小柯机器人

研究解析曲美替尼在KSR/MEK上作用的结构基础
2020-09-17 15:14

美国Tisch癌症研究所Arvin C. Dar小组解析曲美替尼在KSR/MEK上作用的结构基础。2020年9月14日,《自然》杂志在线发表了这项成果。

据研究人员介绍,MAPK/ERK激酶MEK是常见的癌症驱动因子KRAS和BRAF的共同效应物,长期以来人们一直将其作为肿瘤学中的药物靶标,最近也在免疫治疗和衰老得以应用。但是,由于靶标毒性和耐药性,许多MEK抑制剂(MEKi)受到限制。因此,对生理复合物中MEK的结构和功能的分子理解可以为设计更安全,更有效的疗法提供模板。
 
研究人员报告了与各种MEKi(包括各种临床药物曲美替尼在内)一起结合到支架KSR(RAS的激酶抑制剂)的MEK晶体结构。该结构揭示了一种意外的结合方式,其中曲美替尼直接在MEK界面上与KSR结合。通过复合,KSR重塑了原型MEKi变构囊,从而影响结合和动力学,包括药物停留时间。而且,曲美替尼能够结合KSR-MEK,但通过一种进化保守的机制来破坏了相关的RAF-MEK复合物。基于这些见解,研究人员创造了trametiglue,其通过增强的界面结合来限制对MEKi的适应性抵抗力。
 
总之,这些结果揭示了MEK亚复合物中界面口袋的可塑性,这对靶向RAS途径的下一代药物设计有意义。
 
附:英文原文

Title: Structural basis for the action of the drug trametinib at KSR-bound MEK

Author: Zaigham M. Khan, Alexander M. Real, William M. Marsiglia, Arthur Chow, Mary E. Duffy, Jayasudhan R. Yerabolu, Alex P. Scopton, Arvin C. Dar

Issue&Volume: 2020-09-14

Abstract: The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology1, and more recently in immunotherapy2,3 and aging4. However, many MEK inhibitors (MEKi) are limited due to on-target toxicities5–7 and drug resistance8–10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEKi, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including drug residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these subcomplexes. Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. Together, our results reveal the plasticity of an interface pocket within MEK subcomplexes that has implications for the design of next-generation drugs targeting the RAS pathway.

DOI: 10.1038/s41586-020-2760-4

Source: https://www.nature.com/articles/s41586-020-2760-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0