小柯机器人

CDK抑制剂CR8可作为分子胶水来降解细胞周期素K
2020-06-05 09:28
来源：小柯机器人

美国哈佛大学Benjamin L. Ebert、瑞士弗里德里希·米舍尔生物医学研究所Nicolas H. Thomä等研究人员合作发现，CDK抑制剂CR8可作为分子胶水来降解细胞周期素K。2020年6月3日，《自然》在线发表了这一成果。

通过系统地挖掘数据库来了解4,518个临床和临床前小分子的细胞毒性与数百种人类癌细胞系中E3连接酶成分表达水平之间的相关性，研究人员确定了CR8（一种细胞周期蛋白依赖性激酶（CDK）的抑制剂）可作为分子胶水。CR8的CDK结合形式具有一个与溶剂接触的吡啶基部分，可诱导CDK12–细胞周期素K和CUL4衔接蛋白DDB1之间形成复合物，从而绕过了对底物受体的需求，并使得细胞周期素K被泛素化和降解。
 
这项研究表明，表面暴露部分的化学变化能够让抑制剂获得分子胶水的性能。因此，研究人员认为这将是一种更广泛的策略，从而将靶标结合分子转化为分子胶水。
 
据了解，分子胶水化合物诱导蛋白质间相互作用，在泛素连接酶作用下导致蛋白质降解。与传统的酶抑制剂不同，这些分子胶降解剂在化学计量上起催化作用，以快速消耗以前无法接近的靶标。它们在临床上有效且广受欢迎，但迄今为止只是偶然发现的。
 
附：英文原文

Title: The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

Author: Mikoaj Sabicki, Zuzanna Kozicka, Georg Petzold, Yen-Der Li, Manisha Manojkumar, Richard D. Bunker, Katherine A. Donovan, Quinlan L. Sievers, Jonas Koeppel, Dakota Suchyta, Adam S. Sperling, Emma C. Fink, Jessica A. Gasser, Li R. Wang, Steven M. Corsello, Rob S. Sellar, Max Jan, Dennis Gillingham, Claudia Scholl, Stefan Frhling, Todd R. Golub, Eric S. Fischer, Nicolas H. Thom, Benjamin L. Ebert

Issue&Volume: 2020-06-03

Abstract: Molecular glue compounds induce protein–protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3,4,5, we identify CR8—a cyclin-dependent kinase (CDK) inhibitor6—as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

DOI: 10.1038/s41586-020-2374-x

Source: https://www.nature.com/articles/s41586-020-2374-x

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