KR102522963B1 - Composition for Antiobesity Comprising Capmatinib - Google Patents
Composition for Antiobesity Comprising Capmatinib Download PDFInfo
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- KR102522963B1 KR102522963B1 KR1020200151076A KR20200151076A KR102522963B1 KR 102522963 B1 KR102522963 B1 KR 102522963B1 KR 1020200151076 A KR1020200151076 A KR 1020200151076A KR 20200151076 A KR20200151076 A KR 20200151076A KR 102522963 B1 KR102522963 B1 KR 102522963B1
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- capmatinib
- pharmaceutical composition
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- cancer
- obesity
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Abstract
본 발명은 캡마티닙(Cabmatinib) 화합물을 포함하는 비만 예방용, 개선용 또는 치료용 조성물에 관한 것이다. 본 발명은 지방을 분해하고, 지방 합성을 억제하는 효과를 나타내므로, 본 발명은 비만의 예방 또는 치료에 널리 활용될 수 있다.The present invention relates to a composition for preventing, improving or treating obesity, including a compound of capmatinib (Cabmatinib). Since the present invention has the effect of decomposing fat and inhibiting fat synthesis, the present invention can be widely used for preventing or treating obesity.
Description
본 발명은 캡마티닙을 포함하는 항비만 조성물에 관한 것이다.The present invention relates to an anti-obesity composition comprising capmatinib.
비만은 일반적으로 체내에 지방 조직이 과다한 상태인 것을 의미하며, 음식물로 섭취한 에너지가 신체활동 등으로 소비한 에너지와 균형을 이루지 못하여 잉여의 에너지가 체지방으로 축적되는 현상이다. 비만의 정도는 체질량지수(BMI, body mass index)로 평가하는데, 체질량지수는 사람의 체중(kg)을 신장의 제곱(m2)으로 나누어 계산한다. Obesity generally means a state in which adipose tissue is excessive in the body, and is a phenomenon in which energy consumed from food is not balanced with energy consumed through physical activities, etc., and thus surplus energy is accumulated as body fat. The degree of obesity is evaluated by body mass index (BMI), which is calculated by dividing a person's weight (kg) by the square of height (m 2 ).
최근 연구결과에 따르면, 비만의 기준이 되는 체질량지수가 높을수록 암종의 유병률이 높아졌다는 연구 결과가 있다. 상기 연구에서는 백혈병, 다발골수종, 췌장암, 자궁 내막암, 직장암, 콩팥세포암종, 악성흑색종, 비호지킨 림프종, 식도암, 뇌종양과 중추신경계 종양, 유방암, 대장암, 담낭암, 폐암, 간암, 난소암, 갑상선암, 방광암, 위암, 전립선암 등 20종의 암에 대하여 체질량지수와의 상관관계를 연구해본 결과, 3종의 암(방광암, 위암, 전립선암)을 제외한 모든 암에서 체질량지수가 암 유병의 관련 요인이 될 수 있다고 밝혀졌다. According to recent research results, there is a research result that the higher the body mass index, which is the criterion for obesity, the higher the prevalence of carcinoma. In the above study, leukemia, multiple myeloma, pancreatic cancer, endometrial cancer, rectal cancer, renal cell carcinoma, malignant melanoma, non-Hodgkin's lymphoma, esophageal cancer, brain tumor and central nervous system tumor, breast cancer, colon cancer, gallbladder cancer, lung cancer, liver cancer, ovarian cancer, As a result of studying the correlation with body mass index for 20 types of cancer, including thyroid, bladder, gastric, and prostate cancers, the body mass index was associated with cancer prevalence in all cancers except for three types of cancer (bladder, stomach, and prostate cancer). It turns out that this could be a factor.
따라서 암의 치료제인 동시에 비만의 억제 기능을 하는 약물이 개발된다면 비만을 예방할 수 있어, 관련 암의 발병을 사전에 예방할 수 있을 것이라 예상하였다. Therefore, it was expected that if a drug that is a cancer treatment and suppresses obesity at the same time is developed, obesity can be prevented, and the occurrence of related cancers can be prevented in advance.
일 양상은 캡마티닙(Capmatinib)을 유효성분으로 포함하는 비만의 예방 또는 치료용 약학적 조성물을 제공한다.One aspect provides a pharmaceutical composition for the prevention or treatment of obesity containing capmatinib as an active ingredient.
일 양상은 하기 화학식 1의 화합물을 유효성분으로 포함하는 비만의 예방 또는 치료용 약학적 조성물을 제공한다. One aspect provides a pharmaceutical composition for preventing or treating obesity comprising a compound of Formula 1 as an active ingredient.
[화학식 1] [Formula 1]
본 발명에서, 상기 화합물은 캡마티닙(Capmatinib)이다. 상기 캡마티닙은 c-Met 억제제로 전이된 MET 엑손14 스키핑(METex14) 변이를 특징으로 하는 비소세포폐암(NSCLC)의 치료에 사용되는 화합물 일 수 있다. 상기 c-Met은 티록신-단백질 키나아제 Met 또는 간세포 성장 인자 수용체(HGFR, hepatocyte growth factor receptor)라고도 하며, 암 발병을 일으킬 수 있는 요인이 될 수 있다. In the present invention, the compound is Capmatinib. The capmatinib may be a compound used for the treatment of non-small cell lung cancer (NSCLC) characterized by metastasized MET exon 14 skipping (METex14) mutation as a c-Met inhibitor. The c-Met is also called thyroxine-protein kinase Met or hepatocyte growth factor receptor (HGFR), and may be a factor that can cause cancer.
일 구체예에 따르면 상기 화합물은 암의 억제할 수 있으며, 동시에 비만을 예방 또는 치료할 수 있는 것일 수 있다. According to one embodiment, the compound may inhibit cancer and at the same time prevent or treat obesity.
일 구체예에 따르면 상기 화합물의 농도는 0.3nM 내지 1.5nM 일 수 있다. 예를 들면 0.8nM 내지 1.2nM일 수 있다. According to one embodiment, the concentration of the compound may be 0.3nM to 1.5nM. For example, it may be 0.8 nM to 1.2 nM.
본 발명의 실시예에 따르면 화합물의 농도가 2nM일 때는 세포 생존율이 급격히 떨어지는 것을 확인하였다. 상기 결과는 본 발명의 화합물이 높은 농도로 사용하였을 때는 지방 세포 생성을 억제하거나, 중성지방을 분해하는 것이 아닌 세포 자체를 공격할 수 있음을 나타내는 것일 수 있다. According to an embodiment of the present invention, it was confirmed that the cell viability decreased rapidly when the concentration of the compound was 2 nM. The above results may indicate that when the compound of the present invention is used at a high concentration, it can attack cells themselves rather than inhibiting fat cell production or decomposing neutral fat.
일 구체예에 따르면 상기 화합물은 지질침착을 억제하는 것일 수 있고, 지방 합성을 억제하는 것일 수 있다. 예를 들면, 상기 화합물은 지방 합성에 관여하는 SREBP1, C/EBPα, FAS 및 SCD1의 단백질 발현을 억제하는 것일 수 있다. According to one embodiment, the compound may inhibit lipid deposition or inhibit fat synthesis. For example, the compound may inhibit protein expression of SREBP1, C/EBPa, FAS and SCD1 involved in fat synthesis.
일 구체예에 따르면 상기 화합물은 지방을 분해하는 것일 수 있다. 예를 들면, 상기 화합물은 중성지방을 지방산과 글리세롤로 분해하는 것일 수 있으며, 글리세롤을 방출하는 것일 수 있다.According to one embodiment, the compound may decompose fat. For example, the compound may decompose neutral fat into fatty acids and glycerol, and may release glycerol.
본 발명의 용어 "예방"은 본 발명에 따른 약학적 조성물의 투여로 비만의 발병을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"는 상기 약학적 조성물의 투여로 비만의 발병 및 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다. The term "prevention" of the present invention refers to any action that suppresses or delays the onset of obesity by administration of the pharmaceutical composition according to the present invention, and "treatment" refers to the onset of obesity and symptoms of a subject by administration of the pharmaceutical composition. means any action that ameliorates or changes favorably.
일 구체예에 따르면 상기 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 동결건조제제 또는 좌제로 제형화하여 제공될 수 있다.According to one embodiment, the pharmaceutical composition may be formulated into tablets, pills, powders, granules, capsules, suspensions, internal solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, freeze-dried preparations or suppositories. there is.
이때, 상기 본 발명의 약학적 조성물은 약학적으로 허용 가능한 담체를 추가로 포함할 수 있다. 본 발명의 용어 "약학적으로 허용 가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제, 기제, 부형제, 윤활제 등 당업계에 공지된 것이라면 제한 없이 사용할 수 있다. 또한 본 발명의 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 나아가, 연고제, 로션제, 스프레이제, 패취제, 크림제, 산제, 현탁제, 겔제 또는 젤의 형태의 피부 외용제의 형태로 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 캡마티닙에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.In this case, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" of the present invention means that it exhibits characteristics that are not toxic to cells or humans exposed to the composition. The carrier may be used without limitation as long as it is known in the art such as a buffer, a preservative, a pain reliever, a solubilizer, an isotonic agent, a stabilizer, a base, an excipient, a lubricant, and the like. In addition, the pharmaceutical composition of the present invention is formulated according to conventional methods into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions. can Furthermore, it may be used in the form of ointments, lotions, sprays, patches, creams, powders, suspensions, gels, or skin external preparations in the form of gels. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations contain at least one excipient in the capmatinib, for example, starch, calcium carbonate, sucrose It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions for internal use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogeratin and the like may be used.
한편, 본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "투여"란, 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미하며 상기 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피 내 투여, 경구 투여, 국소 투여, 비 내 투여, 폐 내 투여, 직장 내 투여될 수 있으나, 이에 제한되지는 않는다.Meanwhile, the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "administration" of the present invention means introducing a predetermined substance into a subject by an appropriate method, and the administration route of the composition may be administered through any general route as long as it can reach the target tissue. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, but not limited thereto.
상기 용어 "개체"란 비만이 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 바람직하게는, 인간을 포함한 포유동물일 수 있다. 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 비만을 효과적으로 예방 또는 치료할 수 있으며, 본 발명의 약학적 조성물은 비만의 예방 또는 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The term "individual" refers to all animals, such as rats, mice, livestock, and the like, including humans who have or may develop obesity. Preferably, it may be a mammal including a human. Obesity can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject, and the pharmaceutical composition of the present invention can be used alone or as an agent for preventing or treating obesity, including surgery, hormone therapy, drug therapy, and biological response modifiers. It can be used in combination with methods using .
상기 용어 "약학적으로 유효한 양"이란 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다.The term "pharmaceutically effective amount" means an amount that is sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's sex, age, and weight , health condition, type of disease, severity, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration, and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other medical fields well known. It can be easily determined by a person skilled in the art according to known factors.
본 발명의 캡마티닙을 포함하는 조성물은 지방을 분해하고, 지방 합성을 억제하는 효과를 나타내므로, 본 발명은 비만의 예방 또는 치료에 널리 활용될 수 있다.Since the composition containing capmatinib of the present invention exhibits effects of decomposing fat and inhibiting fat synthesis, the present invention can be widely used for preventing or treating obesity.
도 1은 캡마티닙의 처리 농도에 따른 세포의 생존율을 나타낸 것이다.
도 2는 캡마티닙 투여시 지방세포의 분화에서 중성지방의 축적이 억제되는 것을 확인한 데이터로, 4일 및 7일차에 오일 레드 오(Oil-Red O) 염색기법을 통해 중성지방의 축적을 확인한 것이다.
도 3은 도 2에서 확인한 중성지방 함량을 정량화한 데이터이다. (A:4일차, B:7일차)
도 4는 분화된 3L3-L1에서 캡마티닙의 중성지방 분해 정도를 확인한 데이터이다.
도 5는 웨스턴 블롯팅을 통해 분화된 지방세포에서 발현한 초기 지질 신생합성에 관련된 SREBP1 단백질을 확인한 수치를 나타낸 데이터이다.
도 6은 웨스턴 블롯팅을 통해 분화된 지방세포에서 발현한 초기 지질 신생합성에 관련된 C/EBPα 단백질을 확인한 수치를 나타낸 데이터이다.
도 7은 웨스턴 블롯팅을 통해 분화된 지방세포에서 발현한 후기 지질 신생합성에 관련된 FAS 단백질을 확인한 수치를 나타낸 데이터이다.
도 8은 웨스턴 블롯팅을 통해 분화된 지방세포에서 발현한 후기 지질 신생합성에 관련된 SCD1 단백질을 확인한 수치를 나타낸 데이터이다.Figure 1 shows the survival rate of cells according to the treatment concentration of capmatinib.
Figure 2 is data confirming that the accumulation of neutral fat is inhibited in the differentiation of adipocytes when capmatinib is administered, confirming the accumulation of neutral fat through Oil-Red O staining technique on
Figure 3 is data quantifying the neutral fat content confirmed in Figure 2. (A:
Figure 4 is data confirming the degree of triglyceride decomposition of capmatinib in differentiated 3L3-L1.
5 is data showing the numerical values of SREBP1 protein related to early lipogenesis expressed in differentiated adipocytes through Western blotting.
6 is data showing the numerical values of C/EBPa protein related to early lipogenesis expressed in differentiated adipocytes through Western blotting.
Figure 7 is data showing the numerical values of the FAS protein related to late lipogenesis expressed in differentiated adipocytes through Western blotting.
8 is data showing the numerical values of SCD1 protein related to late lipogenesis expressed in differentiated adipocytes through Western blotting.
이하 하나 이상의 구체 예를 실시예를 통해 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are intended to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.
실험방법 1. 시약 및 처리 시간
캡마티닙(Capmatinib, CAP)은 Selleckchem에서 구입하여 사용하였다. 캡마티닙(Capmatinib, CAP) 농도는 0.3, 1, 2nM로 각각 24시간 처리하였다. Capmatinib (Capmatinib, CAP) was purchased from Selleckchem and used. Capmatinib (Capmatinib, CAP) concentration was treated for 24 hours, respectively, 0.3, 1, 2nM.
3-이소부틸-1-메틸잔틴 (3-Isobutyl-1-methylxanthine, M; 0.5mM), 덱사메타손 (dexamethasone, D; 1μM), 인슐린 (insulin, I; 10ug/ml)을 조합하여 지방전구세포의 지방 분화 유도제(MDI)로 3일간 사용하였으며, 인슐린 (10ug/ml)을 3일간 추가로 처리하여 분화를 완성하였다.A combination of 3-Isobutyl-1-methylxanthine (M; 0.5mM), dexamethasone (D; 1μM), and insulin (insulin, I; 10ug/ml) It was used as an adipose differentiation inducer (MDI) for 3 days, and insulin (10 ug/ml) was additionally treated for 3 days to complete differentiation.
실험방법 2. 세포 준비 및 시료 처리
마우스의 전지방세포인 3T3-L1을 ATCC에서 구입하여 사용하였다. 상기 세포는 10% 소태아혈청(Fetal calf serum, FCS)과 1% 페니실린 스트렙토마이신(penicillin streptomycin)이 포함된 DMEM (Dulbecco’s modified Eagle’s medium)배지를 이용하여 37℃를 유지하는 CO2 배양기에서 배양하였다. 지방세포분화 kit (Sigma)를 사용하여 6~7일간 분화를 시행하였다. Mouse preadipocytes, 3T3-L1, were purchased from ATCC and used. The cells were cultured in a CO 2 incubator maintained at 37° C. using DMEM (Dulbecco's modified Eagle's medium) medium containing 10% fetal calf serum (FCS) and 1% penicillin streptomycin. . Differentiation was performed for 6 to 7 days using an adipocyte differentiation kit (Sigma).
실험방법 3. 세포생존율 확인 Experiment method 3. Check cell viability
캡마티닙의 독성을 확인하기 위하여 3T3-L1 지방 세포에 각 농도로 처리하고, 유동세포계수분석 (Flow cytometry analysis)을 통해 세포생존율을 확인하였다.In order to confirm the toxicity of capmatinib, 3T3-L1 adipocytes were treated with each concentration, and cell viability was confirmed through flow cytometry analysis.
이를 위해, 100μl PBS를 세포에 첨가하여 재부유시키고 95% 에탄올 200μl를 첨가하여 세포를 와류시킨 후 4℃에서 1시간 동안 인큐베이션하였다. 그 후 세포를 PBS로 세척하고 12.5μg 리보뉴클레아제(ribonuclease, RNase)가 포함된 pH8.4의 1.12% 시트르산나트륨(sodium citrate) 용액 250μl을 첨가하여 재부유시키고 37℃에서 30분간 추가로 인큐베이션하였다.To this end, 100 μl PBS was added to the cells to resuspend, and 200 μl of 95% ethanol was added to vortex the cells, followed by incubation at 4° C. for 1 hour. Thereafter, the cells were washed with PBS, resuspended by adding 250 μl of a 1.12% sodium citrate solution at pH 8.4 containing 12.5 μg ribonuclease (RNase), and further incubated at 37° C. for 30 minutes. did
그 후 세포에 35.4μg/ml 농도의 MTT 용액 100μl를 첨가하고 실온에서 1시간 동안 세포를 염색시켰다. 염색된 세포를 dimethyl sulfoxide(DMSO)에 용해하여 470nm에서 흡광도를 특정하여 세포 생존율을 측정하였다.Then, 100 μl of 35.4 μg/ml MTT solution was added to the cells, and the cells were stained for 1 hour at room temperature. Cell viability was measured by dissolving the stained cells in dimethyl sulfoxide (DMSO) and measuring absorbance at 470 nm.
실험방법 4. 오일 레드 오(Oil red-O) 염색
3T3-L1 지방 세포를 오일 레드 오(Oil red-O) 방법으로 염색하여 세포의 중성지방(TG) 축적 정도를 측정 하였다. 40분동안 10% 포르말린으로 고정시킨 후, 간세포를 Oil-Red-O 용액(Sigma)으로 37℃에서 1시간동안 염색하였다. Oil red-O 염색된 중성지방(TG) 함량을 각 샘플에 이소프로판올을 첨가하여 정량화하였다. 혼합물을 8분간 25℃에서 부드럽게 교반하였다. 마지막으로, 100㎕의 이소프로판올 추출 샘플을 510nm에서 분광광도계로 분석 하였다.3T3-L1 adipocytes were stained with Oil red-O to measure the degree of triglyceride (TG) accumulation in the cells. After fixation with 10% formalin for 40 minutes, hepatocytes were stained with Oil-Red-O solution (Sigma) at 37°C for 1 hour. Oil red-O stained triglyceride (TG) content was quantified by adding isopropanol to each sample. The mixture was stirred gently at 25 °C for 8 minutes. Finally, 100 μl of isopropanol extraction sample was analyzed spectrophotometrically at 510 nm.
실험방법 5. 글리세롤 방출 측정 Experimental method 5. Measurement of glycerol release
지방세포 분화 및 약물 처리가 완료된 세포를 대상으로 Glycerol Assay Kit (Abcam)를 사용하여 시행하였다. It was performed using the Glycerol Assay Kit (Abcam) for cells that had been differentiated into adipocytes and treated with drugs.
실험방법 6. 웨스턴 블롯팅Experimental method 6. Western blotting
분화 완료된 3T3-L1 지방 세포를 수득하고 단백질을 4℃에서 60분동안 용해완충액(PRO-PREP; Intron Biotechnology, Seoul Korea)으로 추출하였다. 추출한 단백질 35㎍을 12% SDS-PAGE로 실시하고 니트로셀룰로오스막(Amersham Bioscience, Westborough, MA, USA)에 옮겼다. 그 후 1차 항체로 검출한 후, 홀스래디쉬 퍼옥시다제(Santa Cruz Biotechnology)를 접합시킨 2차 항체로 탐침하였다. 샘플은 ECL키트로 검출하였다.Differentiated 3T3-L1 adipocytes were obtained, and proteins were extracted with a lysis buffer (PRO-PREP; Intron Biotechnology, Seoul Korea) at 4°C for 60 minutes. 35 μg of the extracted protein was subjected to 12% SDS-PAGE and transferred to a nitrocellulose membrane (Amersham Bioscience, Westborough, MA, USA). After detection with the primary antibody, it was probed with a secondary antibody conjugated with horseradish peroxidase (Santa Cruz Biotechnology). Samples were detected with an ECL kit.
실시예 1: 캡마티닙(Capmatinib)의 세포생존도Example 1: Cell viability of Capmatinib
캡마티닙을 과량으로 투여시 세포에 미치는 영향을 확인하기 위하여, 실험방법 3을 따라 실험하였다. 캡마티닙을 0.3nM, 1nM 및 2nM 농도로 각각 세포에 투여하고, 세포의 생존율을 확인하였다. In order to confirm the effect on cells when capmatinib is administered in excess, an experiment was performed according to Experimental Method 3. Capmatinib was administered to the cells at concentrations of 0.3nM, 1nM, and 2nM, respectively, and cell viability was confirmed.
도 1과 같이, 캡마티닙을 0.3nM 및 1nM 투여한 세포에서는 세포생존율에 영향이 없었으나, 2nM에서는 세포생존율이 현저히 감소하는 것을 확인하였다. As shown in Figure 1, it was confirmed that cell viability was not affected in cells administered with 0.3nM and 1nM of capmatinib, but cell viability significantly decreased at 2nM.
실시예 2: 지방 축적 억제 효과 확인Example 2: Confirmation of fat accumulation inhibitory effect
캡마티닙을 투여시 지방세포의 분화에서 중성지방의 축적이 억제되는 것을 확인하기 위하여 오일 레드 오(Oil red-O) 염색을 하였다.Oil red-O staining was performed to confirm that the accumulation of neutral fat was suppressed in the differentiation of adipocytes when capmatinib was administered.
도 2 및 3과 같이, 캡마티닙 처리농도 및 처리기간의 증가에 따라 중성지방이 더 많이 억제되는 것을 확인하였다. As shown in Figures 2 and 3, it was confirmed that neutral fat was more suppressed according to the increase in capmatinib treatment concentration and treatment period.
실시예 3: 중성지방 분해 효과 확인Example 3: Confirmation of neutral fat decomposition effect
분화된 지방세포에서 캡마티닙에 의한 지방 분해효과를 확인하기 위하여 글리세롤의 방출을 측정하였다.In order to confirm the lipolysis effect of capmatinib in differentiated adipocytes, glycerol release was measured.
도 4와 같이, 캡마티닙을 처리하였을 때 글리세롤 방출량이 농도 의존적으로 증가되는 것을 확인하였다. 상기 결과를 통해 캡마티닙은 지방세포에 축적된 중성지방의 분해를 유도할 수 있음을 알 수 있다.As shown in Figure 4, it was confirmed that the amount of glycerol released was increased in a concentration-dependent manner when treated with capmatinib. Through the above results, it can be seen that capmatinib can induce the decomposition of neutral fat accumulated in adipocytes.
실시예 4: 분화된 지방세포에서 초기 지질 신생합성 단백질 발현 억제 확인Example 4: Confirmation of suppression of early lipogenesis protein expression in differentiated adipocytes
캡마티닙에 의해 초기 지질 신생합성과 관련된 유전자의 단백질 발현이 억제되는지 확인하기 위하여 웨스턴 블롯팅을 하였다. Western blotting was performed to determine whether protein expression of genes related to early lipogenesis was inhibited by capmatinib.
도 5 및 도 6과 같이, 지방생성과정의 핵심 전사인자인 SREBP1과 C/EBPα의 단백질 모두 캡마티닙 의 처리농도에 의존적으로 발현이 감소하는 것을 확인하였고, 캡마티닙 1nM 처리한 경우는 SREBP1 단백질 발현이 MDI를 처리하지 않은 대조군과 비슷할 정도로 억제되는 효과를 확인하였다.5 and 6, it was confirmed that the expression of both SREBP1 and C/EBPα proteins, which are key transcription factors in the lipogenesis process, decreased depending on the treatment concentration of capmatinib, and in the case of capmatinib 1nM treatment, SREBP1 It was confirmed that the protein expression was inhibited to a degree similar to that of the control group not treated with MDI.
실시예 5: 분화된 지방세포에서 후기 지질 신생합성 단백질 발현 억제 확인Example 5: Confirmation of inhibition of late lipogenesis protein expression in differentiated adipocytes
분화된 지방세포에서 후기 지질 신생합성 관련된 지방산 합성효소 FAS 및 스테로일 코에이 불포화효소 SCD1의 단백질 발현이 억제되는지 확인하기 위하여, 웨스턴 블롯팅을 하였다. Western blotting was performed to determine whether the protein expression of FAS, a fatty acid synthase involved in late lipogenesis, and SCD1, a steroyl-CoA desaturase, were suppressed in differentiated adipocytes.
캡마티닙 농도에 의존적으로 FAS 및 SCD1 단백질 발현이 모두 감소하는 것을 확인하였고, 특히 캡마티닙의 농도가 1nM인 경우, FAS 및 SCD1 단백질 발현이 현저히 감소하는 것을 확인하였다.It was confirmed that both FAS and SCD1 protein expressions decreased depending on the capmatinib concentration, and in particular, when the concentration of capmatinib was 1 nM, it was confirmed that the FAS and SCD1 protein expressions significantly decreased.
Claims (3)
[화학식 1]
A pharmaceutical composition for preventing or treating obesity comprising a compound represented by Formula 1 as an active ingredient.
[Formula 1]
The pharmaceutical composition for preventing or treating obesity according to claim 1, wherein the compound has activity in inhibiting lipid deposition, inhibiting fat synthesis, or lipolysis.
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