An allosteric inhibitor of oncogenic K-Ras(G12C)
The Ras family of small GTPases (H-Ras, K-Ras, and N-Ras) function as molecular switches, cycling between a GTP-bound active state and a GDP-bound inactive state, to turn on downstream Raf protein kinases. This initiates complex signaling pathways involved in cell growth, differentiation, and apoptosis. Mutations leading to aberrant Ras activation are frequently associated with various human cancers. 6H05 is a small molecule that allosterically binds to a mutant cysteine on oncogenic K-Ras(G12C), thus inhibiting its function.1 Binding of 6H05 to K-Ras(G12C) disrupts both switch-I and switch-II, altering the native nucleotide preference to favor GDP over GTP, which impedes binding to Raf.1 Because 6H05 is selective for mutant Cys-12, it does not affect wild-type K-Ras.1
1.Ostrem, J.M., Peters, U., Sos, M.L., et al.K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactionsNature503(7477)548-551(2013)
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