Biological Activity:
KRAS-C9 is a potent and selective allosteric inhibitor of oncogenic K-Ras(G12C). It irreversibly binds to a common oncogenic mutant K-Ras(G12C) and blocks K-Ras(G12C) interactions, therefore does not affect the wild-type protein. Binding of KRAS-C9 to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. It can decrease viability and increase apoptosis of K-Ras(G12C)-containing cancer cell lines. KRAS-C9 provides structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.
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Reference:
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