Mutant RAS is common in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) and exists predominantly in the GTP-bound (RAS(ON)) state, leading to excessive, oncogenic downstream signaling. KRASG12C(OFF) inhibitors have provided compelling clin. proof of concept for targeting mutant KRAS, but limitations in response rates and durability suggest the need for second-generation drug approaches that are less susceptible to intrinsic resistance mechanisms. In addition, cancers with RAS mutations other than KRASG12C remain unserved by clin.-stage inhibitors of any class. We have developed a proprietary tri-complex technol. to enable discovery of small mol. inhibitors that act against targets lacking intrinsic drug binding sites by inducing new drug binding pockets. Binding and inhibition occur through small mol.-driven formation of a high affinity ternary complex (tri-complex) between the target protein, the small mol., and a widely expressed cytosolic protein called a chaperone (e.g., FKPB12 or cyclophilin A). This platform technol. is the foundation of our RAS(ON) inhibitor programs. These RAS(ON) tri-complex inhibitors are inspired by natural products "Beyond Rule of 5" compounds The tri-complex technol. platform represents a highly differentiated approach to RAS inhibition by targeting the active form of RAS, or RAS(ON). We have developed a portfolio of tri-complex RAS(ON) inhibitors that target the major oncogenic mutations of RAS. Our current development-stage portfolio includes four compounds: RMC-6236 (RASMULTI), RMC-6291 (KRASG12C), RMC-9805 (KRASG12D), and RMC-8839 (KRASG13C). All of these orally-administered inhibitors drive tumor regressions in vivo in preclin. models representing various target genotypes. Direct inhibitors of RAS(ON) suppress cell growth and survival and are less sensitive to adaptive resistance mechanisms that have been described for KRASG12C(OFF) inhibitors in preclin. models. These properties contribute to a favorable anti-tumor activity profile for RMC-6291, a KRASG12C(ON) inhibitor, compared to a first generation KRASG12C(OFF) inhibitor across a panel of preclin. NSCLC models. The RAS(ON) inhibitors are also designed to drive rational, mechanism-based combinations with approved drugs and investigational drug candidates, particularly in-pathway agents, to achieve optimal tumor suppression in diverse RAS-addicted cancers.