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表观遗传学及其他:以蛋白质赖氨酸甲基化写作者为靶点治疗疾病。

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.

机构信息

Department of Biology, Stanford University, Stanford, CA, USA.

Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

出版信息

Nat Rev Drug Discov. 2021 Apr;20(4):265-286. doi: 10.1038/s41573-020-00108-x. Epub 2021 Jan 19.

Abstract

Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or 'writers' of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases.

摘要

蛋白质赖氨酸甲基化是一种至关重要的翻译后修饰,它调节组蛋白和非组蛋白的功能。蛋白质赖氨酸甲基转移酶(KMTs)的酶或“书写器”的失调与许多疾病的病因有关,包括癌症、精神健康障碍和发育障碍。在过去的十年中,在开发针对涉及组蛋白甲基化和表观遗传调控的 KMT 的药物方面取得了重大进展。这些抑制剂中的第一个,塔美塞他,最近被批准用于治疗上皮样肉瘤和滤泡性淋巴瘤,还有更多的正在临床和临床前评估中。除了染色质之外,许多调节蛋白质合成和其他基本生物过程的 KMT 正在成为治疗各种疾病的药物开发的有前途的新靶点。

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