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

Cell Chemical Biology
Roger S GoodyDaniel Rauh

Abstract

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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Citations

Jan 14, 2021·Cell Chemical Biology·Ruth NussinovVadim Gaponenko
Jan 23, 2021·RSC Medicinal Chemistry·Lisa GoebelDaniel Rauh
Feb 10, 2021·Acta Crystallographica. Section D, Structural Biology·Dieter MoosmayerRoman C Hillig
Nov 18, 2021·Journal of Medicinal Chemistry·Gabriele FumagalliDavid R Spring

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