精氨酸甲基化是哺乳动物体内组蛋白翻译后修饰的重要组成部分,并由蛋白质精氨酸甲基转移酶(protein arginine methyltransferases, PRMTs)负责催化调控。蛋白质精氨酸甲基转移酶1 (PRMT1)是PRMTs家族中第一个被发现的成员,并参与了细胞信号传导、基因转录调节、RNA代谢、DNA损伤修复及蛋白质相互作用等多种细胞生理活动过程。PRMT1的失调和异常通常会导致包括炎症、退行性疾病和癌症等多种疾病的发生。因此通过抑制PRMT1能够达到治疗相关疾病的效果。本文主要介绍PRMT1在癌症中的作用及其抑制剂的研究进展,为以PRMT1为靶点的药物研发提供思路。 Arginine methylation is a significant part of post-transcriptional modifications of histones occurring in mammals and is catalyzed and regulated by protein arginine methyltransferases (PRMTs). Protein arginine methyltransferase 1 (PRMT1) is the first discovered member of the PRMT family, which involved in many physiological activity processes such as cell signaling, gene transcription regulation, RNA metabolism, DNA damage repair, and protein interaction process. Dysregulation and abnormality of PRMT 1 often lead to the development of various diseases including inflammation, degenerative diseases and cancers, so inhibition of PRMT1 can treat related diseases. This review mainly introduces the role of PRMT1 in the tumors and the research progress of PRMT1 inhibitors, hoping to provide ideas for its further research.
组蛋白,翻译后修饰,蛋白质精氨酸甲基转移酶,PRMT1抑制剂, Histones Post-Translational Modifications Protein Arginine Methyltransferases PRMT1 Inhibitors摘要
Research Progress of Protein Arginine Methyltransferase 1 Inhibitors in the Treatment of Antitumor
Zhaohong Zhu, Na Yang, Bo Kong, Weifang Tang*
College of Science, China Pharmaceutical University, Nanjing Jiangsu
Received: Feb. 10th, 2022; accepted: Mar. 8th, 2022; published: Mar. 15th, 2022
ABSTRACT
Arginine methylation is a significant part of post-transcriptional modifications of histones occurring in mammals and is catalyzed and regulated by protein arginine methyltransferases (PRMTs). Protein arginine methyltransferase 1 (PRMT1) is the first discovered member of the PRMT family, which involved in many physiological activity processes such as cell signaling, gene transcription regulation, RNA metabolism, DNA damage repair, and protein interaction process. Dysregulation and abnormality of PRMT 1 often lead to the development of various diseases including inflammation, degenerative diseases and cancers, so inhibition of PRMT1 can treat related diseases. This review mainly introduces the role of PRMT1 in the tumors and the research progress of PRMT1 inhibitors, hoping to provide ideas for its further research.
Keywords:Histones, Post-Translational Modifications, Protein Arginine Methyltransferases, PRMT1 Inhibitors
GSK3368715 (图7)是葛兰素史克(GlaxoSmithKline)公司研发的I型PRMTs的可逆SAM非竞争性抑制剂,可直接结合在SAM结合口袋相邻的肽位点。在细胞实验中,GSK3368715单独用药可以诱导细胞内蛋白底物的甲基化状态实现从ADMA到MMA和SDMA的转变;与PRMT5抑制剂联合使用可减弱I型PRMT抑制引起的MMA和SDMA的积累,并对选择性剪接产生深远的影响,使得剪接调节因子的活性下降,从而抑制转录激活,抑制细胞的生长。GSK3368715在12种肿瘤类型的249个癌细胞系和原发性弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBCL)患者样本中进行了检测 [42],GSK3368715对50%以上的癌细胞具有抑制作用,并且对DLBCL患者样本中的抑制率在80%以上。此外,GSK3368715具有良好的耐受性,在DLBCL、透明细胞肾癌、三阴性乳腺癌和胰腺腺癌的异种移植小鼠模型中,其能显著地抑制肿瘤生长。目前,GSK3368715抑制剂正在进行首次临床试验(NCT03666988),用于实体瘤和弥漫大B细胞淋巴瘤患者进行对安全性、耐受性和药代动力学性质的评估。
朱照宏,杨 娜,孔 博,唐伟方. 蛋白质精氨酸甲基转移酶1抑制剂抗肿瘤研究进展Research Progress of Protein Arginine Methyltransferase 1 Inhibitors in the Treatment of Antitumor[J]. 药物资讯, 2022, 11(02): 102-112. https://doi.org/10.12677/PI.2022.112014
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