Novel, highly potent PROTACs targeting AURORA-A kinase
Jelena Božilović, Lorenz Eing, Benedict‐Tilman Berger, Bikash Adhikari, Janik Weckesser, Nicola Berner, Stephanie Wilhelm, Bernhard Küster, Elmar Wolf, Stefan Knapp
Abstract
The family of AURORA kinases is essential for cell cycle progression and dysregulation of AURORA-A in cancer led to a large number of clinical and pre-clinical inhibitors. However, ATP competitive AURORA-A inhibitors usually do not target non-catalytic functions that have also been identified as mechanisms promoting tumorigenesis. To target non-catalytic as well as catalytic functions, we developed a series of PROTACs (PROteolysis TArgeting Chimeras) based on the selective AURORA-A kinase inhibitor MK-5108 (VX-689) and the CEREBLON E3-ligase ligand thalidomide. The most potent PROTAC, JB301, had good physicochemical properties and cell penetration resulting in degradation of AURORA-A in leukemic cells at single digit nM concentration.