Oncogenic RAS mutations are among the most common drivers of human cancers, with the KRASQ61H mutation accounting for approximately 10,000 new patients each year in the US alone.  Structure-based drug design efforts focused on interactions with KRASQ61H specific residues and led to the discovery of RMC-0708, an orally bioavailable, bis-macrocyclic, RAS(ON) Q61H-selective, noncovalent, tri-complex inhibitor. 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