Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C
Matthew L Landry1, Sushant Malhotra1, Maureen Beresini1
1Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
Mutant KRAS is highly prevalent in human cancer and has been actively pursued as a target for drug discovery. Much progress has been made in drugging KRAS G12C, owing to the ability of inhibitors to covalently target its oncogenic cysteine mutation at codon 12. A number of KRAS G12C inhibitors have advanced to clinical development and are being investigated for the treatment of a variety of solid tumors. Notably, many patients with KRAS G12C-positive non-small cell lung cancer develop brain metastases. Herein, we report the discovery and development of a brain-penetrant inhibitor of KRAS G12C using divarasib as a starting point. Optimization efforts focused on reducing molecular weight and topological polar surface area as well as shielding of hydrogen bond donors. In this manner, active transport by both P-gp and breast cancer resistance protein (BCRP) was attenuated, and high exposure in rodent brain tissue was achieved.
Insights
Researchers developed a new brain-penetrant KRAS G12C inhibitor to treat cancers, including non-small cell lung cancer with brain metastases. This novel drug shows high exposure in rodent brain tissue.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Mutant KRAS is a common driver in human cancers.
- KRAS G12C is a key oncogenic mutation, and inhibitors targeting it show promise.
- Brain metastases are a significant challenge in KRAS G12C-positive non-small cell lung cancer.
Purpose of the Study:
- To discover and develop a novel, brain-penetrant inhibitor of KRAS G12C.
- To overcome limitations of existing KRAS G12C inhibitors in penetrating the central nervous system.
- To identify a potential therapeutic agent for brain metastases in KRAS G12C-driven cancers.
Main Methods:
- Utilized divarasib as a starting point for inhibitor development.
- Employed structure-based drug design principles, focusing on reducing molecular weight and polar surface area.
- Optimized compounds to attenuate active transport by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Main Results:
- Successfully developed a brain-penetrant KRAS G12C inhibitor.
- Achieved significant reduction in molecular weight and topological polar surface area.
- Demonstrated attenuated transport by P-gp and BCRP, leading to high exposure in rodent brain tissue.
Conclusions:
- The developed inhibitor is a promising candidate for treating KRAS G12C-positive cancers, particularly those with brain metastases.
- The optimization strategy successfully enhanced brain penetration while maintaining target engagement.
- Further investigation is warranted to evaluate the therapeutic potential in clinical settings.
