheres. Figure 2 D). These results confirm that the drug maintains its targeting activity in 3D colon cancer models.

[0063] The activity of la is also present in multiple human breast cancer cell lines ( Figure 3The drug was evaluated in A) and the mouse triple-negative breast cancer 4T1 cell line, yielding different drug sensitivities. The behavior of MBoIN179 in breast cancer cell lines recapitulated BOK-dependent apoptosis observed in colon cancer. Figure 3 BD).

[0064] Example 3- la Reduce tumor size and metastasis in an orthotopic TNBC mouse model with syngeneic 4T1. .

[0065] The 4T1 mouse model is an idiogenic in situ breast cancer model that mimics human stage IV metastatic breast cancer. 4T1 cells were injected into the mammary pads of 8-week-old Balb / cByJ female mice to induce tumor formation. One week after tumor growth, the mice were intraperitoneally injected with 1a (75 mg / kg) every 3 days for a total of three administrations. Figure 4 A). Interestingly, Ia treatment reduced tumor volume to a level comparable to that of the MCL1 inhibitor MIK665 and was even more effective in reducing lung metastases. Figure 4 B and E). Immunofluorescence detection of active caspase 3 in tumor sections confirmed that both drugs could induce tumor cell apoptosis. Figure 4 C). Furthermore, immunohistochemical analysis of Ki67 showed that the solvent-treated group had a higher proliferation level compared to the la-treated tumor sections. Figure 4 D).

[0066] Furthermore, hematological parameters and tissue analysis both indicated that la had no acute toxicity in mice at a dose of 75 mg / kg. Figure 5 ).

[0067] More interestingly, no MIK665-induced cardiomyocyte toxicity was observed in the la-treated group, which may be due to the low expression level of BOK in cardiomyocytes. Figure 6 ).

[0068] These findings indicate that LA can inhibit the growth and metastasis of breast tumors without producing harmful side effects in mouse models. This drug may become a therapeutic option for treating cancer cells with inhibited apoptosis. Therefore, LA, as a novel chemical entity, warrants further preclinical and clinical development to explore its therapeutic applications.

[0069] Citation List Non-patent literature -Zhai D, Jin C, Huang Z, Satterthwait AC, Reed JC. “DifferentialRegulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B andMcl-1”; Journal of Biological Chemistry. 2008 April; 283(15): pag. 9580-9586. -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 impactin mice; Cell Death Differ; 2012; June 27;19(6): pag. 915-925.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, （I） in: R1, R2, and R3 are selected from the group consisting of H and C1-C3, and are used as drugs.

2. The compound for the use according to claim 1, wherein, R1 is methyl, R2 is isopropyl, and R3 is H.

3. The compound for the use according to claim 1, wherein, R1 and R2 are methyl groups, and R3 is an ethyl group.

4. The compound as defined in any one of claims 1-3, for treating cancers in mammals, including humans.

5. The compound for the use according to claim 4, wherein, The treatment includes inducing tumor cell apoptosis.

6. The compound for the use according to claim 5, wherein, Cell death is induced by disrupting the MCL1-BOK transmembrane interaction.

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

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

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

10. The compound for use according to any one of 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 one of claims 1-9, wherein, The compound is administered in combination with radiotherapy.

12. The compound for use according to any one of claims 1-11, wherein, The patient administering the compound or pharmaceutical composition has received at least one prior round of cancer treatment; wherein, optionally, the cancer is resistant to the prior treatment or has developed resistance.

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

14. The compound for the use according to claim 13, wherein, The pharmaceutical composition is selected from oral and injectable pharmaceutical compositions.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. （I） in: R1, R2 and R3 are selected from the group consisting of H and C1-C3, and one or more pharmaceutically acceptable excipients or carriers.

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