Discovery of a Highly Subtype-Selective AURKA PROTAC Degrader (CT3) with Superior Activity to the Inhibitor for Hematological Malignancies.

Aurora kinases, especially AURKA, are critical for mitotic regulation, and their dysregulation is linked to tumorigenesis, making AURKA a promising anticancer target. Conventional ATP-competitive AURKA inhibitors suffer from low subtype selectivity and failure to disrupt noncatalytic functions, resulting in limited therapeutic efficacy and substantial toxic side effects. Proteolysis-targeting chimera (PROTAC) technology presents a promising alternative by enabling degradation of the target protein, thereby blocking both catalytic and noncatalytic functions. Here, we developed AURKA degraders based on the allosteric inhibitor CAM2602 and CRBN-recruiting moieties. Compound CT3 was characterized as a potent and subtype-selective AURKA degrader. It displayed enhanced antiproliferative activity compared with the parental inhibitor in Jurkat cells, which have high CRBN and AURKA expression, and demonstrated effective in vivo antitumor effects in Jurkat xenograft models. Further structural optimization is expected to generate promising AURKA degrader candidates for drug development.