Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy

Mesenchymal-epithelial transition factor (MET) is a receptor
tyrosine
kinase that serves a critical function in numerous developmental,
morphogenic, and proliferative signaling pathways. If dysregulated,
MET has been shown to be involved in the development and survival
of several cancers, including non-small cell lung cancer (NSCLC),
renal cancer, and other epithelial tumors. Currently, the clinical
efficacy of FDA approved MET inhibitors is limited by on-target acquired
resistance, dose-limiting toxicities, and less than optimal efficacy
against brain metastasis. Therefore, there is still an unmet medical
need for the development of MET inhibitors to address these issues.
Herein we report the application of structure-based design for the
discovery and development of a novel class of brain-penetrant MET
inhibitors with enhanced activity against clinically relevant mutations
and improved selectivity. Compound 13 with a MET D1228N
cell line IC50 value of 23 nM showed good efficacy in an
intracranial tumor model and increased the median overall survival
of the animals to 100% when dosed orally at 100 mg/kg daily for 21
days.