Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors

Abstract

Piperidine carboxamide <b>1</b> was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC₅₀ = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of <b>1</b> with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure–activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R