Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine <b>9</b> with an IC₅₀ of 37 nM. The X-ray structure of <b>9</b> revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in <b>9</b>. Further optimization of <b>9</b> led to <b>12</b> with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, <b>12</b> displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity