Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2‑(4-(1-(Quinolin-6-ylmethyl)‑1<i>H</i>‑[1,2,3]triazolo[4,5‑<i>b</i>]pyrazin-6-yl)‑1<i>H</i>‑pyrazol-1-yl)ethanol (PF-04217903) for the Treatment of Cancer

The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit <b>6</b> was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor <b>10</b> with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1<i>H</i>-[1,2,3]­triazolo­[4,5-<i>b</i>]­pyrazin-6-yl)-1<i>H</i>-pyrazol-1-yl)­ethanol (<b>2</b>, <b>PF-04217903</b>), an extremely potent and exquisitely selective c-MET inhibitor. <b>2</b> demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. <b>2</b> progressed to clinical evaluation in a Phase I oncology setting