Pharmaceutical composition for preventing or treating cancer, comprising EZH2 inhibitor and JAK3 inhibitor

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, the composition comprising an EZH2 inhibitor and a JAK3 inhibitor. When an EZH2 inhibitor and a JAK3 inhibitor based on proteolysis-targeting chimera (PROTAC) technology are co-administered, a remarkable synergistic effect on anticancer activity is exhibited as compared to when either of the inhibitors is administered by itself. Thus, the present invention was found to be able to create a preventive or therapeutic effect on various cancers such as lymphoma, lung cancer, pancreatic cancer, breast cancer, and colorectal cancer.

Description

Pharmaceutical composition for preventing or treating cancer comprising an EZH2 inhibitor and a JAK3 inhibitor

[0001] This patent application claims priority to Republic of Korea Patent Application No. 10-2023-0177278, filed with the Korean Intellectual Property Office on December 8, 2023, the disclosure of which is incorporated herein by reference.

[0002] The present invention was made possible by the support of the Ministry of Science and ICT under the project identification number 1711172425, project number 2022R1F1A1061005 (Industry-Academia Cooperation Group Number: 202203890001). The research management specialized organization of the project is the Industry-Academia Cooperation Group of Inje University, the research project name is "Basic Research", the research project name is "Development of a combination immunotherapy using a PROTAC-based epigenetic regulator EZH2 target drug and an immune checkpoint inhibitor for the treatment of refractory lymphoma", the main organization is the Industry-Academia Cooperation Group of Inje University, and the research period is 2022.06.01 ~ 2025.02.28.

[0003] The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising an EZH2 inhibitor and a JAK3 inhibitor, and more particularly, to a combination therapy use of an EZH2 inhibitor and a JAK3 inhibitor for preventing or treating cancer.

[0004] PROteolysis Targeting Chimera (PROTAC) technology, which utilizes the ubiquitin-proteasome system (UPS) as a targeted treatment for cancer cells, has been proposed and research is currently underway. PROTAC induces ubiquitination of a target protein by positioning it adjacent to an E3 ubiquitin ligase, resulting in natural protein degradation by the patient's body's protein degradation system. It is a technology with high potential as a treatment for various diseases, including blood cancer.

[0005] However, there are reports that PROTAC-based tumor protein degradation does not result in an effective level of tumor growth inhibition, or that the target protein degradation effect of PROTAC varies greatly depending on the tissue of administration. Therefore, there is a need to develop a PROTAC-based anticancer therapy that can exhibit an anticancer effect greater than that of conventional chemical drugs.

[0006] EZH2 (Enhancer of zeste homolog 2) is a histone-lysine N-methyltransferase enzyme that catalyzes the methylation of H3K27me3, thereby promoting transcriptional repression. EZH2 has been implicated in the development and progression of various cancers, including hematological malignancies, breast cancer, colon cancer, lymphoma, ovarian cancer, and liver cancer, and its high expression level is known to be correlated with a poor prognosis. Because of this role of EZH2 in tumorigenesis, EZH2 has become a powerful target for anticancer therapy. Because existing EZH2 inhibitors that suppress methyltransferase activity do not effectively suppress the oncogenic activity of EZH2, PROTAC-based EZH2 degraders are being developed.

[0007] Janus kinase 3 (JAK3) is a tyrosine kinase belonging to the Janus family of kinases known to play a role in various cytokine- and growth factor receptor-mediated signaling pathways. While most JAK family members are ubiquitously expressed, JAK3 is primarily restricted to the hematopoietic lineage, where it plays a crucial role in lymphoid cell development and homeostasis. Because JAK-STAT signaling is known to be constitutively activated in various hematological malignancies, JAK3 has become a target for cancer therapy in hematological malignancies.

[0008] However, since PROTAC-based EZH2 inhibitors are not currently used in clinical practice, and the indications for JAK3 inhibitors currently approved by the FDA are rheumatoid arthritis, ulcerative colitis, ankylosing spondylitis, and alopecia areata, technological development for the use of EZH2 inhibitors and JAK3 inhibitors in cancer treatment is necessary.

[0009] Accordingly, the present inventors have confirmed that when an EZH2 inhibitor and a JAK3 inhibitor are administered in combination based on proteolysis-targeting chimera (PROTAC) technology, there is a synergistic effect that shows remarkable anticancer activity compared to when they are administered alone, and thus, it can create a preventive or therapeutic effect on various cancers such as lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

[0010] Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

[0011] Another object of the present invention is to provide a combination kit for preventing or treating cancer comprising (i) an EZH2 inhibitor and (ii) a JAK3 inhibitor.

[0012] Another object of the present invention is to provide a combination kit for preventing or treating cancer comprising (i) an EZH2 inhibitor and (ii) a JAK3 inhibitor.

[0013] Another object of the present invention is to provide a method for preventing or treating cancer using a pharmaceutical composition comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

[0014] Another object of the present invention is to provide a use of an EZH2 inhibitor and a JAK3 inhibitor for the prevention or treatment of cancer.

[0015] Another object of the present invention is to provide a combination therapy use of an EZH2 inhibitor and a JAK3 inhibitor for the prevention or treatment of cancer.

[0016] The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor, and lymphoma, lung cancer, pancreatic cancer, breast cancer, or colon cancer can be effectively prevented or treated through the pharmaceutical composition of the present invention.

[0017] Hereinafter, the present invention will be described in more detail.

[0018] One aspect of the present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

[0019] The term "EZH2" in this specification refers to a histone-lysine N-methyltransferase that catalyzes the methylation of H3K27me3 and promotes transcriptional repression. EZH2 is involved in the development and progression of various cancers, including hematological cancer, breast cancer, colon cancer, lymphoma, ovarian cancer, and liver cancer, and its high expression level is known to be correlated with a poor prognosis. Therefore, drugs such as Tazemetostat, Valemetostat, GSK126, GSK343, CPI-1205, PF-06821497, and SHR2554 are continuously being developed to degrade the EZH2 protein or inhibit gene expression.

[0020] The term “EZH2 inhibitor” as used herein refers to an agent that targets and degrades the EZH2 protein.

[0021] The term "JAK3" in this specification refers to a tyrosine kinase belonging to the Janus family of kinases known to play a role in various cytokine and growth factor receptor-mediated signaling pathways. Because JAK-STAT signaling is known to be persistently activated in various hematological malignancies, JAK3 has become a target for cancer therapy in hematological malignancies. Accordingly, drugs such as tofacitinib, baricitinib, and upadacitinib are continuously being developed to degrade the JAK3 protein or inhibit its gene expression.

[0022] The term “JAK3 inhibitor” as used herein means an agent that inhibits the activity of JAK3.

[0023] The term "comprising as an active ingredient" in this specification means including an amount sufficient to achieve a specific effect of an EZH2 inhibitor or a JAK3 inhibitor, for example, activity for preventing or treating cancer for the purposes of the present invention.

[0024] The term “prevention” in this specification means any action that inhibits or delays the progression of cancer by administering the pharmaceutical composition of the present invention.

[0025] The term “treatment” as used herein means inhibition of cancer development, alleviation of cancer, and elimination of cancer.

[0026] In the present invention, the composition may be for combined administration of an EZH2 inhibitor and a JAK3 inhibitor.

[0027] In the present invention, the EZH2 inhibitor may be based on PROTAC (Proteolysis targeting chimera).

[0028] In the present invention, the PROTAC molecule is a heterobifunctional compound composed of a ubiquitin ligase binding ligand, a target protein binding ligand, and a linker connecting them, which can bring a target protein into the vicinity of an E3 ligase and consequently cause degradation of the target protein.

[0029] In one embodiment of the present invention, the EZH2 inhibitor is a PROTAC molecule.

[0030] In one embodiment of the present invention, the PROTAC-based EZH2 inhibitor is an agent that brings the EZH2 protein into the vicinity of the E3 ligase, thereby degrading the EZH2 protein.

[0031] In the present invention, the EZH2 inhibitor may be MS1943 or MS177, but is not necessarily limited thereto.

[0032] In one embodiment of the present invention, the MS1943 is a compound having a structure represented by the following structural formula 1.

[0033] [Structural formula 1]

[0034]

[0035] In one embodiment of the present invention, the MS177 is a compound having a structure of structural formula 2 below.

[0036] [Structural formula 2]

[0037]

[0038] In the present invention, the JAK3 inhibitor may be Decernotinib, but is not necessarily limited thereto.

[0039] In one embodiment of the present invention, the desernotinib is a compound having a structure represented by structural formula 3 below.

[0040] [Structural formula 3]

[0041]

[0042] The present inventors confirmed that when the EZH2 inhibitor and the JAK3 inhibitor were each used alone, the minimum molar concentration at which the effect was observed was 5 μM for both drugs. Accordingly, when the EZH2 inhibitor and the JAK3 inhibitor were used in combination, these results were reflected and the minimum molar concentration at which the effect was observed was 5 μM for each drug, and the pharmaceutical composition was included in a molar ratio of 1:1. As a result, the combination treatment showed a superior cancer cell growth inhibition effect, i.e., a superior anticancer activity, compared to the single treatment, and it was confirmed that the combination treatment had a synergistic effect.

[0043] In one embodiment of the present invention, the molar ratio of the EZH2 inhibitor and the JAK3 inhibitor is 1:10 to 10:1, for example, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, 1:10 to 1:1, 1:9 to 10:1, 1:9 to 9:1, 1:9 to 8:1, 1:9 to 7:1, 1:9 to 6:1, 1:9 to 5:1, 1:9 to 4:1, 1:9 to 3:1, 1:9 to 2:1, 1:9 to 1:1, 1:8 to 10:1, 1:8 to 9:1, 1:8 to 8:1, 1:8 to 7:1, 1:8 to 6:1, 1:8 to 5:1, 1:8 to 4:1, 1:8 to 3:1, 1:8 to 2:1, 1:8 to 1:1, 1:7 to 10:1, 1:7 to 9:1, 1:7 to 8:1, 1:7 to 7:1, 1:7 to 6:1, 1:7 to 5:1, 1:7 to 4:1, 1:7 to 3:1, 1:7 to 2:1, 1:7 to 1:1, 1:6 to 10:1, 1:6 to 9:1, 1:6 to 8:1, 1:6 to 7:1, 1:6 to 6:1, 1:6 to 5:1, 1:6 to 4:1, 1:6 to 3:1, 1:6 to 2:1, 1:6 to 1:1, 1:5 to 10:1, 1:5 to 9:1, 1:5 to 8:1, 1:5 to 7:1, 1:5 to 6:1, 1:5 to 5:1, 1:5 to 4:1, 1:5 to 3:1, 1:5 to 2:1, 1:5 to 1:1, 1:4 to 10:1, 1:4 to 9:1, 1:4 to 8:1, 1:4 to 7:1, 1:4 to 6:1, 1:4 to 5:1, 1:4 to 4:1, 1:4 to 3:1, 1:4 to 2:1, 1:4 to 1:1, 1:3 to 10:1, 1:3 to 9:1, 1:3 to 8:1, 1:3 to 7:1, 1:3 to 6:1, 1:3 to 5:1, 1:3 to 4:1,1:3 to 3:1, 1:3 to 2:1, 1:3 to 1:1, 1:2 to 10:1, 1:2 to 9:1, 1:2 to 8:1, 1:2 to 7:1, 1:2 to 6:1, 1:2 to 5:1, 1:2 to 4:1, 1:2 to 3:1, 1:2 to 2:1, 1:2 to 1:1, 1:1 to 10:1, 1:1 to 9:1, 1:1 to 8:1, 1:1 to 7:1, 1:1 to 6:1, 1:1 to 5:1, 1:1 to 4:1, 1:1 to 3:1, or 1:1 to 2:1, for example, 1:3 to 3:1, but It is not limited to,

[0044] In one embodiment of the present invention, the pharmaceutical composition comprises an EZH2 inhibitor at a concentration of 1 to 20 μM and a JAK3 inhibitor at a concentration of 1 to 20 μM.

[0045] In one embodiment of the present invention, the pharmaceutical composition comprises an EZH2 inhibitor at a concentration of 1 to 20 μM, 1 to 15 μM, 1 to 10 μM, 2 to 20 μM, 2 to 15 μM, 2 to 10 μM, 3 to 20 μM, 3 to 15 μM, 3 to 10 μM, 4 to 20 μM, 4 to 15 μM, 4 to 10 μM, 4 to 8 μM, 4 to 6 μM, 5 to 20 μM, 5 to 15 μM, or 5 to 10 μM, for example, at a concentration of 5 μM or 10 μM,

[0046] The JAK3 inhibitor may be included at a concentration of 1 to 20 μM, 1 to 15 μM, 1 to 10 μM, 2 to 20 μM, 2 to 15 μM, 2 to 10 μM, 3 to 20 μM, 3 to 15 μM, 3 to 10 μM, 4 to 20 μM, 4 to 15 μM, 4 to 10 μM, 4 to 8 μM, 4 to 6 μM, 5 to 20 μM, 5 to 15 μM, or 5 to 10 μM, for example, at a concentration of 5 μM or 10 μM.

[0047] In the present invention, the cancer may be at least one selected from the group consisting of lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

[0048] In the present invention, the lymphoma may be at least one T-cell lymphoma (TCL) selected from the group consisting of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), angioimmunoblastic T-cell lymphoma (AITL), extranodal NK / T-cell lymphoma, and hepatosplenic T-cell lymphoma, but is not necessarily limited thereto.

[0049] In the present invention, the lymphoma is Burkitt's lymphoma, B cell non-Hodgkin lymphoma (NHL), B cell chronic lymphocytic leukemia (B-CLL), B cell acute lymphoblastic leukemia (B-ALL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), intravascular large B cell lymphoma (IVLBCL), primary effusion lymphoma, It may be one or more types of B-cell lymphoma (BCL) selected from the group consisting of, but not necessarily limited to, lymphomatoid granulomatosis, primary central nervous system lymphoma (PCNSL), ALK-positive large B-cell lymphoma, and plasmablastic lymphoma (PBL).

[0050] In one embodiment of the present invention, the lung cancer may be, but is not necessarily limited to, non-small cell lung cancer, small cell lung cancer, pancoast tumor, or lung carcinoid tumor.

[0051] In one embodiment of the present invention, the non-small cell lung cancer may be, but is not necessarily limited to, squamous cell carcinoma, adenocarcinoma, or large-cell carcinoma.

[0052] In one embodiment of the present invention, the pancreatic cancer may be at least one pancreatic cystic tumor selected from the group consisting of serous cystadenoma, mucinous cystic neoplasm, intraductal papillary mucinous neoplasm (IPMN), and solid pseudopapillary tumor, or at least one malignant pancreatic tumor selected from the group consisting of pancreatic ductal adenocarcinoma, acinar cell carcinoma, and neuroendocrine tumor, but is not necessarily limited thereto.

[0053] In one embodiment of the present invention, the breast cancer may be at least one selected from the group consisting of triple negative breast cancer (TNBC), metastatic breast cancer, refractory breast cancer, androgen receptor (AR)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, and receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer, or may be breast cancer that has failed treatment with at least one therapeutic agent selected from the group consisting of tamoxifen, toremifene, exemestane, anastrozole, letrozole, trastuzumab, ado-trastuzumab, emtansine, pertuzumab, lapatinib, bevacizumab, and fulvestrant.

[0054] In one embodiment of the present invention, the colon cancer may be, but is not necessarily limited to, adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, or lymphoma.

[0055] The pharmaceutical composition of the present invention may additionally comprise a pharmaceutically acceptable carrier.

[0056] The term "pharmaceutically acceptable" as used herein means, as commonly used in the pharmaceutical field, that when administered, it does not stimulate the organism and does not inhibit the biological activity and properties of the administered compound.

[0057] In the present invention, any carrier commonly used in the art may be used as the carrier. Non-limiting examples of the carrier include saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, or combinations thereof.

[0058] The pharmaceutical composition of the present invention may be used by adding other pharmaceutically acceptable additives, such as excipients, diluents, antioxidants, buffers, or bacteriostatic agents, if necessary, and may be used by additionally adding fillers, bulking agents, wetting agents, disintegrating agents, dispersing agents, surfactants, binders, or lubricants.

[0059] The pharmaceutical composition of the present invention may be administered in various dosages depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. The dosage may be determined or prescribed as an effective dosage for the desired treatment or prevention. For example, the daily dosage of the pharmaceutical composition of the present invention may be 0.0001-1000 mg / kg.

[0060] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and thereby. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, suppository, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer, but is not limited thereto.

[0061] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity, and may be administered once or several times a day at regular intervals, depending on the judgment of a doctor or pharmacist. For example, the daily dosage may be 1 to 1000 ug / mL based on the active ingredient content, but this is an example of an average case, and the dosage may be higher or lower depending on individual differences.

[0062] Another aspect of the present invention relates to a combination kit for preventing or treating cancer, comprising (i) an EZH2 inhibitor and (ii) a JAK3 inhibitor.

[0063] In one embodiment of the present invention, the (i) EZH2 inhibitor and (ii) JAK3 inhibitor may be contained in the same container or in different containers.

[0064] The above kit may additionally include not only the active ingredients (i) EZH2 inhibitor and (ii) JAK3 inhibitor, but also containers, materials, package inserts, etc. commonly used in the art suitable for use as a combination kit for preventing or treating cancer.

[0065] The above containers may include, but are not necessarily limited to, vials, syringes, bottles, etc.

[0066] The above materials may include, but are not necessarily limited to, diluents such as saline solution, filters, IV bags and lines, needles and syringes, etc.

[0067] The package insert may be instructions for using (i) an EZH2 inhibitor and (ii) a JAK3 inhibitor in combination to treat or delay the progression of cancer, or instructions for treating a subject for cancer using (i) an EZH2 inhibitor and (ii) a JAK3 inhibitor.

[0068] In the present invention, the EZH2 inhibitor may be MS1943 or MS177, but is not necessarily limited thereto.

[0069] In the present invention, the JAK3 inhibitor may be Decernotinib, but is not necessarily limited thereto.

[0070] In the present invention, the (i) EZH2 inhibitor and (ii) JAK3 inhibitor may be administered simultaneously or sequentially.

[0071] The term “simultaneously” as used herein means that two preparations or pharmaceutical compositions are administered at the same time.

[0072] The term "sequentially" as used herein means that the active ingredients or pharmaceutical compositions are administered one after the other, rather than simultaneously. For example, "sequentially" administration may mean that one agent / pharmaceutical composition is administered within 1 minute, 5 minutes, 10 minutes, 30 minutes, or several hours, for example, within 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours, of another agent / pharmaceutical composition, provided that the circulating half-life of the first agent administered is sufficiently long to allow both agents to be present simultaneously in therapeutically effective amounts, but is not necessarily limited thereto. The time delay in administration between components may vary depending on the exact nature, interactions, and respective half-lives of the components.

[0073] In one embodiment of the present invention, the (i) EZH2 inhibitor and (ii) JAK3 inhibitor may be administered at the same time or at different time intervals.

[0074] In one embodiment of the present invention, the (i) EZH2 inhibitor and (ii) JAK3 inhibitor may be administered via the same or different administration routes.

[0075] In the present invention, the cancer may be one or more selected from the group consisting of lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer, but is not necessarily limited thereto. Since the kit of the present invention comprises the effective ingredient of the pharmaceutical composition described above, redundant descriptions are omitted to avoid excessive complexity of the present specification.

[0076] Another aspect of the present invention relates to a method for preventing or treating cancer by administering to a subject a pharmaceutical composition comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

[0077] In one embodiment of the present invention, the EZH2 inhibitor and the JAK3 inhibitor may be administered simultaneously, sequentially, or alternatingly. When the EZH2 inhibitor and the JAK3 inhibitor are administered alternately, each agent may be sequentially administered at a time interval of, but not limited to, about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks.

[0078] In one embodiment of the present invention, the EZH2 inhibitor may be administered at a dose of, but is not limited to, 0.1 mg / kg to 1000 mg / kg, 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 50 mg / kg, 1 mg / kg to 1000 mg / kg, 1 mg / kg to 500 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 5 mg / kg to 1000 mg / kg, 5 mg / kg to 500 mg / kg, 5 mg / kg to 100 mg / kg, or 5 mg / kg to 50 mg / kg.

[0079] In one embodiment of the present invention, the JAK3 inhibitor may be administered at a dose of, but is not limited to, 0.1 mg / kg to 1000 mg / kg, 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 50 mg / kg, 1 mg / kg to 1000 mg / kg, 1 mg / kg to 500 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 5 mg / kg to 1000 mg / kg, 5 mg / kg to 500 mg / kg, 5 mg / kg to 100 mg / kg, or 5 mg / kg to 50 mg / kg.

[0080] In one embodiment of the present invention, the pharmaceutical composition may be administered 1 to 6 times, 1 to 5 times, 1 to 4 times, or 1 to 3 times daily, as needed, but is not limited thereto.

[0081] In one embodiment of the present invention, the pharmaceutical composition may be in the form of, but is not limited to, tablets, capsules, granules, syrups, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, and injections.

[0082] The term "subject" in this specification may be a mammal including a human, for example, but not limited to, a human, monkey, cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit or guinea pig.

[0083] The term "administration" as used herein means providing a given substance to a subject by any suitable method, and the route of administration of the composition comprising the EZH2 inhibitor and the JAK3 inhibitor of the present invention as active ingredients may be administered orally or parenterally through any common route as long as it can reach the target tissue. In addition, the composition of the present invention may be administered using any device capable of delivering the active ingredient to the target cell. For example, the pharmaceutical composition of the present invention may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intrathecal administration, ocular administration, skin administration, and transdermal administration, but is not limited thereto.

[0084] Another aspect of the present invention relates to the use of a pharmaceutical composition comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients for the prevention or treatment of cancer.

[0085] Another aspect of the present invention relates to a use of a combination therapy of an EZH2 inhibitor and a JAK3 inhibitor for the prevention or treatment of cancer.

[0086] Another aspect of the present invention relates to a method for preventing or treating cancer, comprising administering to a subject in need of treatment an effective amount of an EZH2 inhibitor and a JAK3 inhibitor.

[0087] The term “subject” in this specification is meant to include humans (e.g., patients) and mammals (e.g., mice, rats, dogs, cats, rabbits, chickens, monkeys, etc.).

[0088] The term "effective amount" as used herein means an amount (e.g., dose) of a pharmaceutical composition that provides a significant reduction in the clinical symptoms of a disease or condition to be treated without causing excessive toxic side effects.

[0089] The term “dose” as used herein means the weight (e.g., milligrams (mg)) of active substance per kilogram (kg) of body weight of the subject.

[0090] In one embodiment of the present invention, the EZH2 inhibitor and the JAK3 inhibitor may exist as separate formulations, but are not limited thereto.

[0091] In one embodiment of the present invention, the EZH2 inhibitor and the JAK3 inhibitor may be administered simultaneously, sequentially, or alternately. In one embodiment of the present invention, the EZH2 inhibitor and the JAK3 inhibitor may be administered in combination.

[0092] The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor. It has been confirmed that when an EZH2 inhibitor and a JAK3 inhibitor are administered in combination based on proteolysis-targeting chimera (PROTAC) technology, a synergistic effect is achieved in which a remarkable anticancer activity is exhibited compared to when they are administered alone, and thus, it is possible to create a preventive or therapeutic effect for various cancers such as lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

[0093] Figure 1 is a graph comparing the cell proliferation rate when an EZH2 inhibitor (MS1943) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a cutaneous T-cell lymphoma (CTCL) cell line, HuT78.

[0094] Figure 2 is a graph comparing cell survival rates when an EZH2 inhibitor (MS1943 or MS177) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a lung cancer cell line (A549).

[0095] Figure 3 is a graph comparing cell survival rates when an EZH2 inhibitor (MS1943 or MS177) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a pancreatic cancer cell line (Capan-1).

[0096] Figure 4 is a graph comparing cell survival rates when an EZH2 inhibitor (MS1943 or MS177) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a breast cancer cell line (MDA-MB-231).

[0097] Figure 5 is a graph comparing cell survival rates when an EZH2 inhibitor (MS1943 or MS177) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a colon cancer cell line (HCT-116).

[0098] Figure 6 is a graph comparing cell survival rates when an EZH2 inhibitor (MS1943 or MS177) and a JAK3 inhibitor (desernotinib) according to one embodiment of the present invention are treated alone or in combination with a lymphoma cell line (Daudi).

[0099] The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

[0100] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only intended to illustrate the present invention, and the scope of the present invention is not limited by these examples.

[0101] Unless otherwise stated, all numbers, values ​​and / or expressions expressing ingredients, reaction conditions and quantities of ingredients used in this specification are approximations that inherently reflect, among other things, the various uncertainties of measurement that arise in obtaining such values ​​and therefore should be understood as being modified in all instances by the term "about", and when a numerical range is disclosed herein, such range is continuous and includes every value from the minimum value to the maximum value inclusive, unless otherwise stated.

[0102] Also, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, where the connection or use between constructions is not otherwise specified or clear from the context, i.e., if X includes A; X includes B; or X includes both A and B, "X includes A or B" can be applied to any of these cases.

[0103] And, throughout the specification, whenever a part is said to "include" a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0104]

[0105] Example 1: Experimental study of combined treatment with EZH2 inhibitor and JAK3 inhibitor on lymphoma cell lines.

[0106] 2.0×10 HuT78 cells of CTCL (cutaneous T-lymphocyte cell; cutaneous T-cell lymphoma) SS (Sezary Syndrome) type 4Dogs were treated with MS1943, an EZH2 inhibitor, alone at 5 μM or 10 μM, or with Decernotinib, a JAK3 inhibitor, alone at 5 μM or 10 μM, or with a combination of EZH2 inhibitor (MS1943 5 μM) and JAK3 inhibitor (Decernotinib 5 μM). The survival rate was determined 48 hours later using CCK-8 (Cell Counting Kit-8). The group treated only with DMSO (Dimethyl sulfoxide) served as the control group.

[0107] As can be seen in Figure 1 and Table 1, the EZH2 inhibitor (dEZH2) MS1943 single treatment group and the JAK3 inhibitor (iJAK3) desernotinib single treatment group did not have a significant effect on the proliferation rate of the HuT78 cell line, whereas the combination treatment group of the EZH2 inhibitor and the JAK3 inhibitor statistically significantly inhibited the proliferation rate of the HuT78 cell line.

[0108] In particular, the average value of the proliferation rate of the EZH2 inhibitor MS1943 10 μM single treatment group and the JAK3 inhibitor desernotinib 10 μM single treatment group (62.9985% + 67.9185%) / 2 = 65.4585% was significantly lower than the proliferation rate of the combination treatment group of EZH2 inhibitor MS1943 5 μM and JAK3 inhibitor desernotinib 5 μM, confirming that the combination treatment group of EZH2 inhibitor and JAK3 inhibitor had a synergistic effect compared to the single treatment group.

[0109] Treatment group Proliferation rate (%) Control group (DMSO) 99.9709 MS1943 alone treatment group (5 μM) 87.0742 MS1943 alone treatment group (10 μM) 62.9985 Desernotinib alone treatment group (5 μM) 81.1645 Desernotinib alone treatment group (10 μM) 67.9185 MS1943 (5 μM) + desernotinib (5 μM) combination treatment group 28.6754

[0110]

[0111] Example 2: Experimental study of combined treatment with EZH2 inhibitor and JAK3 inhibitor on lung cancer cell lines.

[0112] 5.0×10 A549 (A-549) cells, a lung cancer cell line 3 Dogs were treated with 5 μM or 10 μM of the EZH2 inhibitors MS1943 or MS177 alone, 5 μM or 10 μM of the JAK3 inhibitor desernotinib alone, or with a combination of the EZH2 inhibitor (MS1943 5 μM) and the JAK3 inhibitor (desernotinib 5 μM), or with a combination of the EZH2 inhibitor (MS177 5 μM) and the JAK3 inhibitor (desernotinib 5 μM). The survival rate was determined by CCK-8 48 hours later. The untreated group served as the control group, and the survival rates of the control group and the group treated with DMSO alone were also determined.

[0113] As can be seen in Fig. 2 and Table 2, the survival rate inhibition effect of the A549 cell line was not significant in the group treated with EZH2 inhibitor (dEZH2) MS1943 or MS177 alone and the group treated with JAK3 inhibitor (iJAK3) desernotinib alone, whereas the combined treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib statistically significantly inhibited the survival rate of the A549 cell line.

[0114] In particular, the survival rate of the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib was significantly lower at 68.13% than the average survival rate of the EZH2 inhibitor MS1943 10 μM monotherapy group and the JAK3 inhibitor desernotinib 10 μM monotherapy group (76.51% + 72.36%) / 2 = 74.435%, confirming that the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0115] In addition, the survival rate of the combination treatment group of EZH2 inhibitor MS177 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 54.28% than the average survival rate of the EZH2 inhibitor MS177 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (81.24% + 72.36%) / 2 = 76.8%, confirming that the combination treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0116] Treatment group Cell viability (%) Control group 100 DMSO only treatment group 75.35 dEZH2 (MS1943) only treatment group (5 μM) 87.89 dEZH2 (MS1943) only treatment group (10 μM) 76.51 dEZH2 (MS177) only treatment group (5 μM) 90.14 dEZH2 (MS177) only treatment group (10 μM) 81.24 iJAK3 only treatment group (5 μM) 80.14 iJAK3 only treatment group (10 μM) 72.36 dEZH2 (MS1943) + iJAK3 (5 μM) combination treatment group 68.13 dEZH2 (MS177) + iJAK3 (5 μM) combination treatment group 54.28

[0117]

[0118] Example 3: Experimental study of combined treatment with EZH2 inhibitor and JAK3 inhibitor on pancreatic cancer cell lines.

[0119] 5.0×10 Capan-1 cells, a pancreatic cancer cell line 3Dogs were treated with 5 μM or 10 μM of the EZH2 inhibitors MS1943 or MS177 alone, 5 μM or 10 μM of the JAK3 inhibitor desernotinib alone, or with a combination of the EZH2 inhibitor (MS1943 5 μM) and the JAK3 inhibitor (desernotinib 5 μM), or with a combination of the EZH2 inhibitor (MS177 5 μM) and the JAK3 inhibitor (desernotinib 5 μM). The survival rate was determined by CCK-8 48 hours later. The untreated group served as the control group, and the survival rates of the control group and the group treated with DMSO alone were also determined.

[0120] As can be seen in Figure 3 and Table 3, the survival rate inhibition effect of the Capan-1 cell line was not significant in the EZH2 inhibitor (dEZH2) MS1943 or MS177 monotherapy group and the JAK3 inhibitor (iJAK3) desernotinib monotherapy group, whereas the combined treatment group of the EZH2 inhibitor MS177 and the JAK3 inhibitor desernotinib statistically significantly inhibited the survival rate of the Capan-1 cell line.

[0121] In particular, the survival rate of the combination treatment group of EZH2 inhibitor MS1943 5 μM and JAK3 inhibitor desernotinib 5 μM was lower at 64.18% than the average survival rate of the EZH2 inhibitor MS1943 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (68.55% + 63.04%) / 2 = 65.795%, confirming that the combination treatment group of EZH2 inhibitor MS1943 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0122] In addition, the survival rate of the combination treatment group of EZH2 inhibitor MS177 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 57.39% than the average survival rate of the EZH2 inhibitor MS177 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (76.20% + 63.04%) / 2 = 69.62%, confirming that the combination treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0123] Treatment group Cell viability (%) Control group 100.02 DMSO only treatment group 73.77 dEZH2 (MS1943) only treatment group (5 μM) 87.74 dEZH2 (MS1943) only treatment group (10 μM) 68.55 dEZH2 (MS177) only treatment group (5 μM) 80.38 dEZH2 (MS177) only treatment group (10 μM) 76.20 iJAK3 only treatment group (5 μM) 81.78 iJAK3 only treatment group (10 μM) 63.04 dEZH2 (MS1943) + iJAK3 (5 μM) combination treatment group 64.18 dEZH2 (MS177) + iJAK3 (5 μM) combination treatment group 57.39

[0124]

[0125] Example 4: Experimental study of combined treatment of EZH2 inhibitor and JAK3 inhibitor on breast cancer cell lines.

[0126] 5.0×10 MDA-MB-231 cells, a breast cancer cell line 3Dogs were treated with 5 μM or 10 μM of the EZH2 inhibitors MS1943 or MS177 alone, 5 μM or 10 μM of the JAK3 inhibitor desernotinib alone, or with a combination of the EZH2 inhibitor (MS1943 5 μM) and the JAK3 inhibitor (desernotinib 5 μM), or with a combination of the EZH2 inhibitor (MS177 5 μM) and the JAK3 inhibitor (desernotinib 5 μM). The survival rate was determined by CCK-8 48 hours later. The untreated group served as the control group, and the survival rates of the control group and the group treated with DMSO alone were also determined.

[0127] As can be seen in Figure 4 and Table 4, the survival rate inhibition effect of the MDA-MB-231 cell line was not significant in the EZH2 inhibitor (dEZH2) MS1943 or MS177 monotherapy group and the JAK3 inhibitor (iJAK3) desernotinib monotherapy group, whereas the combined treatment group of the EZH2 inhibitor MS1943 and the JAK3 inhibitor desernotinib and the combined treatment group of the EZH2 inhibitor MS177 and the JAK3 inhibitor desernotinib statistically significantly inhibited the survival rate of the MDA-MB-231 cell line.

[0128] In particular, the survival rate of the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib was significantly lower at 40.39% than the average survival rate of the EZH2 inhibitor MS1943 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (77.42% + 54.47%) / 2 = 65.945%, confirming that the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0129] In addition, the survival rate of the combination treatment group of EZH2 inhibitor MS177 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 29.42% than the average survival rate of the EZH2 inhibitor MS177 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (36.17% + 54.47%) / 2 = 45.32%, confirming that the combination treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0130] Treatment group Cell viability (%) Control group 100 DMSO only treatment group 70.57 dEZH2 (MS1943) only treatment group (5 μM) 80.28 dEZH2 (MS1943) only treatment group (10 μM) 77.42 dEZH2 (MS177) only treatment group (5 μM) 39.69 dEZH2 (MS177) only treatment group (10 μM) 36.17 iJAK3 only treatment group (5 μM) 68.02 iJAK3 only treatment group (10 μM) 54.47 dEZH2 (MS1943) + iJAK3 (5 μM) combination treatment group 40.39 dEZH2 (MS177) + iJAK3 (5 μM) combination treatment group 29.42

[0131]

[0132] Example 5: Experimental study of combined treatment of EZH2 inhibitor and JAK3 inhibitor on colon cancer cell lines.

[0133] 5.0×10 HCT-116 cells, a colon cancer cell line 3Dogs were treated with 5 μM or 10 μM of the EZH2 inhibitors MS1943 or MS177 alone, 5 μM or 10 μM of the JAK3 inhibitor desernotinib alone, or with a combination of the EZH2 inhibitor (MS1943 5 μM) and the JAK3 inhibitor (desernotinib 5 μM), or with a combination of the EZH2 inhibitor (MS177 5 μM) and the JAK3 inhibitor (desernotinib 5 μM). The survival rate was determined by CCK-8 48 hours later. The untreated group served as the control group, and the survival rates of the control group and the group treated with DMSO alone were also determined.

[0134] As can be seen in Figure 5 and Table 5, the survival rate inhibition effect of HCT-116 cell lines was not significant in the EZH2 inhibitor (dEZH2) MS1943 or MS177 monotherapy group and the JAK3 inhibitor (iJAK3) desernotinib monotherapy group, whereas the combined treatment group of EZH2 inhibitor MS1943 and JAK3 inhibitor desernotinib and the combined treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib statistically significantly inhibited the survival rate of HCT-116 cell lines.

[0135] In particular, the survival rate of the combination treatment group of EZH2 inhibitor MS1943 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 57.08% than the average survival rate of the EZH2 inhibitor MS1943 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (83.88% + 87.68%) / 2 = 85.78%, confirming that the combination treatment group of EZH2 inhibitor MS1943 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0136] In addition, the survival rate of the combination treatment group of EZH2 inhibitor MS177 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 51.12% than the average survival rate of the EZH2 inhibitor MS177 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (74.71% + 87.68%) / 2 = 81.195%, confirming that the combination treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0137] Treatment group Cell viability (%) Control group 99.99 DMSO only treatment group 97.94 dEZH2 (MS1943) only treatment group (5 μM) 79.98 dEZH2 (MS1943) only treatment group (10 μM) 83.88 dEZH2 (MS177) only treatment group (5 μM) 88.64 dEZH2 (MS177) only treatment group (10 μM) 74.71 iJAK3 only treatment group (5 μM) 94.81 iJAK3 only treatment group (10 μM) 87.68 dEZH2 (MS1943) + iJAK3 (5 μM) combination treatment group 57.08 dEZH2 (MS177) + iJAK3 (5 μM) combination treatment group 51.12

[0138]

[0139] Example 6: Experimental study of combined treatment of EZH2 inhibitor and JAK3 inhibitor on Burkitt's lymphoma cell line.

[0140] 5.0×10 Daudi cells, a Burkitt's Lymphoma cell line 3Dogs were treated with 5 μM or 10 μM of the EZH2 inhibitors MS1943 or MS177 alone, 5 μM or 10 μM of the JAK3 inhibitor desernotinib alone, or with a combination of the EZH2 inhibitor (MS1943 5 μM) and the JAK3 inhibitor (desernotinib 5 μM), or with a combination of the EZH2 inhibitor (MS177 5 μM) and the JAK3 inhibitor (desernotinib 5 μM). The survival rate was determined by CCK-8 48 hours later. The untreated group served as the control group, and the survival rates of the control group and the group treated with DMSO alone were also determined.

[0141] As can be seen in Figure 6 and Table 6, the survival rate inhibition effect of the Daudi cell line was not significant in the group treated with EZH2 inhibitor (dEZH2) MS1943 or MS177 alone and the group treated with JAK3 inhibitor (iJAK3) desernotinib alone, whereas the combined treatment group of EZH2 inhibitor MS1943 and JAK3 inhibitor desernotinib and the combined treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib statistically significantly inhibited the survival rate of the Daudi cell line.

[0142] In particular, the survival rate of the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib was significantly lower at 37.03% than the average survival rate of the EZH2 inhibitor MS1943 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (42.31% + 68.28%) / 2 = 55.295%, confirming that the combination treatment group of 5 μM EZH2 inhibitor MS1943 and 5 μM JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0143] In addition, the survival rate of the combination treatment group of EZH2 inhibitor MS177 5 μM and JAK3 inhibitor desernotinib 5 μM was significantly lower at 26.22% than the average survival rate of the EZH2 inhibitor MS177 10 μM monotherapy group and the survival rate of the JAK3 inhibitor desernotinib 10 μM monotherapy group (34.79% + 68.28%) / 2 = 51.535%, confirming that the combination treatment group of EZH2 inhibitor MS177 and JAK3 inhibitor desernotinib had a synergistic effect compared to the monotherapy group.

[0144] Treatment group Cell viability (%) Control group 99.95 DMSO only treatment group 51.97 dEZH2 (MS1943) only treatment group (5 μM) 77.22 dEZH2 (MS1943) only treatment group (10 μM) 42.31 dEZH2 (MS177) only treatment group (5 μM) 43.63 dEZH2 (MS177) only treatment group (10 μM) 34.79 iJAK3 only treatment group (5 μM) 88.06 iJAK3 only treatment group (10 μM) 68.28 dEZH2 (MS1943) + iJAK3 (5 μM) combination treatment group 37.03 dEZH2 (MS177) + iJAK3 (5 μM) combination treatment group 26.22

[0145]

[0146] Sintering

[0147] From the above results, the inventors of the present invention confirmed that when combined with an EZH2 inhibitor (MS1943, MS177) and a JAK3 inhibitor (desernotinib), compared to when treated alone, there was a synergistic effect on anticancer activity that significantly inhibited cell proliferation and cell viability in CTCL (HuT78), lung cancer (A549), pancreatic cancer (Capan-1), breast cancer (MDA-MB-231), colon cancer (HCT-116), and Burkitt's lymphoma (Daudi).

[0148] Therefore, although PROTAC-based EZH2 inhibitors are not currently used in clinical trials, when EZH2 inhibitors are used together with JAK3 inhibitors, which are drugs that are currently used for other cancers, the drug expandability of EZH2 inhibitors was confirmed because they have a combined treatment effect not only for CTCL, which has had limited treatment options so far, but also for other cancers such as lung cancer, pancreatic cancer, breast cancer, colon cancer, and lymphoma.

[0149] In addition, CTCL is a type of peripheral T-cell lymphoma that is characterized by chronic relapse and long-term treatment efficacy, so various treatment options are required. It is thought that the combined treatment of EZH2 inhibitor and JAK3 inhibitor produced a synergistic effect by simultaneously inhibiting EZH2, which is involved in tumorigenesis when overexpressed, and the JAK / STAT pathway, which is a major oncogenic pathway of CTCL.

[0150]

[0151] The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor. It has been confirmed that when an EZH2 inhibitor and a JAK3 inhibitor are administered in combination based on proteolysis-targeting chimera (PROTAC) technology, a synergistic effect is achieved in which a remarkable anticancer activity is exhibited compared to when they are administered alone, and thus, it is possible to create a preventive or therapeutic effect for various cancers such as lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

Claims

1. A pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a JAK3 inhibitor as active ingredients.

2. A pharmaceutical composition according to claim 1, wherein the composition is for combined administration of an EZH2 inhibitor and a JAK3 inhibitor.

3. A pharmaceutical composition according to claim 1, characterized in that the EZH2 inhibitor is PROTAC (Proteolysis targeting chimera)-based.

4. A pharmaceutical composition in claim 1, wherein the EZH2 inhibitor is MS1943 or MS177.

5. A pharmaceutical composition according to claim 1, wherein the JAK3 inhibitor is Decernotinib.

6. A pharmaceutical composition according to claim 1, wherein the molar ratio of the EZH2 inhibitor and the JAK3 inhibitor is 1:10 to 10:

1.

7. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises an EZH2 inhibitor at a concentration of 1 to 20 μM and a JAK3 inhibitor at a concentration of 1 to 20 μM.

8. A pharmaceutical composition according to claim 1, wherein the cancer is at least one selected from the group consisting of lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

9. A pharmaceutical composition according to claim 8, wherein the lymphoma is at least one T cell lymphoma selected from the group consisting of cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), adult T cell leukemia / lymphoma (ATLL), angioimmunoblastic T cell lymphoma (AITL), extranodal NK / T cell lymphoma, and hepatosplenic T cell lymphoma.

10. In the 8th paragraph, the lymphoma is Burkitt's lymphoma, B cell non-Hodgkin lymphoma (NHL), B cell chronic lymphocytic leukemia (B-CLL), B cell acute lymphoblastic leukemia (B-ALL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma, chronic lymphocytic leukemia (CLL), mantle cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), intravascular large B cell lymphoma (IVLBCL), primary effusion lymphoma (PMBCL), A pharmaceutical composition, wherein the B-cell lymphoma is at least one selected from the group consisting of effusion lymphoma, lymphomatoid granulomatosis, primary central nervous system lymphoma (PCNSL), ALK-positive large B-cell lymphoma, and plasmablastic lymphoma (PBL).

11. (i) A combination kit for preventing or treating cancer comprising an EZH2 inhibitor and (ii) a JAK3 inhibitor.

12. A combination kit in claim 11, wherein the EZH2 inhibitor is MS1943 or MS177.

13. A combination kit according to claim 11, wherein the JAK3 inhibitor is Decernotinib.

14. A combination kit according to claim 11, wherein (i) the EZH2 inhibitor and (ii) the JAK3 inhibitor are administered simultaneously or sequentially.

15. A combination kit according to claim 11, wherein the cancer is at least one selected from the group consisting of lymphoma, lung cancer, pancreatic cancer, breast cancer, and colon cancer.

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