Selective inhibitors of c-Met, an intracellular receptor tyrosine kinase and known oncogene, could have utility as monotherapy or in combination with other targeted therapies for the treatment of human cancers, specifically for a variety of tumors showing dysregulated c-Met activity. In recent years, a number of reports have emerged describing a novel binding mode of certain c-Met-specific inhibitors to inactive c-Met, supported by X-ray structures of protein-inhibitor complexes. Building further on these disclosures, a virtual screen of chemical scaffolds against a model of the unactivated conformation of c-Met was performed. The scaffolds were then scored and translated by the chemistry team into synthetically feasible targets. Ultimately, a pyridazin-4(1H)-one core produced a moderately active hit (1, IC50 = 810 nM), which was rapidly transformed into a highly selective lead (2, IC50 = 43 nM) with a promising pharmacokinetic profile. Further optimization, focusing on improving potency while maintaining selectivity and in vivo profile, provided inhibitors with nanomolar cellular activities that were suitable for further development.

c-Met inhibitors from hit to lead: Discovery and optimization of a series of pyridazin-4(1H)-ones

250th National Meeting (2015)

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