KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here we describe ARS-853, a selective, covalent inhibitor of KRAS-G12C that inhibits mutant KRAS driven signaling by binding to the GDP bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant specific mass spectrometry based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS G12C is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS G12C mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics.
- Received September 10, 2015.
- Revision received January 4, 2016.
- Accepted January 5, 2016.
- Copyright © 2016, American Association for Cancer Research.