Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Clinical reports indicate a need for dual inhibitors of wild-type (WT) and mutant c-MET kinase in cancer treatment.
• c-MET kinase is a key target in various cancers, and its inhibition is a focus of therapeutic development.

Purpose of the Study:

• To design and optimize a novel chemical series of ATP-competitive type-III inhibitors targeting both WT and D1228V mutant c-MET.
• To evaluate the selectivity, potency, pharmacokinetic profiles, and brain penetration of these novel inhibitors.

Main Methods:

• Structure-based drug design and computational analyses were employed for optimization.
• Biochemical and cellular assays were used to determine inhibitor activity.
• In vivo pharmacokinetic studies in rats were conducted to assess drug exposure and brain penetration.

Main Results:

• A highly selective chemical series of c-MET inhibitors with nanomolar activity was developed.
• Ligand 2 was optimized, demonstrating potent inhibition of both WT and D1228V mutant c-MET.
• The optimized inhibitors exhibited favorable pharmacokinetic profiles and promising free-brain exposures in rat studies.

Conclusions:

• The novel chemical series represents a promising advancement in the development of dual c-MET inhibitors.
• These findings support the potential for designing brain-permeable drugs to treat c-MET driven cancers.
• The developed inhibitors offer a potential therapeutic strategy for cancers reliant on c-MET signaling.