Mutant-Specific Targeting of Ras G12C Activity by Covalently Reacting Small Molecules

鸟苷 鸟嘌呤核苷酸交换因子 GTP酶 GTP' 鸟嘌呤 鸟苷二磷酸 克拉斯 鸟苷三磷酸 突变体 共价键 核苷酸 化学 小型GTPase 小分子 细胞生物学 生物化学 突变 立体化学 生物 信号转导 有机化学 基因
作者
Roger S. Goody,Matthias Müller,Daniel Rauh
出处
期刊:Cell chemical biology [Elsevier]
卷期号:26 (10): 1338-1348 被引量:11
标识
DOI:10.1016/j.chembiol.2019.07.005
摘要

In this review we discuss and compare recently introduced molecules that are able to react covalently with an oncogenic mutant of KRas, KRas G12C. Two different classes of compounds in question have been developed, both leading to the mutant being locked in the inactive (guanosine diphosphate [GDP]-bound) state. The first are compounds that interact reversibly with the switch-II pocket (S-IIP) before covalent interaction. The second class interact in a competitive manner with the GDP/guanosine triphosphate (GTP) binding site. The fundamental physico-chemical principles of the two inhibitor classes are evaluated. For GDP/GTP-competing molecules, we show that special attention must be paid to the influence of guanine nucleotide exchange factors (GEFs) and their elevated activity in cells harboring abnormally activated Ras mutants. A new approach is suggested involving compounds that interact with the guanine binding site of the GTPase, but in a manner that is independent of the interaction of the GTPase with its cognate GEF. In this review we discuss and compare recently introduced molecules that are able to react covalently with an oncogenic mutant of KRas, KRas G12C. Two different classes of compounds in question have been developed, both leading to the mutant being locked in the inactive (guanosine diphosphate [GDP]-bound) state. The first are compounds that interact reversibly with the switch-II pocket (S-IIP) before covalent interaction. The second class interact in a competitive manner with the GDP/guanosine triphosphate (GTP) binding site. The fundamental physico-chemical principles of the two inhibitor classes are evaluated. For GDP/GTP-competing molecules, we show that special attention must be paid to the influence of guanine nucleotide exchange factors (GEFs) and their elevated activity in cells harboring abnormally activated Ras mutants. A new approach is suggested involving compounds that interact with the guanine binding site of the GTPase, but in a manner that is independent of the interaction of the GTPase with its cognate GEF.
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