[CAS NO. 1698055-85-4]  ARS-1620

ARS-1620 covalently inhibits KRAS (G12C) activity with high potency and atropisomeric selectivity in p.G12C mutant cancer cells. ARS-1620 rapidly engaged G12C in a concentration- and time- dependent manner consistent with its covalent mechanism of inhibition. Across a panel of cell lines harboring the mutant allele, ARS-1620 exhibited a half maximal G12C target engagement (TE50) at ~0.3 μM and near complete engagement at 3.0 μM after 2 hr of treatment. RS-1620 inhibits RAS-GTP and the phosphorylation of MEK, ERK, RSK, S6, and AKT in a dose-dependent and selective manner in H358 (p.G12C) but not in negative control lung cancer cell lines lacking p.G12C (A549, H460, and H441). ARS-1620 elicits sub-micromolar allele-specific potency (IC50 = 0.3 μM; IC90 = 1 μM). The activity of ARS-1620 is specific to the G12C allele and mediated by the covalent modification of Cys-12.