Oral bis-macrocycle RMC-0708 targets active KRAS Q61H via tri-complex
- Structure-guided optimization within the tri-complex inhibitor platform produced RMC-0708, a noncovalent bis-macrocycle that engages GTP-bound KRAS Q61H.
- The compound is orally bioavailable and shows selectivity for the mutant over wild-type RAS.
- In Q61H-driven xenograft models, single oral doses gave sustained suppression of RAS pathway signaling, and dosing led to marked tumor regressions.
💡 Points Based on the abstract
A noncovalent RAS(ON) inhibitor is a different game from the cysteine-trapping G12C compounds: potency has to come from the tri-complex's shape complementarity alone, with no warhead to bail you out. I'd want to see what the switch-II Q61H contact actually buys over wild-type, and whether a bis-macrocycle still leaves room to trim size and polarity for oral exposure across species.