Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C - PubMed
6 hours ago
- #KRAS G12C
- #Drug Discovery
- #Brain-Penetrant Inhibitor
- Discovery and optimization of a potent, efficacious, and brain-penetrant inhibitor of KRAS G12C.
- Mutant KRAS is highly prevalent in human cancer and has been a target for drug discovery.
- KRAS G12C inhibitors have advanced to clinical development for treating solid tumors.
- Many KRAS G12C-positive non-small cell lung cancer patients develop brain metastases.
- Development of a brain-penetrant inhibitor using divarasib as a starting point.
- Optimization focused on reducing molecular weight and topological polar surface area.
- Shielding hydrogen bond donors attenuated active transport by P-gp and BCRP.
- Achieved high exposure in rodent brain tissue.