KRAS G12C片段筛选生成新的结合袋。

Q2 Biochemistry, Genetics and Molecular Biology
Small GTPases Pub Date : 2022-01-01 Epub Date: 2021-09-24 DOI:10.1080/21541248.2021.1979360
Magali Mathieu, Valérie Steier, Florence Fassy, Cécile Delorme, David Papin, Bruno Genet, Francis Duffieux, Thomas Bertrand, Laure Delarbre, Hélène Le-Borgne, Annick Parent, Patrick Didier, Jean-Pierre Marquette, Maryse Lowinski, Jacques Houtmann, Annabelle Lamberton, Laurent Debussche, Rak Alexey
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引用次数: 7

摘要

KRAS基因属于癌症中最常发生突变的癌基因家族。在三分之一的肺癌、一半的结直肠癌和胰腺癌病例中发现了G12C突变,据信这是导致大量癌症死亡的原因。30年来,KRAS一直是广泛的药物靶向研究的主题,这些研究不仅针对KRAS蛋白本身,还针对其翻译后修饰、膜定位、蛋白-蛋白相互作用和下游信号通路。到目前为止,大多数KRAS靶向策略都失败了,也没有KRAS特异性药物可用。然而,针对KRAS G12C蛋白的临床候选药物最近已经开发出来。MRTX849和最近批准的Sotorasib是靶向突变的半胱氨酸12的共价结合物,占据Switch II口袋。在此,我们描述了两个片段筛选药物发现活动,这些活动导致鉴定了KRAS G12C表面上以前未描述的结合口袋。其中一个筛选主要针对KRAS G12C的非共价结合物,另一个筛选针对共价结合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

KRAS G12C fragment screening renders new binding pockets.

KRAS G12C fragment screening renders new binding pockets.

KRAS G12C fragment screening renders new binding pockets.

KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.

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来源期刊
Small GTPases
Small GTPases Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
6.10
自引率
0.00%
发文量
6
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