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

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Aurora kinases (A, B, C) are crucial for mitosis and often overexpressed in cancers.
• Existing treatments include Aurora kinase inhibitors, but selective degraders are lacking.
• Aurora kinase A (AURKA) and dual AURKA/AURKB degraders have been reported, but not AURKB-specific ones.

Purpose of the Study:

• To discover and characterize the first selective degrader of Aurora kinase B (AURKB).
• To evaluate the compound's efficacy in inhibiting cancer cell proliferation.
• To establish AURKB degradation as a potential therapeutic strategy for cancer.

Main Methods:

• Discovery of MS44, a von Hippel-Lindau (VHL) E3 ligase-recruiting proteolysis-targeting chimera (PROTAC).
• Assessment of AURKB degradation using biochemical assays, confirming VHL and ubiquitin-proteasome system (UPS) dependence.
• Evaluation of compound 18's selectivity against AURKA and other kinases.
• Testing compound 18's antiproliferative effects on various cancer cell lines.

Main Results:

• MS44 (compound 18) is the first reported selective degrader of AURKB.
• Potent degradation of AURKB achieved with DC50 < 100 nM in a time-, concentration-, VHL-, and UPS-dependent manner.
• Compound 18 demonstrated selectivity for AURKB over AURKA and related kinases.
• Effective inhibition of proliferation observed across multiple cancer cell lines.

Conclusions:

• Compound 18 represents a significant advancement as a chemical biology tool and potential therapeutic agent.
• Pharmacological degradation of AURKB offers a promising alternative therapeutic approach for AURKB-dependent tumors.
• The discovery validates targeting AURKB degradation for cancer treatment.