Progress on Covalent Inhibition of KRAS(G12C).

Recent reports of small-molecule approaches to directly inhibit oncogenic KRAS(G12C) have invigorated the RAS research community by raising the possibility of drugging a protein that was long considered "undruggable." A new iteration of covalent compounds targeting the allosteric switch II pocket of KRAS(G12C) showed improved potency and selectivity and enabled studies demonstrating that KRAS(G12C) rapidly cycles its nucleotide substrate. This report illustrates the value of chemical probes in dissecting RAS biology and raises additional hope for development of viable pharmacologic strategies for directly targeting KRAS(G12C).