Combinations of roginolix with maltl-gl inhibitors

Abstract

Disclosed is a compound represented by Formula I: Formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject, wherein the treatment comprises administering to the subject i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, separately, sequentially, or simultaneously.

Description

Technical Field

[0001] This disclosure relates to methods for treating cancer in patients in need. Background Technology

[0002] Despite significant progress in cancer treatment, the need for targeted therapies continues to grow, and many cancer patients still suffer from incurable diseases. Therefore, it is crucial to continue searching for more effective new treatments for those with incurable cancers.

[0003] Mucosa-associated lymphoid tissue lymphoma transloin 1 (MALT1) has emerged as a promising therapeutic target in cancer treatment (Solsona 2022). It is involved in cancer pathogenesis, promoting aberrant activation of the nuclear factor-κB (NF-κB) pathway, which is involved in cell survival and proliferation, acquisition of cancer stem cell characteristics, metastasis formation, metabolic reprogramming, and suppression of anti-tumor immune responses. MALT1 is a protease that cleaves various substrates involved in mRNA stability, NF-κB signaling regulation, adhesion, lymphocyte activation, and inflammation (Jaworski and Thome 2016). MALT1 is also a key regulator of glutamine metabolism.

[0004] Proliferating cancer cells largely depend on glutamine for survival and proliferation. Glutaminase (GLS) is an enzyme responsible for catalyzing the conversion of the amino acid glutamine into glutamate, providing a nitrogen source for amino acid and nucleotide biosynthesis and a carbon source to supplement the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathways (Jin, 2023). Many cancer cells exhibit increased dependence on glutamine metabolism to meet their energy and biosynthetic needs.

[0005] Although targeting the MALT1-GLS pathway is a promising therapeutic approach, few drugs have been developed. Tumor metabolism is influenced by a variety of microenvironmental factors, including nutrient availability. Cancer cells evade the effects of glutamine metabolism inhibitors through several mechanisms; these include increased metabolic flexibility, uptake of extracellular amino acids via compensatory transporters and macropinocytosis, and expression of nutrient stress response proteins (Jin, 2023).

[0006] The PI3K pathway is frequently activated in cancer cells, making PI3K an attractive therapeutic target in oncology. This has led to considerable interest in developing inhibitors targeting this pathway (Buchanan 2019). Although many PI3K inhibitors have reached various stages of clinical development, few have been approved for clinical use. While these drugs are clinically effective, their use is associated with a number of serious class-specific and drug-specific side effects. Some of these are believed to be immune-mediated, including skin reactions, severe diarrhea with or without colitis, hepatotoxicity, and pneumonia. PI3K inhibitors also induce various metabolic abnormalities, such as hyperglycemia and hypertriglyceridemia. Among the numerous publications related to PI3K inhibitor compounds, WO2011 / 058149 describes a tricyclic pyrazolamide derivative as a PI3K inhibitor and its use in the treatment of autoimmune diseases, inflammatory diseases, multiple sclerosis, and other diseases such as cancer.

[0007] In light of the above, there is a need in the art for compounds that restore resistance to better-tolerated MALT1-GLS pathway inhibitors and PI3K inhibitors. Furthermore, there is a need in the art for improved methods of treating cancer. Summary of the Invention

[0008] This invention relates to novel therapies for cancer patients. In some embodiments, a method of treating cancer in a subject with this need is disclosed, comprising administering to the subject a first dose of a compound represented by formula I: Molecular formula I The first and second doses comprise a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In this method, the first and second doses together constitute a therapeutically effective amount. The compound represented by molecular formula I may be referred to herein as "compound 1".

[0009] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for treating cancer in a subject, wherein the treatment comprises administering to the subject, respectively, sequentially or simultaneously, i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is disclosed for treating cancer in a subject, wherein the treatment comprises administering, separately, sequentially or simultaneously to the subject i) the MALT1-GLS inhibitor or a pharmaceutically acceptable salt thereof, and ii) compound 1 or a pharmaceutically acceptable salt thereof.

[0011] MALT1-GLS pathway inhibitors can inhibit MALT1 or GLS. In some of the embodiments described above, the MALT1-GLS pathway inhibitor is a MALT1 inhibitor. In other embodiments described above, the MALT1-GLS pathway inhibitor is a GLS inhibitor.

[0012] In some implementations, cancer is improved by inhibiting the MALT1-GLS pathway. In some of these implementations, cancer is improved by inhibiting MALT1. In other implementations, cancer is improved by inhibiting GLS.

[0013] In some implementations, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, stomach cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including multiple myeloma), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer. For example, the cancer can be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, or mesothelioma. In some cases, the melanoma is advanced or metastatic melanoma or ocular / uveal melanoma. Advanced or metastatic melanoma may be histologically confirmed unresectable stage III or IV melanoma. In some cases, the cancer is B-cell lymphoma. In some cases, the cancer is T-cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

[0014] In some implementations, cancer is a solid tumor.

[0015] In some implementations, cancer is a blood malignancy, which can be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorders.

[0016] In some implementations, the cancer is lymphoma.

[0017] In some implementations, the cancer is cutaneous T-cell leukemia or cutaneous T-cell lymphoma.

[0018] In some implementations, the cancer is peripheral T-cell lymphoma.

[0019] In some implementations, the cancer is mantle cell lymphoma.

[0020] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, a kit is disclosed comprising: a first pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0022] Compared to current monotherapy or combination therapy, the combination of compound 1 and a MALT1-GLS pathway inhibitor can be synergistic and / or can lead to improved treatment outcomes or patient prognosis, such as reduced side effects and improved tolerability. This may be because compound 1 blocks the survival pathway that is activated upon administration of a MALT1-GLS pathway inhibitor, and vice versa. Attached Figure Description

[0023] Figure 1 The dose-response data for the combination of compound 1 and the MALT1 inhibitor safimaltib in the HH cell line (a cutaneous T-cell lymphoma cell line) are shown.

[0024] Figure 2 The dose-response data for the combination of compound 1 and the MALT1 inhibitor safimaltib in the SP53 cell line (mantle cell lymphoma cell line) are shown.

[0025] Figure 3 Dose-response data for the combination of compound 1 and the GLS inhibitor telaglenastat in the HH cell line (a cutaneous T-cell lymphoma cell line) are presented.

[0026] Figure 4 The dose-response data for the combination of compound 1 and the GLS inhibitor telaglenastat in the SP53 cell line (mantle cell lymphoma cell line) are shown. Detailed Implementation

[0027] Compound 1 is Example 339 of WO2011 / 058149, which is incorporated herein by reference in its entirety. Its structure conforms to molecular formula I: Molecular formula I In IUPAC nomenclature, compound 1 above can be called 6-fluoro-3-(morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl)phenyl]-1,4-dihydrothiocyaneno[4,3-c]pyrazol 5,5-dioxide. Alternatively, the above structural formula can be described as [6-fluoro-1-(4-morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiocyaneno[4,3-C]pyrazol-3-yl]-morpholin-4-yl-methyl ketone.

[0028] Compound 1 can be prepared as described in the published patent application WO 2011 / 058149 A1 (see compound 339 on page 69; preparation on pages 303-307; and characterization on pages 481 and 414-418), which is incorporated herein by reference in particular.

[0029] Based on the method disclosed in WO 2011 / 058149 A1, the authors of Haselmayer 2014 described a five-step preparation procedure for this compound. This step begins with the reaction of 8-fluoro-2,3-dihydro-4-benzothiaran-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinobenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with m-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, and subsequently coupled with morpholine to give the compound represented by formula I.

[0030] Alternatively, the reaction intermediate of 8-fluoro-2,3-dihydro-4H-thiopyren-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. Benzoic acid is reduced with a borane-THF complex, and the thioether is oxidized to the corresponding sulfone by reaction with m-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid, and the acid and alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to give compound 1.

[0031] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of Compound 1 are described in WO2014 / 121901, which is incorporated herein by reference in its entirety.

[0032] As used herein, compound 1 is provided as an anhydrous hemifumarate (structural formula shown in the figure). Its synthesis and characterization are described in WO2014 / 121901 (page 4). It is referred to as solid form A1. A hemifumarate hydrate (H1) was also discovered. The anhydrous hemifumarate used is crystalline and has a powder X-ray peak list as described in WO2014 / 121901. It should be understood that the discoveries of the present invention are not limited to the use of this solid form, although it is preferred.

[0033] Therefore, in some cases, compound 1 is administered in the form of a hemifumarate (molecular formula Ia). However, it should be understood that the invention is not limited thereto, and other solid forms (e.g., other pharmaceutically acceptable salts) are also conceivable.

[0034] Molecular formula Ia Haselmayer also described the compound as a highly selective PI3Kδ inhibitor in 2014. Tarantelli (2022) and Johnson (2023) further described the activity of compound 1 in lymphoma cell lines, and Carlo-Stella (2022) reported the first dose group data of a clinical study of compound 1 in FL patients (NCT04328844).

[0035] MALT1, or mucosa-associated lymphoid tissue lymphoma translocation protein 1, is a protease encoded by the MALT1 gene. MALT1 is a member of the evolutionarily conserved caspase-like protein superfamily and participates in the antigen-induced nuclear factor kappa (NF-κB) activated CARMA1-Bcl10 pathway (Ruefli-Brasse 2003). GLS, or glutaminase, is a downstream target of MALT1 and is an amidolytic enzyme that produces glutamate from glutamine (Xia 2020).

[0036] MALT1-GLS pathway inhibitors include, but are not limited to, safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0037] In some implementations, the MALT1-GLS pathway inhibitor is a MALT1 inhibitor selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, and Val-Arg-Pro-DL-Arg-fluoromethyl ketone.

[0038] In some implementations, the MALT1-GLS pathway inhibitor is a MALT1 inhibitor and is safimaltib.

[0039] In some implementations, the MALT1-GLS pathway inhibitor is a GLS inhibitor selected from IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0040] In some implementations, the MALT1-GLS pathway inhibitor is a GLS inhibitor and is telaglenastat.

[0041] Safimaltib (also known as JNJ-67856633 or JNJ-6633) is an orally bioavailable, potent, selective, and allosteric MALT1 inhibitor (Hamp 2021). It is under development for the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma (NCT03900598). Safimaltib has the following structure:

[0042] The IUPAC name for safimaltib is 1-(1-oxo-2H-isoquinoline-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazol-4-carboxamide.

[0043] The compound, its preparation method, its crystalline polymorphs, and specific pharmaceutical formulations are disclosed in US2018 / 0170909, WO2020 / 169736, and WO2020 / 169738, the entire contents of which are incorporated herein by reference.

[0044] ABBV-525 is a selective, orally bioavailable MALT1 inhibitor. It is under development for the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma (NCT05618028).

[0045] ONO-7018 (also known as CTX-177) is a potent, selective, orally bioavailable MALT1 inhibitor (Morishita 2022). It is under development for the treatment of relapsed or refractory non-Hodgkin's lymphoma or chronic lymphocytic leukemia (NCT05515406).

[0046] SGR-1505 is a selectively orally bioavailable MALT1 inhibitor. It is under development for the treatment of relapsed or refractory B-cell lymphoma (NCT05544019). Its structure is as follows:

[0047] MPT-0118 is a selectively orally bioavailable MALT1 inhibitor. It is under development for the treatment of advanced or metastatic refractory solid tumors (NCT04859777).

[0048] RGT-068A is a potent, selective, and orally bioavailable MALT1 inhibitor. RGT-068A has the following structure:

[0049] XL114 (also known as AUR 104) is a selectively orally bioavailable MALT1 inhibitor. It is under development for the treatment of non-Hodgkin's lymphoma (NCT05144347).

[0050] MLT-943 is a selectively orally bioavailable MALT1 inhibitor. MLT-943 has the following structure:

[0051] IPN60090 is an orally active and highly selective GLS inhibitor (Soth 2020). It is under development for the treatment of advanced solid tumors (NCT03894540). IPN60090 has the following structure:

[0052] Telaglenastat (also known as CB-839) is an orally active and highly selective GLS inhibitor. It is under development for the treatment of several solid tumors, particularly in combination with other therapies. Telaglenastat has the following structure:

[0053] definition The term "pharmaceutical composition" includes compositions containing an active ingredient and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is compound 1 or a pharmaceutically acceptable salt thereof, or a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. The term "pharmaceuticalally acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with tissues in humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, as determined by a person skilled in the art. In some embodiments, the pharmaceutical composition is in a solid dosage form, such as capsules, tablets, granules, powders, or sachets. In some embodiments, the pharmaceutical composition is in the form of a sterile injectable solution in one or more aqueous or non-aqueous, non-toxic, parenteral-acceptable buffer systems, diluents, solubilizers, cosolvents, or carriers. Sterile injectable formulations may also be sterile injectable aqueous or oily suspensions or suspensions in non-aqueous diluents, carriers, or cosolvents, which may be formulated using one or more suitable dispersants or wetting agents and suspending agents according to known methods. The pharmaceutical composition may be a solution for intravenous bolus / infusion injection, or a lyophilized system (with or without excipients) for reconfiguration with a buffer system. The lyophilized material may be prepared from non-aqueous or aqueous solvents. The dosage form may also be a concentrate for further dilution before subsequent infusion.

[0054] The terms “treating,” “treatment,” and “under treatment” include reducing or inhibiting tumor cells in a subject’s blood malignancy, improving one or more symptoms of a subject’s blood malignancy, or slowing or delaying the progression of a subject’s blood malignancy. The terms “treating,” “treatment,” and “under treatment” also include reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject.

[0055] The terms “inhibition,” “inhibition,” or “inhibition in progress” include a reduction in the baseline activity of a biological activity or process.

[0056] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject has cancer.

[0057] The term "therapeuticly effective amount" includes the amount of compound 1 and the MALT1-GLS pathway inhibitor that, together, will induce a biological or medical response in a subject, such as a reduction or inhibition of tumor cells; improvement of cancer symptoms; or slowing or delaying cancer development. In some embodiments, the term "therapeuticly effective amount" includes the amount of compound 1 and the MALT1-GLS pathway inhibitor that, together, effectively at least partially alleviate, inhibit, and / or improve cancer in a subject or inhibit tumor cells and / or reduce or inhibit cancer cell proliferation.

[0058] In some embodiments, methods for treating cancer in subjects in need are disclosed, including administering to the subject a first dose of compound 1 or a pharmaceutically acceptable salt thereof, and a second dose of a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In this method, the first and second doses together constitute a therapeutically effective amount.

[0059] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for treating cancer in a subject, wherein the treatment comprises administering to the subject, respectively, sequentially or simultaneously, i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is disclosed for treating cancer in a subject, wherein the treatment comprises administering, separately, sequentially or simultaneously to the subject i) the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, and ii) compound 1 or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a subject’s cancer is disclosed, wherein the treatment comprises administering to the subject, individually, sequentially, or simultaneously, i) the medicament comprising compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are administered separately, sequentially, or simultaneously during a treatment cycle. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered continuously during a treatment cycle, and a MALT1 inhibitor or a pharmaceutically acceptable salt thereof is also administered continuously during a treatment cycle.

[0063] In some implementations, the MALT1-GLS pathway inhibitor is selected from safimaltib, MPT-0118, ABBV-525, ONO-7018, SGR-1505, RGT-068A, XL114, MLT-943, INP60090, and telaglenastat.

[0064] In a further embodiment, the MALT1-GLS pathway inhibitor is safimaltib. In a further embodiment, the MALT1-GLS pathway inhibitor is telaglenastat.

[0065] The term "continuous" or "continuously" refers to the application of a therapeutic agent, such as compound 1, at regular time intervals without cessation or interruption, i.e., without ineffective days. An "ineffective day" is a day on which no therapeutic agent was applied.

[0066] As used herein, “cycle,” “treatment cycle,” or “dosing regimen” refers to a period of combined treatment repeated according to a standard regimen. For example, treatment may be administered for one, two, or three weeks, wherein compound 1 and the MALT1-GLS pathway inhibitor are administered synergistically. In some embodiments, the treatment cycle is from about one week to about three months. In some embodiments, the treatment cycle is from about five days to about one month. In some embodiments, the treatment cycle is from about one week to about three weeks. In some embodiments, the treatment cycle is from about one week, about ten days, about two weeks, about three weeks, about four weeks, about two months, or about three months.

[0067] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are administered to a human subject in one or more treatment cycles (e.g., a treatment course). A “treatment course” comprises multiple treatment cycles, which may be repeated periodically or adjusted to a gradually decreasing schedule as the patient’s disease progression is monitored. For example, at the start of a treatment course (e.g., when the patient is first diagnosed), a patient’s treatment cycle may have a longer treatment period and / or a shorter rest period, and as the cancer enters remission, the rest period lengthens, thereby increasing the length of a treatment cycle. Technicians can determine and adjust the treatment and rest times, the number of treatment cycles, and the duration of the treatment course throughout the treatment process based on the patient’s disease progression, treatment tolerance, and prognosis. In some embodiments, the method comprises 1-10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0068] In some implementations, compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days during a 28-day treatment cycle.

[0069] dose In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, compound 1 in the hemifumarate form is administered at a dose of 40 mg daily. In some embodiments, compound 1 in the hemifumarate form is administered at a dose of 80 mg daily.

[0070] In some embodiments, the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is in capsule form. In some embodiments, the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 gram daily.

[0071] In some implementations, MALT1-GLS pathway inhibitors or pharmaceutically acceptable salts thereof are administered via intravenous (IV) infusion.

[0072] In some implementations, compound 1 and the MALT1-GLS pathway inhibitor are taken together on an empty stomach, two hours before, and one hour after administration of food.

[0073] In some implementations, compound 1 is taken on an empty stomach, two hours before and one hour after the onset of food, while MALT1-GLS pathway inhibitors are taken with food, thus at least two hours before or one hour after compound 1.

[0074] In some implementations, MALT1-GLS pathway inhibitors are administered twice daily.

[0075] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are separate dosage forms.

[0076] In some embodiments, a kit is disclosed comprising: a first pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0077] In some implementations, the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0078] In some implementations, the MALT1-GLS pathway inhibitor is safimaltib.

[0079] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) safimaltib or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and safimaltib or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and safimaltib or a pharmaceutically acceptable salt thereof are present as separate dosage forms.

[0080] In some implementations, the MALT1-GLS pathway inhibitor is telaglenastat.

[0081] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) telaglenastat or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and telaglenastat or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and telaglenastat or a pharmaceutically acceptable salt thereof are present as separate dosage forms.

[0082] In some implementations, cancer is improved by inhibiting the MALT1-GLS pathway. In some of these implementations, cancer is improved by inhibiting MALT1. In other implementations, cancer is improved by inhibiting GLS.

[0083] In some implementations, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, stomach cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including multiple myeloma), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer. For example, the cancer can be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, or mesothelioma. In some cases, the melanoma is advanced or metastatic melanoma or ocular / uveal melanoma. Advanced or metastatic melanoma may be histologically confirmed unresectable stage III or IV melanoma. In some cases, the cancer is B-cell lymphoma. In some cases, the cancer is T-cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

[0084] In some implementations, the cancer is lymphoma. In other implementations, the cancer is a solid tumor.

[0085] In some implementations, the cancer is cutaneous T-cell leukemia or cutaneous T-cell lymphoma.

[0086] In some implementations, the cancer is peripheral T-cell lymphoma.

[0087] In some implementations, the cancer is mantle cell lymphoma.

[0088] Without being bound by theoretical frameworks, the combination of compound 1 and a MALT1-GLS pathway inhibitor may be beneficial for patients who are unresponsive or refractory to either compound 1 or a MALT1-GLS pathway inhibitor. Furthermore, this combination may deepen or prolong the response to either compound 1 or a MALT1-GLS pathway inhibitor. Additionally, it may reduce the dosage of the MALT1-GLS pathway inhibitor, thereby improving tolerability and quality of life.

[0089] The method of the present invention As described in more detail below, the inventors have surprisingly discovered that the combination of compound 1 and an inhibitor of the MALT1-GLS pathway has a synergistic effect on the proliferation of cancer cell lines. Therefore, a combination therapy with improved antiproliferative activity can be provided.

[0090] Secondly, the inventors have surprisingly discovered that the synergistic antitumor activity of the combination of compound 1 and a MALT1-GLS pathway inhibitor is not limited to specific malignant tumors. Therefore, a combination therapy with improved therapeutic activity against a variety of malignant tumors can be provided.

[0091] Furthermore, the inventors surprisingly discovered that the combination of compound 1 with an inhibitor of the MALT1-GLS pathway resulted in tumor cell killing that was not observed when either inhibitor was used alone. Therefore, a combination capable of reducing tumor burden can be provided.

[0092] Furthermore, the inventors have surprisingly discovered that the combination of compound 1 with a MALT1-GLS pathway inhibitor already exhibits a synergistic effect at subtherapeutic doses. Therefore, a combination with improved tolerability can be provided.

[0093] Example The compounds of this application will now be further explained with reference to the following non-limiting examples.

[0094] Example 1. Using the cutaneous T-cell lymphoma (CTCL) cell line HH and the mantle cell lymphoma (MCL) cell line In in vitro studies of SP53, the efficacy of compound 1 in combination with the MALT1-GLS pathway inhibitor safimaltib was demonstrated. HH (CRL-2105) and SP53 cells were exposed to increased doses of compound 1, increased doses of safimaltib (JNJ-67856633), and increased doses of a combination of compound 1 and safimaltib. The maximum concentration of safimaltib was 20 μmol / L, following an eight-fold dose-response design based on a 1:2 compound dilution plus an untreated control. Compound 1 was used at a maximum concentration of 10 µM, following an eight-fold dose-response design based on a 1:3 compound dilution plus an untreated control.

[0095] Cells were cultured at 37°C and 5% CO2 for 72 h. The antiproliferative effects of single and combined treatments were determined by adding 20 μL of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and incubating the plates at 37°C for 4 h, followed by adding 50 μL of sodium dodecyl sulfate (SDS) lysis buffer (250 µM SDS, 0.21% fuming HCl). Lysed cells were stored overnight, and absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effects of the combinations were determined according to the Chou-Talalay Combination Index (CI) (Chou 2008, Chou 2010) and calculated using the Synergy R software package (Lee 2007). The combined effect is defined as strong synergy when the CI value is below 0.3, synergy when the CI value is between 0.3 and 0.9, additive when the CI value is between 0.9 and 1.1, and antagonism when the CI value is above 1.1.

[0096] Figure 1 and Figure 2 Data from two representative experiments are shown.

[0097] The combination of compound 1 and safimaltib in HH showed a synergistic effect, with a median CI of 0.48. The combination of compound 1 and safimaltib in SP53 also showed a synergistic effect, with a median CI of 0.66.

[0098] Example 2. Using the cutaneous T-cell lymphoma (CTCL) cell line HH and the mantle cell lymphoma (MCL) cell line In in vitro studies of SP53, the efficacy of compound 1 in combination with the MALT1-GLS pathway inhibitor telaglenastat was demonstrated. HH (CRL-2105) and SP53 cells were exposed to increased doses of compound 1, increased doses of telaglenastat, and increased doses of a combination of compound 1 and telaglenastat. Telaglenastat was administered at a maximum concentration of 10 μmol / L, following an eight-fold dose-response design based on a 1:3 compound dilution plus an untreated control. Compound 1 was administered at a maximum concentration of 10 μmol / L, following an eight-fold dose-response design based on a 1:3 compound dilution plus an untreated control.

[0099] Cells were cultured at 37°C and 5% CO2 for 72 h. The antiproliferative effects of single and combined treatments were determined by adding 20 μL of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and incubating the plates at 37°C for 4 h, followed by adding 50 μL of sodium dodecyl sulfate (SDS) lysis buffer (250 µM SDS, 0.21% fuming HCl). Lysed cells were stored overnight, and absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effects of the combinations were determined according to the Chou-Talalay Combination Index (CI) (Chou 2008, Chou 2010) and calculated using the Synergy R software package (Lee 2007). The combined effect is defined as strong synergy when the CI value is below 0.3, synergy when the CI value is between 0.3 and 0.9, additive when the CI value is between 0.9 and 1.1, and antagonism when the CI value is above 1.1.

[0100] Figure 3 and Figure 4 Data from two representative experiments are shown.

[0101] The combination of compound 1 and telaglenastat in HH exhibits a synergistic effect, with a median CI of 0.47. The combination of compound 1 and safimaltib in SP53 shows a strong synergistic effect, with a median CI of 0.16.

[0102] Table 1. CI values ​​of the combination of compound 1 and MALT1-GLS pathway inhibitor in different cancer cell lines.

[0103] Summary of Chou-Talalay combined indices (<0.3, strong synergistic effect; 0.3-0.9, synergistic effect; 0.9-1.1, additive effect). conf. int. = confidence interval.

[0104] References Numerous publications have been cited above to provide a more comprehensive description and disclosure of the invention and the current state of the art to which it pertains. The full citations of these references are as follows. The entire contents of each of these references are incorporated herein by reference.

[0105]

[0106] statement 1. A method for treating cancer in a subject in need, comprising administering to the subject a first dose of a compound of formula I: Molecular formula I The first and second doses of a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the first and second doses together constitute a therapeutically effective dose.

[0107] 2. The method according to Statement 1, wherein the cancer is improved by inhibiting the MALT1-GLS pathway.

[0108] 3. According to the method of statement 1 or 2, the cancer is a hematologic malignancy, which may be lymphoma, leukemia, myeloma, myelodysplastic syndrome and myeloproliferative disorder.

[0109] 4. According to the method of statement 1 or 2, the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0110] 5. According to the method of statement 1 or 2, the cancer described therein is a solid tumor.

[0111] 6. According to the methods of statements 1-5, the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0112] 7. The method according to statements 1-6, wherein compound 1 is administered in the form of hemifumarate at a dose of 40 mg or 80 mg daily.

[0113] 8. The method according to statements 1-8, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

[0114] 9. The method according to statements 1-8, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

[0115] 10. According to the method of statements 1-8, the MALT1-GLS pathway inhibitor is telaglenastat.

[0116] 11. A compound represented by molecular formula I: Molecular formula I, The compound or a pharmaceutically acceptable salt thereof, for treating a subject’s cancer, wherein the treatment comprises administering, separately, sequentially or simultaneously, to the subject i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0117] 12. Compound 1 or a pharmaceutically acceptable salt thereof as used in claim 11, wherein the cancer is improved by inhibiting the MALT1-GLS pathway.

[0118] 13. The compound 1 or a pharmaceutically acceptable salt thereof used according to statement 12, wherein the cancer is a hematologic malignancy, and wherein the hematologic malignancy may be lymphoma, leukemia, myeloma, myelodysplastic syndrome and myeloproliferative disorder.

[0119] 14. Compound 1 or a pharmaceutically acceptable salt thereof used in accordance with Statement 12, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0120] 15. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-14, wherein the cancer is a solid tumor.

[0121] 16. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-15, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0122] 17. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-16, wherein compound 1 is administered in the form of a hemifumarate at a dose of 40 mg or 80 mg per day.

[0123] 18. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-16, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

[0124] 19. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-17, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

[0125] 20. Compound 1 or a pharmaceutically acceptable salt thereof used according to any one of statements 11-17, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0126] 21. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof for treating cancer in a subject, wherein the treatment comprises administering, separately, sequentially, or simultaneously, to the subject i) the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound represented by formula I: Molecular formula I, Or its pharmaceutically acceptable salt.

[0127] 22. An inhibitor of the MALT1-GLS pathway or a pharmaceutically acceptable salt thereof used in accordance with Statement 21, wherein the cancer is a cancer that is improved by inhibiting the MALT1-GLS pathway.

[0128] 23. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in accordance with Statement 22, wherein the cancer is a hematologic malignancy, which may be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorders.

[0129] 24. An inhibitor of the MALT1-GLS pathway or a pharmaceutically acceptable salt thereof used in accordance with Statement 22, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, or mantle cell lymphoma.

[0130] 25. An inhibitor of the MALT1-GLS pathway or a pharmaceutically acceptable salt thereof used in accordance with Statement 22, wherein the cancer is a solid tumor.

[0131] 26. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used according to any one of statements 21-24, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0132] 27. An inhibitor of the MALT1-GLS pathway or a pharmaceutically acceptable salt thereof used according to any one of statements 21-26, wherein compound 1 is administered in the form of a hemifumarate at a dose of 40 mg or 80 mg daily.

[0133] 28. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used according to any one of statements 21-27, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

[0134] 29. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used according to any one of statements 21-27, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

[0135] 30. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used according to any one of statements 21-27, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0136] 31. Compounds represented by molecular formula I: Molecular formula I, The use of the drug or a pharmaceutically acceptable salt thereof, wherein the use is in the preparation of a medicament for treating cancer, wherein the treatment comprises, separately, sequentially or simultaneously, administering to the subject i) the medicament comprising compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0137] 32. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in statement 31, wherein the cancer is a cancer that is improved by inhibiting the MALT1-GLS pathway.

[0138] 33. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in statement 32, wherein the cancer is a hematologic malignancy, which may be lymphoma, leukemia, myeloma, myelodysplastic syndrome and myeloproliferative disorder.

[0139] 34. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in statement 32, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0140] 35. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in statement 32, wherein the cancer is a solid tumor.

[0141] 36. Use of compound 1 or a pharmaceutically acceptable salt thereof according to any one of statements 31-35, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0142] 37. Use of compound 1 or a pharmaceutically acceptable salt thereof according to any one of statements 31-36, wherein compound 1 is administered in the form of a hemifumarate at a dose of 40 mg or 80 mg per day.

[0143] 38. Use of compound 1 or a pharmaceutically acceptable salt thereof according to any one of statements 31-37, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

[0144] 39. Use of compound 1 or a pharmaceutically acceptable salt thereof according to any one of statements 31-38, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

[0145] 40. Use of compound 1 or a pharmaceutically acceptable salt thereof according to any one of statements 31-37, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0146] 41. A pharmaceutical product comprising a compound represented by molecular formula I: Molecular formula I, and ii) MALT1-GLS pathway inhibitors or their pharmaceutically acceptable salts.

[0147] 42. A kit comprising: a first pharmaceutical composition containing a compound represented by formula I; Molecular formula I, Or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof; and instructions for use of the first and second pharmaceutical compositions in combination.

Claims

1. A compound represented by molecular formula I: Molecular formula I The compound or a pharmaceutically acceptable salt thereof, for treating a subject’s cancer, wherein the treatment comprises administering, separately, sequentially or simultaneously, to the subject i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

2. The compound 1 used in claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer is a cancer that is improved by inhibiting the MALT1-GLS pathway.

3. The compound 1 or a pharmaceutically acceptable salt thereof used according to claim 2, wherein the cancer is a hematologic malignancy, and wherein the hematologic malignancy may be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorders.

4. The compound 1 or a pharmaceutically acceptable salt thereof used according to claim 2, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, or mantle cell lymphoma.

5. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-4, wherein the cancer is a solid tumor.

6. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-5, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

7. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-6, wherein the compound 1 is administered in the form of a hemifumarate at a dose of 40 mg or 80 mg per day.

8. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-6, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

9. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-7, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

10. The compound 1 or a pharmaceutically acceptable salt thereof used in any one of claims 1-7, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

11. A MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof for treating cancer in a subject, wherein the treatment comprises administering, separately, sequentially, or simultaneously, to the subject i) the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound represented by formula I: Molecular formula I Or its pharmaceutically acceptable salt.

12. The MALT1-GLS pathway inhibitor used in claim 11 or a pharmaceutically acceptable salt thereof, wherein the cancer is a cancer that is improved by inhibiting the MALT1-GLS pathway.

13. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in claim 12, wherein the cancer is a hematologic malignancy, and wherein the hematologic malignancy may be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorders.

14. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in claim 12, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, or mantle cell lymphoma.

15. The MALT1-GLS pathway inhibitor used in claim 12 or a pharmaceutically acceptable salt thereof, wherein the cancer is a solid tumor.

16. The MALT1-GLS pathway inhibitor used in any one of claims 11-14, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, piperacizine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-fluoromethyl ketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

17. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in any one of claims 11-16, wherein compound 1 is administered in the form of a hemifumarate at a dose of 40 mg or 80 mg per day.

18. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in any one of claims 11-17, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose between 10 mg and 1 gram per day.

19. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in any one of claims 11-17, wherein the MALT1-GLS pathway inhibitor is safimaltib or a pharmaceutically acceptable salt thereof.

20. The MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof used in any one of claims 11-17, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

21. A pharmaceutical product comprising i) a compound represented by molecular formula I; Molecular formula I and ii) MALT1-GLS pathway inhibitors or their pharmaceutically acceptable salts.

22. A reagent kit, comprising: A first pharmaceutical composition comprising a compound represented by molecular formula I; Molecular formula I Or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof; and instructions for use of the first pharmaceutical composition and the second pharmaceutical composition in combination.

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