ARS-853

Description: ARS-853 is a novel, potent, selective, and covalent inhibitor of KRAS(G12C) with IC50 of 2.5 uM. It inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. KRAS gain-of-function mutations occur in approximately 30% of all human cancers. To date, no targeted therapy has been discovered for cancers with KRAS mutations. 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, 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.

References: Cancer Discov. 2016 Mar; 6(3):316-29; Science. 2016 Feb 5; 351(6273):604-8.