KR20240072935A - Pharmaceutical composition for the prevention or treatment of cancer, comprising EZH2 degrader and BTK inhibitor - Google Patents
Pharmaceutical composition for the prevention or treatment of cancer, comprising EZH2 degrader and BTK inhibitor Download PDFInfo
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- KR20240072935A KR20240072935A KR1020230156549A KR20230156549A KR20240072935A KR 20240072935 A KR20240072935 A KR 20240072935A KR 1020230156549 A KR1020230156549 A KR 1020230156549A KR 20230156549 A KR20230156549 A KR 20230156549A KR 20240072935 A KR20240072935 A KR 20240072935A
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- cancer
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- lymphoma
- inhibitor
- ezh2
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Abstract
본 발명은 EZH2 저해제 및 BTK 억제제를 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것으로, 지금까지 치료효과가 낮았던 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종뿐만 아니라 다른 암종에도 치료 효과가 현저히 우수한 것을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing an EZH2 inhibitor and a BTK inhibitor, which treats not only Epstein-Barr virus (EBV)-related lymphoma, which has had a low therapeutic effect so far, but also other cancer types. It was confirmed that the effect was significantly excellent.
Description
본 발명은 EZH2 저해제 및 BTK 억제제를 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것으로, 지금까지 치료효과가 낮았던 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종뿐만 아니라 다른 암종에도 치료 효과가 현저히 우수한 것을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing an EZH2 inhibitor and a BTK inhibitor, which treats not only Epstein-Barr virus (EBV)-related lymphoma, which has had a low therapeutic effect so far, but also other cancer types. It was confirmed that the effect was significantly excellent.
림프종은 B 또는 T 림프구가 암이 되는 경우 발생하는 혈액암이다. 림프종은 림프결절, 비장, 골수, 혈액 또는 다른 기관에서 발달되고 결국 암이 될 수 있다. 림프종은 림프조직에 생기는 악성종양으로 림프 조직이 아닌 부위에도 발생할 수 있다. 림프조직이 아닌 부위에서 발생하는 경우를 림프절 외 림프종이라고 하는데, 주로 코 속과 목구멍이 연결되는 곳이나 위장관, 뇌 등에 잘 나타나는 것으로 알려져 있다. 림프종은 미국의 경우 전체 암 발생의 2.1%, 영국의 경우 2.8%를 차지하며, 우리 나라의 경우 4%를 차지하여 동양에서는 빈도가 높은 편의 암이다. 림프종은 크게 호지킨 림프종과 비호지킨 림프종으로 구분되며, WHO 통계에 따르면 2020년 기준 림프종 신규 발병자는 627,439명, 이 중 호지킨 림프종과 비호지킨 림프종 발병비율은 각각 13% 및 87%이다.Lymphoma is a blood cancer that occurs when B or T lymphocytes become cancerous. Lymphoma can develop in lymph nodes, spleen, bone marrow, blood, or other organs and eventually become cancer. Lymphoma is a malignant tumor that occurs in lymphoid tissue and can occur in areas other than lymphoid tissue. Cases that occur in areas other than lymphoid tissue are called extranodal lymphomas, and are known to occur mainly in areas where the nose and throat are connected, the gastrointestinal tract, and the brain. Lymphoma accounts for 2.1% of all cancers in the United States, 2.8% in the United Kingdom, and 4% in Korea, making it a common cancer in the East. Lymphoma is largely divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma. According to WHO statistics, as of 2020, there are 627,439 new cases of lymphoma, of which the incidence rates of Hodgkin's lymphoma and non-Hodgkin's lymphoma are 13% and 87%, respectively.
헤르페스 바이러스(Herpes virus)에 속하는 엡스타인-바 바이러스(Ebstein-Barr virus; EBV)는 90% 이상의 정상인에게 감염되어 대부분의 사람에서 무증상의 잠복 감염을 일으키나, 골수 이식 후 또는 장기이식 등으로 면역체계가 장기적으로 저하된 개인에서 EBV는 림프세포증식성 질환(Lymphoproliferative disease), 버킷 림프종(Burkitt's lymphoma), 비인두암종(Nasopharyngeal carcinoma; NPC), 호지킨스 질환(Hodgkin's disease) 등의 종양을 유발하는 원인으로 알려져 있다.Epstein-Barr virus (EBV), a herpes virus, infects more than 90% of normal people and causes asymptomatic latent infection in most people, but the immune system is weakened after bone marrow transplant or organ transplant. In individuals with long-term decline, EBV is known to cause tumors such as lymphoproliferative disease, Burkitt's lymphoma, Nasopharyngeal carcinoma (NPC), and Hodgkin's disease. there is.
EBV와 연관성이 있는 림프세포성질환으로 호지킨 림프종을 포함하여 비형(nasal type) 림프절외 NK-T세포림프종과 이식 후 림프증식성 질환(post-transplant lymphoproliferative disease; PTLD)등이 있다.Lymphocytic diseases associated with EBV include Hodgkin's lymphoma, nasal type extranodal NK-T cell lymphoma, and post-transplant lymphoproliferative disease (PTLD).
림프종 중에서도 EBV 연관 종양, 예를 들어, 버킷 림프종의 기존의 치료법으로는 면역억제제의 감량, 항바이러스제의 사용, 항암화학요법, 및 리툭시맙 (Rituximab) 항체 투여 등이 시행되어 오고 있으나, 치료 반응율의 차이가 있어 아직까지 효과적인 치료법은 정립되지 않은 상황이다. 따라서 현재로서는 EBV 연관 종양의 치료 및 완치를 위한 새로운 치료법 개발 노력이 시급한 실정이다.Among lymphomas, conventional treatments for EBV-related tumors, such as Burkitt's lymphoma, include reduction of immunosuppressants, use of antiviral drugs, chemotherapy, and administration of rituximab antibody, but treatment response rate is low. Due to differences in treatment, an effective treatment has not yet been established. Therefore, there is currently an urgent need to develop new treatments for the treatment and cure of EBV-related tumors.
우리 몸의 뼈는 몸의 체형을 유지하고 운동을 할 수 있게 하며 칼슘 조절에 관여하는 기능을 하고, 뼈의 내부에는 뼈보다는 촘촘하지 않은 골수라는 조직이 있는데, 이곳에서 백혈구, 적혈구, 혈소판 등의 혈액 세포를 만드는 기능을 한다. 백혈병이란 이러한 혈액 세포에 발생한 암으로서, 비정상적인 혈액세포 (대부분 백혈구에서 유래하며 드물게 적혈구계, 혈소판 계에서도 가능)가 과도하게 증식하여 정상적인 백혈구와 적혈구, 혈소판의 생성이 억제되는 혈액암을 통칭하는 용어이다.The bones in our body maintain the body's shape, enable exercise, and are involved in calcium regulation. Inside the bone, there is a tissue called bone marrow, which is less dense than bone, where white blood cells, red blood cells, platelets, etc. It functions to create blood cells. Leukemia is a cancer that occurs in these blood cells, and is a general term for blood cancer in which abnormal blood cells (mostly derived from white blood cells, but rarely also from the erythroid and platelet systems) proliferate excessively, suppressing the production of normal white blood cells, red blood cells, and platelets. am.
정상적인 백혈구 수가 감소하면 면역저하를 일으켜 세균감염에 의한 패혈증을 일으킬 수 있고, 적혈구의 감소는 빈혈 증상(어지러움, 두통, 호흡곤란)을 가져오며, 혈소판의 감소는 출혈 경향을 일으킨다. 또한, 과다 증식된 백혈병 세포 자체로 인하여 고열, 피로감, 뼈의 통증, 설사, 의식저하, 호흡곤란, 출혈 경향도 일으킬 수 있다.A decrease in the normal number of white blood cells can cause a decrease in immunity and cause sepsis due to bacterial infection. A decrease in red blood cells causes symptoms of anemia (dizziness, headache, difficulty breathing), and a decrease in platelets causes bleeding tendencies. Additionally, the overproliferated leukemia cells themselves can cause high fever, fatigue, bone pain, diarrhea, decreased consciousness, difficulty breathing, and bleeding tendencies.
백혈병은 세포의 분화 정도, 즉 악화 속도에 따라 급성과 만성으로 나뉘고, 세포의 기원에 따라 골수성과 림프구성으로 나뉜다. 흔히 급성 골수성 백혈병 (Acute myeloid leukemia), 급성 림프구성 백혈병 (Acute lymphocytic leukemia), 만성 골수성 백혈병 (Chronic myeloid leukemia) 및 만성 림프구성 백혈병 (Chronic lymphocytic leukemia)의 네 가지 형태로 분류된다.Leukemia is divided into acute and chronic depending on the degree of cell differentiation, that is, the rate of deterioration, and is divided into myeloid and lymphocytic depending on the origin of the cell. It is commonly classified into four types: Acute myeloid leukemia, Acute lymphocytic leukemia, Chronic myeloid leukemia, and Chronic lymphocytic leukemia.
대장은 충수, 맹장, 결장, 직장, 그리고 항문관으로 나뉘며, 결장은 다시 상행 결장, 횡행 결장, 하행 결장, 에스상 결장으로 나뉘는데, 대장암은 이 가운데 맹장, 결장과 직장에 생기는 악성 종양이다. 발생 위치에 따라 결장에 생기면 결장암, 직장에 생기면 직장암이라고 하며, 이를 통칭하여 대장암 혹은 결장직장암이라고 한다.The large intestine is divided into the appendix, cecum, colon, rectum, and anal canal. The colon is further divided into the ascending colon, transverse colon, descending colon, and sigmoid colon. Colon cancer is a malignant tumor that occurs in the appendix, colon, and rectum. Depending on where it occurs, it is called colon cancer if it occurs in the colon, and rectal cancer if it occurs in the rectum. These are collectively called colon cancer or colorectal cancer.
유방암은 유방 안에 머무는 양성 종양과 달리 유방 밖으로 퍼져 생명을 위협할 수 있는 악성 종양이다. 유방에는 여러 종류의 세포가 있는데 어느 것이든 암세포로 변할 수 있으므로 발생 가능한 유방암의 종류는 꽤 많다.Unlike benign tumors that stay within the breast, breast cancer is a malignant tumor that can spread outside the breast and threaten life. There are many different types of cells in the breast, and any of them can turn into cancerous cells, so there are quite a few types of breast cancer that can occur.
유방암은 미국이나 유럽 등 선진 국가에서의 여성암 중에서 가장 흔한 암으로，40세에서 55세 사이의 미국 여성의 제1의 사망원인이 되고 있다. 평생 동안 9명의 여성 중 1명에서 유방암이 발생하고 유방암 환자 수 역시 매년 약 15%씩 증가하는 추세이다. 한국에서는 1995년 여성 암 환자 중 약 11.9%를 유방암이 차지하고 있으며 자궁 경부암과 위암에 이어 세 번째로 흔한 암이 되었고， 위암， 간암, 자궁암， 폐암에 이어 다섯 번째로 사망률이 높은 암으로, 그 빈도가 매년 증가하는 추세에 있다.Breast cancer is the most common cancer among women in developed countries such as the United States and Europe, and is the leading cause of death for American women between the ages of 40 and 55. Breast cancer develops in one in nine women during her lifetime, and the number of breast cancer patients is also increasing by about 15% every year. In Korea, breast cancer accounted for approximately 11.9% of female cancer patients in 1995, becoming the third most common cancer after cervical cancer and stomach cancer, and the fifth highest mortality rate after stomach cancer, liver cancer, uterine cancer, and lung cancer. There is a trend of increasing every year.
EZH2 (Enhancer of zeste homolog 2)는 히스톤 메틸화 및 궁극적으로 전사 억제에 참여하는 EZH2 유전자에 의해 암호화되는 히스톤-리신 N-메틸트랜스퍼라제 효소이다. EZH2 레벨은 정상 조직과 비교하여 암 조직에서 비정상적으로 상승하며, EZH2는 후기 종양 또는 불량한 예후에서 가장 높게 발현된다. EZH2는 종양 발달을 억제하는 유전자를 억제하거나 EZH2 활성을 차단하면 종양 성장을 늦출 수 있다.EZH2 (Enhancer of zeste homolog 2) is a histone-lysine N-methyltransferase enzyme encoded by the EZH2 gene that participates in histone methylation and ultimately transcriptional repression. EZH2 levels are abnormally elevated in cancer tissues compared to normal tissues, and EZH2 is most highly expressed in late-stage tumors or poor prognosis. EZH2 can slow tumor growth by suppressing genes that suppress tumor development or by blocking EZH2 activity.
BTK (Bruton's tyrosine kinase)는 티로신 키나아제 서브패밀리의 일원이며, 키나아제의 Tec 패밀리에 속한다. 이것은 B 세포에서 주로 발현되며, 림프계, 조혈계 및 혈액계에 분포한다. B 세포 수용체(BCR)는 만성 림프구성 백혈병(CLL) 및 비-호지킨 림프종(NHL), 맨틀 세포 림프종(MCL), 및 미만성 거대 B-세포 림프종(DLBCL)을 포함하는 다양한 림프종의 증식 및 생존을 조절하는데 결정적인 역할을 한다. 브루톤 티로신 키나아제(BTK)는 BCR 신호전달 경로에서의 핵심 단백질 키나아제로서, B 세포 림프 조직 질병의 다양한 질환과 매우 연관된다. 따라서, BTK를 표적으로 하는 소분자 억제제는 B 세포 악성물 및 자가면역 질환의 치료에 유익할 수 있다.BTK (Bruton's tyrosine kinase) is a member of the tyrosine kinase subfamily and belongs to the Tec family of kinases. It is mainly expressed in B cells and is distributed throughout the lymphatic, hematopoietic, and hematological systems. The B cell receptor (BCR) promotes proliferation and survival in chronic lymphocytic leukemia (CLL) and various lymphomas, including non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). plays a decisive role in regulating. Bruton's tyrosine kinase (BTK) is a key protein kinase in the BCR signaling pathway and is highly implicated in a variety of B cell lymphoid tissue diseases. Therefore, small molecule inhibitors targeting BTK may be beneficial in the treatment of B cell malignancies and autoimmune diseases.
이에 본 발명자들은 PROTAC (Proteolysis targeting chimera) 기반의 EZH2 저해제 및 BTK 억제제를 병용하여 사용함으로써 지금까지 치료효과가 낮았던 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종뿐만 아니라 다른 암종에도 치료 효과가 우수한 것을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors used a PROTAC (Proteolysis targeting chimera)-based EZH2 inhibitor and a BTK inhibitor in combination to demonstrate a therapeutic effect not only on Epstein-Barr virus (EBV)-related lymphoma, which has had a low therapeutic effect so far, but also on other cancer types. After confirming that it was excellent, the present invention was completed.
본 발명의 목적은 EZH2 저해제 및 BTK 억제제를 포함하는, 암의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a BTK inhibitor.
본 발명의 다른 목적은 EZH2 저해제 및 BTK 억제제를 포함하는 약제학적 조성물의 암 치료 용도를 제공하는 것이다.Another object of the present invention is to provide a use of a pharmaceutical composition comprising an EZH2 inhibitor and a BTK inhibitor for treating cancer.
본 발명의 다른 목적은 EZH2 저해제 및 BTK 억제제를 병용 투여함으로써 암을 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method of treating cancer by combined administration of an EZH2 inhibitor and a BTK inhibitor.
본 발명은 EZH2 저해제 및 BTK 억제제를 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것으로, 지금까지 치료효과가 낮았던 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종뿐만 아니라 다른 암종에도 치료 효과가 현저히 우수한 것을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing an EZH2 inhibitor and a BTK inhibitor, which treats not only Epstein-Barr virus (EBV)-related lymphoma, which has had a low therapeutic effect so far, but also other cancer types. It was confirmed that the effect was significantly excellent.
이하 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 예는 EZH2 저해제 및 BTK 억제제를 포함하는, 암의 예방 또는 치료용 약제학적 조성물에 관한 것이다.One example of the present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising an EZH2 inhibitor and a BTK inhibitor.
본 발명에 있어서 EZH2 저해제는 PROTAC (Proteolysis targeting chimera) 기반인 것을 특징으로 하는 것일 수 있다.In the present invention, the EZH2 inhibitor may be based on PROTAC (Proteolysis targeting chimera).
PROTAC은 2개의 활성 도메인과 링커로 구성된 이종이기능성 소분자로서, 세포 내 단백질 분해를 유도하여 원하지 않는 특정 단백질을 제거할 수 있는 기능을 가진다.PROTAC is a heterobifunctional small molecule composed of two active domains and a linker, and has the ability to remove specific unwanted proteins by inducing intracellular protein degradation.
본 발명에 있어서 PROTAC 기반의 EZH2 저해제는 EZH2 단백질의 분해를 목적으로 하는 물질을 의미하는 것일 수 있다.In the present invention, PROTAC-based EZH2 inhibitor may refer to a substance aimed at decomposing EZH2 protein.
본 발명에 있어서 EZH2 저해제는 MS1943 또는 MS177인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor may be MS1943 or MS177, but is not limited thereto.
본 발명에 있어서 EZH2 저해제는 하기 구조식 1 (MS1943) 또는 구조식 2 (MS177)의 구조를 갖는 화합물인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor may be a compound having the structure of Structural Formula 1 (MS1943) or Structural Formula 2 (MS177) below, but is not limited thereto.
[구조식 1][Structural Formula 1]
[구조식 2][Structural Formula 2]
본 발명에 있어서 BTK 억제제는 이브루티닙 (Ibrutinib), 아칼라브루티닙 (acalabrutinib) 및 자누브루티닙 (zanubrutinib)으로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the BTK inhibitor may be one or more selected from the group consisting of ibrutinib, acalabrutinib, and zanubrutinib, but is not limited thereto.
본 발명에 있어서 암은 림프종, 백혈병, 대장암, 유방암, 췌장암, 폐암, 위암, 뇌암, 자궁암, 난소암, 전립선암, 고환암, 방광암, 식도암, 간암, 담낭암, 육종, 피부암, 다발성 골수종, 갑상선암 및 두경부암으로 이루어진 군으로부터 선택되는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, cancer includes lymphoma, leukemia, colon cancer, breast cancer, pancreatic cancer, lung cancer, stomach cancer, brain cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, esophageal cancer, liver cancer, gallbladder cancer, sarcoma, skin cancer, multiple myeloma, thyroid cancer, and It may be selected from the group consisting of head and neck cancer, but is not limited thereto.
본 발명에 있어서 림프종은 불응성 림프종인 것일 수 있다.In the present invention, the lymphoma may be a refractory lymphoma.
본 발명에 있어서 림프종은 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종인 것일 수 있다.In the present invention, the lymphoma may be Epstein-Barr virus (EBV)-related lymphoma.
본 발명에 있어서 림프종은 림프세포증식성 질환 (Lymphoproliferative disease), 버킷 림프종 (Burkitt's lymphoma), 비인두암종 (Nasopharyngeal carcinoma(NPC)), 호지킨스 질환 (Hodgkin's disease) 및 미만선 큰 B세포 림프종(Diffuse large B cell lymphoma)으로 이루어진 군에서 선택된 1종 이상인 것일 수 있다. In the present invention, lymphoma includes lymphoproliferative disease, Burkitt's lymphoma, Nasopharyngeal carcinoma (NPC), Hodgkin's disease, and diffuse large B-cell lymphoma. It may be one or more types selected from the group consisting of B cell lymphoma.
본 발명에 있어서 EZH2 저해제 및 BTK 억제제는 각각 별개의 제제로 존재하는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor and the BTK inhibitor may exist as separate agents, but are not limited thereto.
본 발명에 있어서 EZH2 저해제 및 BTK 억제제는 동시에, 순차적으로, 또는 교번으로 투여되는 것일 수 있다.In the present invention, the EZH2 inhibitor and the BTK inhibitor may be administered simultaneously, sequentially, or alternately.
본 발명에 있어서 EZH2 저해제 및 BTK 억제제는 약 1분, 약 5분, 약 10분, 약 15분, 약 30분, 약 45분, 약 1시간, 약 2시간, 약 4시간, 약 6시간, 약 12시간, 약 24시간, 약 48시간, 약 72시간, 약 96시간, 약 1주, 약 2주, 약 3주, 약 4주, 약 5주, 약 6주, 약 8주, 또는 약 12주의 시간 간격으로 순차적으로 투여될 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor and the BTK inhibitor are administered for 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 It may be administered sequentially at a time interval of 12 weeks, but is not limited to this.
본 발명에 있어서 EZH2 저해제는 0.1 mg/kg 내지 1000 mg/kg, 0.1 mg/kg 내지 500 mg/kg, 0.1 mg/kg 내지 100 mg/kg, 0.1 mg/kg 내지 50 mg/kg, 1 mg/kg 내지 1000 mg/kg, 1 mg/kg 내지 500 mg/kg, 1 mg/kg 내지 100 mg/kg, 1 mg/kg 내지 50 mg/kg, 5 mg/kg 내지 1000 mg/kg, 5 mg/kg 내지 500 mg/kg, 5 mg/kg 내지 100 mg/kg 또는 5 mg/kg 내지 50 mg/kg의 용량으로 투여되는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor is used in an amount of 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. 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 It may be administered at a dose of kg to 500 mg/kg, 5 mg/kg to 100 mg/kg, or 5 mg/kg to 50 mg/kg, but is not limited thereto.
본 발명에 있어서 BTK 억제제는 0.1 mg/kg 내지 1000 mg/kg, 0.1 mg/kg 내지 500 mg/kg, 0.1 mg/kg 내지 100 mg/kg, 0.1 mg/kg 내지 50 mg/kg, 1 mg/kg 내지 1000 mg/kg, 1 mg/kg 내지 500 mg/kg, 1 mg/kg 내지 100 mg/kg, 1 mg/kg 내지 50 mg/kg, 5 mg/kg 내지 1000 mg/kg, 5 mg/kg 내지 500 mg/kg, 5 mg/kg 내지 100 mg/kg 또는 5 mg/kg 내지 50 mg/kg의 용량으로 투여되는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the BTK inhibitor is 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. 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 It may be administered at a dose of kg to 500 mg/kg, 5 mg/kg to 100 mg/kg, or 5 mg/kg to 50 mg/kg, but is not limited thereto.
본 발명에 있어서 약제학적 조성물은, 필요에 따라, 매일 1 내지 6회, 1 내지 5회, 1 내지 4회 또는 1 내지 3회 투여될 수 있으나, 이에 한정되는 것은 아니다.In 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, if necessary, but is not limited thereto.
본 발명에 있어서 약제학적 조성물은 다음의 방식으로 투여될 수 있다: 경구, 협측, 흡입 스프레이, 설하, 직장, 경피, 질 점막, 점막경유, 국소, 비강, 또는 장내 투여; 비경구 투여, 예컨대 근육내 주사, 피하 주사, 골수내 주사, 뿐만 아니라 척수강내 또는 뇌 직접 투여, 인시튜 투여, 피하, 복강내, 정맥내 주사, 관절내 활막, 흉골내, 간내, 병변내, 두개내, 복내, 비강, 또는 안구내 주사; 또는 기타 약물 전달 방식.The pharmaceutical composition of the present invention can be administered in the following ways: oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal mucosal, transmucosal, topical, nasal, or enteral administration; Parenteral administration, such as intramuscular injection, subcutaneous injection, intramedullary injection, as well as intrathecal or direct cerebral administration, in situ administration, subcutaneous, intraperitoneal, intravenous injection, intraarticular synovial, intrasternal, intrahepatic, intralesional, Intracranial, intraperitoneal, nasal, or intraocular injection; or other methods of drug delivery.
본 발명에 있어서 약제학적 조성물은 제약상 허용되는 담체, 희석제, 또는 부형제를 추가로 포함할 수 있다.In the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable carrier, diluent, or excipient.
본 발명에 있어서 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다. In the present invention, carriers commonly used in preparation include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, and polyvinyl. It may be one or more selected from the group consisting of pyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. .
본 발명에 있어서 희석제는 인산이칼슘, 황산칼슘, 락토즈, 소르비톨, 수크로즈, 이노시톨, 셀룰로스, 카올린, 만니톨, 염화나트륨, 건조 전분 및 분말 당으로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the diluent may be one or more selected from the group consisting of dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar, but is limited thereto. It doesn't work.
본 발명에 있어서 부형제는 부착방지제, 결합제, 코팅제, 착색제, 염료, 붕해제, 향미제, 활택제, 윤활제, 보존제, 흡착제, 감미제, 비히클, 습윤제, 유화제 및 pH 완충제로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the excipient is one or more selected from the group consisting of anti-adhesion agents, binders, coating agents, colorants, dyes, disintegrants, flavoring agents, lubricants, lubricants, preservatives, adsorbents, sweeteners, vehicles, wetting agents, emulsifiers, and pH buffering agents. It may be, but is not limited to this.
본 발명에 있어서 약제학적 조성물은 정제, 캡슐, 과립, 시럽, 산제, 로젠지, 샤세제, 카세제, 엘릭시르제, 현탁액, 유제, 용액, 시럽, 에어로졸, 연고, 크림, 및 주사제 형태일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the pharmaceutical composition may be in the form of tablets, capsules, granules, syrups, powders, lozenges, cachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, and injections. , but is not limited to this.
본 발명에 있어서 용어 "치료"는 질환 또는 병태의 증상의 감소, 완화, 또는 개선, 잠재적 대사로 인한 증상의 개선, 질환 또는 증상의 억제, 예컨대 질환 또는 장애의 진행 방지, 질환 또는 병태의 개선, 질환 또는 병태의 퇴행 유발, 질환 또는 병태로 인한 상태의 완화, 또는 질환 또는 병태의 증상 예방을 의미한다.As used herein, the term "treatment" refers to reducing, alleviating, or improving the symptoms of a disease or condition, improving symptoms due to metabolic potential, suppressing the disease or symptoms, such as preventing the progression of the disease or disorder, improving the disease or condition, It means causing regression of a disease or condition, alleviating the condition caused by the disease or condition, or preventing symptoms of the disease or condition.
본원에 사용된 용어 "약"은 수식하는 값의 ±10%, 더 바람직하게는 ±5%, 가장 바람직하게는 ±2%를 의미하므로, 당업자는 수식된 값에 따라 용어 "약"의 범위를 명확하게 결정할 수 있다.As used herein, the term "about" means ±10%, more preferably ±5%, and most preferably ±2% of the value it modifies, so those skilled in the art will be able to determine the range of the term "about" according to the modified value. can be decided clearly.
본 발명의 다른 일 예는 EZH2 저해제 및 BTK 억제제를 포함하는 약제학적 조성물의 암 치료 용도에 관한 것이다.Another example of the present invention relates to the use of a pharmaceutical composition containing an EZH2 inhibitor and a BTK inhibitor for treating cancer.
본 발명의 또 다른 일 예는 치료를 필요로 하는 대상체에게 유효량의 EZH2 저해제 및 BTK 억제제를 투여하는 단계를 포함하는 암 치료 방법에 관한 것이다.Another example of the present invention relates to a method of treating cancer comprising administering an effective amount of an EZH2 inhibitor and a BTK inhibitor to a subject in need of treatment.
본원에 사용된 용어 "대상체"는 인간 (예를 들어, 환자) 및 동물 (예를 들어, 마우스, 래트, 개, 고양이, 토끼, 닭, 원숭이 등)을 포함하는 의미이다.As used herein, the term “subject” is meant to include humans (e.g., patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, monkeys, etc.).
본원에 사용된 용어 "유효량"은 과도한 독성 부작용을 일으키지 않으면서 치료될 질환 또는 병태의 임상 증상의 유의한 감소를 제공하는 약제학적 조성물의 양 (예를 들어, 용량)을 의미한다.As used herein, the term “effective amount” means an amount (e.g., dose) of a pharmaceutical composition that provides a significant reduction in the clinical symptoms of the disease or condition being treated without causing excessive toxic side effects.
본원에 사용된 용어 "용량"은 대상체 체중의 킬로그램(kg) 당 활성 물질의 중량 (예를 들어, 밀리그램(mg))을 의미한다.As used herein, the term “dose” refers to the weight (e.g., milligrams (mg)) of active agent per kilogram (kg) of a subject's body weight.
본 발명에 있어서 EZH2 저해제 및 BTK 억제제는 각각 별개의 제제로 존재하는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the EZH2 inhibitor and the BTK inhibitor may exist as separate agents, but are not limited thereto.
본 발명에 있어서 EZH2 저해제 및 BTK 억제제는 동시에, 순차적으로, 또는 교번으로 투여되는 것일 수 있다.In the present invention, the EZH2 inhibitor and the BTK inhibitor may be administered simultaneously, sequentially, or alternately.
본 발명은 EZH2 저해제 및 BTK 억제제를 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것으로, 지금까지 치료효과가 낮았던 엡스타인-바 바이러스 (Ebstein-Barr virus; EBV) 연관 림프종뿐만 아니라 다른 암종에도 치료 효과가 현저히 우수한 것을 확인하였다.The present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing an EZH2 inhibitor and a BTK inhibitor, which treats not only Epstein-Barr virus (EBV)-related lymphoma, which has had a low therapeutic effect so far, but also other cancer types. It was confirmed that the effect was significantly excellent.
도 1은 B세포 림프종 세포주 (Daudi)에 EZH2 저해제 또는 BTK 억제제를 각각 단독 처리한 경우, 및 EZH2 저해제 및 BTK 억제제를 병용 처리한 경우의 흡광도를 측정한 결과를 나타낸 그래프이다.
도 2는 T세포 백혈병 세포주 (Jurkat)에 EZH2 저해제 또는 BTK 억제제를 각각 단독 처리한 경우, 및 EZH2 저해제 및 BTK 억제제를 병용 처리한 경우의 흡광도를 측정한 결과를 나타낸 그래프이다.
도 3은 대장암 세포주 (HCT-116)에 EZH2 저해제 또는 BTK 억제제를 각각 단독 처리한 경우, 및 EZH2 저해제 및 BTK 억제제를 병용 처리한 경우의 흡광도를 측정한 결과를 나타낸 그래프이다.
도 4는 유방암 세포주 (MDA-MB-231)에 EZH2 저해제 또는 BTK 억제제를 각각 단독 처리한 경우, 및 EZH2 저해제 및 BTK 억제제를 병용 처리한 경우의 흡광도를 측정한 결과를 나타낸 그래프이다.Figure 1 is a graph showing the results of measuring absorbance when a B-cell lymphoma cell line (Daudi) was treated with an EZH2 inhibitor or a BTK inhibitor alone, and when an EZH2 inhibitor and a BTK inhibitor were combined.
Figure 2 is a graph showing the results of measuring absorbance when a T-cell leukemia cell line (Jurkat) was treated with an EZH2 inhibitor or a BTK inhibitor alone, and when an EZH2 inhibitor and a BTK inhibitor were combined.
Figure 3 is a graph showing the results of measuring absorbance when a colon cancer cell line (HCT-116) was treated with an EZH2 inhibitor or a BTK inhibitor alone, and when an EZH2 inhibitor and a BTK inhibitor were combined.
Figure 4 is a graph showing the results of measuring absorbance when a breast cancer cell line (MDA-MB-231) was treated with an EZH2 inhibitor or a BTK inhibitor alone, and when an EZH2 inhibitor and a BTK inhibitor were combined.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
실험예 1. 암 세포주의 흡광도 측정Experimental Example 1. Measurement of absorbance of cancer cell lines
B세포 림프종 세포주 (Daudi), T세포 백혈병 세포주 (Jurkat), 대장암 세포주 (HCT-116), 및 유방암 세포주 (MDA-MB-231)를 사용하여 하나의 well당 2×10^4/100μL의 세포를 10% FBS (Gibco), antibiotics (Gibco), glutamax (Gibco)를 넣은 RPMI 배지 (Gibco)에서 배양하였다. BTK 억제제 (Ibrutinib)와 PROTAC 기반 EZH2 저해제 (MS1943, MS177)를 조건 별로 각각 자극한 후, 72시간 동안 CO2 인큐베이터에서 배양하였다. 그 다음, Cell Counting Kit-8 (BIOMAX) 시약을 well당 10μL으로 자극하여 3시간이 지난 후 450nm에서 흡광도를 측정하여 그 결과를 표 1 및 도 1 (B세포 림프종 세포주; Daudi), 표 2 및 도 2 (T세포 백혈병 세포주; Jurkat), 표 3 및 도 3 (대장암 세포주; HCT-116), 및 표 4 및 도 4 (유방암 세포주; MDA-MB-231)에 나타내었다. 통계는 t-test를 통해 분석하였으며, * < .05, ** < .01, *** < .001, **** < .0001을 의미한다.2×10^4/100μL per well using B-cell lymphoma cell line (Daudi), T-cell leukemia cell line (Jurkat), colon cancer cell line (HCT-116), and breast cancer cell line (MDA-MB-231). Cells were cultured in RPMI medium (Gibco) supplemented with 10% FBS (Gibco), antibiotics (Gibco), and glutamax (Gibco). After stimulation with BTK inhibitor (Ibrutinib) and PROTAC-based EZH2 inhibitor (MS1943, MS177) for each condition, the cells were cultured in a CO2 incubator for 72 hours. Next, stimulate with 10 μL per well of Cell Counting Kit-8 (BIOMAX) reagent and measure absorbance at 450 nm after 3 hours. The results are shown in Table 1 and Figure 1 (B-cell lymphoma cell line; Daudi), Table 2 and It is shown in Figure 2 (T-cell leukemia cell line; Jurkat), Table 3 and Figure 3 (colon cancer cell line; HCT-116), and Table 4 and Figure 4 (breast cancer cell line; MDA-MB-231). Statistics were analyzed using t-test, meaning * < .05, ** < .01, *** < .001, **** < .0001.
상기 표 1에서 확인할 수 있듯이, B 세포 림프종 세포주 (Daudi)에서 BTK 억제제인 Ibrutinib 단독 처리군은 10uM에서 0.390, PROTAC 기반 EZH2 저해제인 MS1943 단독 처리군은 10uM에서 0.539의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS1943 (5uM)의 병용 처리군은 0.256으로 흡광도 값이 현저히 감소한 것을 확인하였다. 그리고 또다른 PROTAC 기반 EZH2 저해제인 MS177의 단독 처리군은 10uM에서 0.339의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS177 (5uM)의 병용 처리군은 0.233으로 흡광도 값이 현저히 감소한 것을 확인하였다.As can be seen in Table 1, in the B-cell lymphoma cell line (Daudi), the group treated only with Ibrutinib, a BTK inhibitor, showed an absorbance value of 0.390 at 10uM, and the group treated only with MS1943, a PROTAC-based EZH2 inhibitor, showed an absorbance value of 0.539 at 10uM, while Ibrutinib ( In the group treated with the combination of 5uM) and MS1943 (5uM), the absorbance value was confirmed to be significantly reduced to 0.256. In addition, the group treated alone with MS177, another PROTAC-based EZH2 inhibitor, showed an absorbance value of 0.339 at 10uM, while the group treated in combination with Ibrutinib (5uM) and MS177 (5uM) showed a significant decrease in absorbance value to 0.233.
상기 표 2에서 확인할 수 있듯이, T 세포 백혈병 세포주 (Jurkat)에서 BTK 억제제인 Ibrutinib 단독 처리군은 10uM에서 1.033, PROTAC 기반 EZH2 저해제인 MS1943 단독 처리군은 10uM에서 0.671의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS1943 (5uM)의 병용 처리군은 0.323으로 흡광도 값이 현저히 감소한 것을 확인하였다. 그리고 또다른 PROTAC 기반 EZH2 저해제인 MS177의 단독 처리군은 10uM에서 0.491의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS177 (5uM)의 병용 처리군은 0.193으로 흡광도 값이 현저히 감소한 것을 확인하였다.As can be seen in Table 2, in the T cell leukemia cell line (Jurkat), the group treated only with Ibrutinib, a BTK inhibitor, showed an absorbance value of 1.033 at 10uM, and the group treated only with MS1943, a PROTAC-based EZH2 inhibitor, showed an absorbance value of 0.671 at 10uM, while Ibrutinib ( In the group treated with the combination of 5uM) and MS1943 (5uM), the absorbance value was confirmed to be significantly reduced to 0.323. In addition, the group treated alone with MS177, another PROTAC-based EZH2 inhibitor, showed an absorbance value of 0.491 at 10uM, while the group treated in combination with Ibrutinib (5uM) and MS177 (5uM) showed a significant decrease in absorbance value to 0.193.
상기 표 3에서 확인할 수 있듯이, 대장암 세포주 (HCT-116)에서 BTK 억제제인 Ibrutinib 단독 처리군은 10uM에서 2.100, PROTAC 기반 EZH2 저해제인 MS1943 단독 처리군은 10uM에서 1.588의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS1943 (5uM)의 병용 처리군은 1.076으로 흡광도 값이 현저히 감소한 것을 확인하였다. 그리고 또다른 PROTAC 기반 EZH2 저해제인 MS177의 단독 처리군은 10uM에서 1.63의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS177 (5uM)의 병용 처리군은 1.08으로 흡광도 값이 현저히 감소한 것을 확인하였다.As can be seen in Table 3 above, in the colon cancer cell line (HCT-116), the group treated only with Ibrutinib, a BTK inhibitor, showed an absorbance value of 2.100 at 10uM, and the group treated only with MS1943, a PROTAC-based EZH2 inhibitor, showed an absorbance value of 1.588 at 10uM, while Ibrutinib In the group treated with the combination of (5uM) and MS1943 (5uM), the absorbance value was confirmed to be significantly reduced to 1.076. In addition, the group treated alone with MS177, another PROTAC-based EZH2 inhibitor, showed an absorbance value of 1.63 at 10uM, while the group treated in combination with Ibrutinib (5uM) and MS177 (5uM) showed a significant decrease in absorbance value to 1.08.
상기 표 4에서 확인할 수 있듯이, 유방암 세포주 (MDA-MB-231)에서 BTK 억제제인 Ibrutinib 단독 처리군은 10uM에서 1.342, PROTAC 기반 EZH2 저해제인 MS1943 단독 처리군은 10uM에서 1.038의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS1943 (5uM)의 병용 처리군은 0.785로 흡광도 값이 현저히 감소한 것을 확인하였다. 그리고 또다른 PROTAC 기반 EZH2 저해제인 MS177의 단독 처리군은 10uM에서 0.827의 흡광도 값을 나타낸 반면, Ibrutinib (5uM)과 MS177 (5uM)의 병용 처리군은 0.508으로 흡광도 값이 현저히 감소한 것을 확인하였다.As can be seen in Table 4, in the breast cancer cell line (MDA-MB-231), the group treated only with Ibrutinib, a BTK inhibitor, showed an absorbance value of 1.342 at 10uM, and the group treated only with MS1943, a PROTAC-based EZH2 inhibitor, showed an absorbance value of 1.038 at 10uM. In the group treated with the combination of Ibrutinib (5uM) and MS1943 (5uM), the absorbance value was confirmed to be significantly reduced to 0.785. In addition, the group treated alone with MS177, another PROTAC-based EZH2 inhibitor, showed an absorbance value of 0.827 at 10uM, while the group treated in combination with Ibrutinib (5uM) and MS177 (5uM) showed a significant decrease in absorbance value to 0.508.
상기 결과를 통하여, BTK 억제제와 PROTAC 기반의 EZH2 저해제를 병용 처리할 경우, 이들을 각각 단독으로 처리할 경우에 비하여 암 세포주의 성장 억제 효과가 현저히 우수함을 확인하였다.Through the above results, it was confirmed that the combined treatment of the BTK inhibitor and the PROTAC-based EZH2 inhibitor had a significantly superior growth inhibition effect on cancer cell lines compared to the treatment of each agent alone.
Claims (7)
[구조식 1]
[구조식 2]
The pharmaceutical composition of claim 1, wherein the EZH2 inhibitor is a compound having the structure of Structural Formula 1 or Structural Formula 2 below.
[Structural Formula 1]
[Structural Formula 2]
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