2. Academic Validation
  3. Discovery of the first-in-class Aurora B kinase selective degrader

Discovery of the first-in-class Aurora B kinase selective degrader

  • Eur J Med Chem. 2025 Nov 15:298:118006. doi: 10.1016/j.ejmech.2025.118006.
Xiaoping Hu 1,  Kevin Graciano 2,  Jianping Hu 1,  Chang Liu 3,  Jiuyi Zhang 3,  Ling Xie 4,  Xian Chen 4,  Yan Xiong 1,  Jian Jin 5,  Jia Xu 6
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
  • 2 Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35294, United States; O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, 35233, United States.
  • 3 Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35294, United States.
  • 4 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
  • 5 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: jian.jin@mssm.edu.
  • 6 Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, 35294, United States; O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, 35233, United States. Electronic address: xuj@uab.edu.
PMID: 40730065 DOI: 10.1016/j.ejmech.2025.118006
Abstract

Aurora kinases, consisting of Aurora A, B, and C, play critical roles in the regulation of Mitosis and are frequently overexpressed in multiple types of Cancer. Several Aurora Kinase inhibitors have been developed and tested in clinical trials. Additionally, Aurora Kinase A (AURKA) degraders and dual degraders of AURKA and Aurora Kinase B (AURKB) have been reported. However, no AURKB selective degrader has been reported. Here, we report the discovery of the first-in-class AURKB selective degrader, MS44 (18), a von Hippel-Lindau (VHL) E3 ligase-recruiting proteolysis-targeting chimera (PROTAC), which potently degrades AURKB with a DC50 < 100 nM in a time-, concentration-, VHL-, and ubiquitin-proteasome system (UPS)-dependent manner. Compound 18 selectively degrades AURKB over AURKA and Other related kinases. Notably, compound 18 effectively inhibits the proliferation in multiple Cancer cell lines. Overall, compound 18 is a valuable chemical biology tool and a potential therapeutic. Our findings suggest that pharmacological degradation of AURKB could offer an alternative therapeutic approach for treating AURKB-dependent tumors.

Keywords

AZD1152; Aurora B; Degrader; Kinase; PROTAC.

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