2. Academic Validation
  3. Discovery of a Potent, Selective and In Vivo Active Aurora A PROTAC Degrader from a Promiscuous Kinase Inhibitor

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

  • J Med Chem. 2026 Jun 11;69(11):13207-13221. doi: 10.1021/acs.jmedchem.6c00183.
Yulin Mao 1,  Meiying Zhang 2,  Hao Tang 1 2,  Jiaguo Li 3,  Jie Wang 2,  Fengtao Zhou 1,  Jinwei Zhang 2,  Weixue Huang 2,  Xiaomei Ren 2,  Ke Ding 1 2,  Zhen Wang 2
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
  • 2 State Key Laboratory of Chemical Biology and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 3 Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
PMID: 42214088 DOI: 10.1021/acs.jmedchem.6c00183
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.

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