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

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 DC(50) < 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.