Discovery of a Potent, Selective and In Vivo Active Aurora A PROTAC Degrader from a Promiscuous Kinase Inhibitor

Discovering novel kinase modulators that combine high selectivity with the ability to regulate noncatalytic functions remains a crucial goal in kinase drug discovery. Here, we use Aurora A as a case study to demonstrate that proteolysis-targeting chimeras (PROTACs) provide a compelling solution to these challenges. We discovered M9101, a potent, selective and in vivo active Aurora A PROTAC degrader, developed from a promiscuous kinase inhibitor warhead. M9101 potently degrades Aurora A with a DC50 value of 2.3 nM in MD-MBA-231 cells and demonstrates exceptional selectivity in a global proteomic analysis. Furthermore, M9101 effectively depletes Aurora A in vivo. This study presents a valuable chemical tool for probing the noncatalytic biology of the kinase and, importantly, highlights that selective kinase degraders are achievable even from promiscuous binding ligands.