Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal–Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)

TLDR

Aberrant c‑MET and ALK signaling drives cancer, making these receptor tyrosine kinases attractive therapeutic targets. Using the cocrystal structure of PHA‑665752 bound to c‑MET, the authors designed a 2‑amino‑5‑aryl‑3‑benzyloxypyridine series to exploit the novel ATP‑binding pocket. The optimized lead, crizotinib (PF‑02341066), exhibited potent c‑MET and ALK inhibition, effective tumor growth suppression, and favorable pharmacological properties.

Abstract

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.