甲硫氨酸腺苷转移酶2A在肿瘤发生中的作用及其抑制剂研发现状  

The Role of Methionine Adenosyltransferase 2A in Tumorigenesis and the Development of Its Inhibitors

作　　者：王鹏飞 陈奕 WANG Pengfei;CHEN Yi(Division of Anti-Tumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Shandong Provincial Laboratory of Drug Discovery(Yantai),Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264000,China)

机构地区：[1]国家新药重点实验室肿瘤药理组,中国科学院上海药物研究所,上海201203 [2]中国科学院大学,北京100049 [3]烟台新药创制山东省实验室,中科环渤海(烟台)药物高等研究院,山东烟台264000

出　　处：《药学进展》2022年第12期884-897,共14页Progress in Pharmaceutical Sciences

基　　金：中科院上海药物研究所新药研究国家重点实验室开发课题(No.SIMM2205KF-04)。

摘　　要：在哺乳动物中通常以甲硫氨酸腺苷转移酶(methionine adenosyltransferase,MAT)催化甲硫氨酸和腺苷三磷酸(adenosine triphosphate,ATP)生成的S-腺苷甲硫氨酸(S-adenosylmethionine,SAM)作为主要甲基供体。MAT家族包括MAT1A,MAT2A和MAT2B。其中MAT2A负责肝外正常组织和癌组织的SAM合成,MAT1A只负责正常肝组织和胆管上皮细胞的SAM合成,MAT2B则不具有催化活性。研究表明MAT2A在肿瘤发生发展中具有重要作用,不仅通过介导癌症代谢以促进肿瘤发展,还能作为转录辅助因子等直接促进癌症发生发展。因此,MAT2A被视为癌症治疗的潜在靶点,尤其是近年发现MAT2A抑制和甲硫腺苷磷酸化酶(methylthioadenosine phosphorylase,MTAP)缺失具有合成致死的效应后,更是进一步推动了MAT2A抑制剂的研发。目前该类抑制剂主要包括底物竞争性抑制剂和变构抑制剂,用于治疗MTAP缺失的肿瘤患者,同时也有大量研究致力于探索联用策略。综述重点总结了MAT2A的致癌机制、MAT2A抑制剂的发展进程及其潜在应用策略的相关研究,以期为癌症的精准治疗提供新的靶点以及为联合用药提供新的策略。Methionine adenosyltransferase(MAT)catalyzes the formation of S-adenosylmethionine(SAM),serving as the primary methyl group donor in mammalian cells,from methionine and adenosine triphosphate(ATP).MAT family consists of MAT1A,MAT2A and MAT2B.MAT2A is responsible for the synthesis of SAM in extrahepatic normal tissues and cancer tissues,MAT1A is solely responsible for SAM synthesis in normal liver tissue and bile duct epithelial cells,while MAT2B has no catalytic activity.Accumulated evidence illuminates that MAT2A has a cancerogenic role by mediating cancer metabolism,functioning as a transcriptional cofactor.MAT2A,therefore,has been known as a site of therapeutic vulnerability for cancer.Particularly,after finding that MAT2A inhibition and methylthioadenosine phosphorylase(MTAP)loss are synergistically lethal,more attention has been paid to the promising discovery of diverse kinds of MAT2A inhibitors,which mainly include substrate-competitive inhibitors and allosteric inhibitors,in an attempt to treat MTAP-deleted tumors and explore the strategy of combined therapy.This review summarizes the oncogenic mechanisms of MAT2A and the development of MAT2A inhibitors,with a focus on the potential strategies of applying MAT2A inhibitors,hoping to identify a novel target for precisive cancer treatment and new strategies for drug combination.

关 键 词：甲硫氨酸腺苷转移酶2A 癌症 致癌机制 甲硫氨酸腺苷转移酶2A抑制剂 

分 类 号：R979.1[医药卫生—药品] R966[医药卫生—药学]