Discovery of a Potent, Selective and In Vivo Active Aurora A PROTAC Degrader from a Promiscuous Kinase Inhibitor
Abstract
Abstract 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.
Fields of Study & Subjects
Protein Degradation and Inhibitors
Chromatin Remodeling and Cancer
Microtubule and mitosis dynamics
Publication details
- Journal / source
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Volume
- 69
- Issue
- 11
- Pages
- 13207–13221
- Publication date
- 29 May 2026
- Language
- EN