ARS-1323

Description: ARS-1323 is the racemic mixture of ARS-1620, and is a novel and potent inhibitor of mutant K-ras G12C. ARS-1620 is a novel, potent, oral and covalent inhibitor of KRASG12C with high potency and selectivity for KRASG12C. It was identified from structure-based design and can achieve rapid and sustained in vivo target occupancy to induce tumor regression. KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. ARS-1620 was used to dissect oncogenic KRAS dependency and demonstrated that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

References: WO 2015054572 A1.