Next-Generation Pan-KRAS Inhibition: Differentiated Chemistry to Address the Limitations of Contemporary KRAS Therapies
- A novel switch II-targeting scaffold can deliver pseudo-irreversible target engagement with low nanomolar potency across diverse KRAS mutations, addressing the narrow mutational coverage that limits currently approved G12C-specific agents
- Allosteric, non-covalent binding of inactive KRAS, with a slow-off rate and long resident time, can block downstream effector interactions and achieve durable tumor regression in diverse preclinical models
- Oral bioavailability and improved drug-like properties, achievable though a differentiated chemical scaffold, support the translation of these novel pan-KRAS inhibitors toward clinical development