Summary: Recent reports of small-molecule approaches to directly inhibit oncogenic KRASG12C 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 KRASG12C showed improved potency and selectivity and enabled studies demonstrating that KRASG12C 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 KRASG12C. Cancer Discov; 6(3); 233–4. ©2016 AACR.
See related article by Patricelli et al., p. 316.
- ©2016 American Association for Cancer Research.