Discovery of RMC-0708, an Oral, Bis-Macrocyclic, RAS(ON) Q61H-Selective, Noncovalent, Tri-Complex Inhibitor

Oncogenic RAS mutations are among the most common drivers of human cancers, with the KRAS Q61H mutation accounting for approximately 7500 new patients each year in the US alone. To target the active, GTP-bound state of the KRAS(ON) Q61H mutant protein directly, we have employed an innovative tri-complex inhibitor (TCI) modality. Herein, we report structure-guided medicinal chemistry efforts that led to the discovery of RMC-0708, an orally bioavailable, bis-macrocyclic, RAS(ON) Q61H-selective, noncovalent, tri-complex inhibitor. Oral administration of a single dose of RMC-0708 resulted in dose-dependent, deep, and durable suppression of tumor RAS pathway activity for up to 72 h in preclinical xenograft models of KRAS Q61H-driven cancers in vivo. RMC-0708 drove deep tumor regressions in several xenograft models of human KRAS Q61H mutant tumors. The discovery of RMC-0708 further underscores the potential of the TCI platform to identify potent and selective noncovalent inhibitors of mutant RAS(ON) with demonstrated selectivity over wild-type RAS.