AURKA TPX2-tethering ligand

AURKA TPX2-tethering ligands represent a first-in-class category of kinase-sparing small molecules designed to stabilize the protein-protein interaction (PPI) between Aurora Kinase A (AURKA) and its binding partner TPX2. Unlike traditional ATP-competitive AURKA inhibitors that disrupt kinase activity, these ligands act as molecular tethers that lock the AURKA-TPX2 complex in mitotic cells. This stabilization leads to the formation of multipolar spindles and subsequent mitotic catastrophe, specifically in cancer cells with low expression of the anti-apoptotic protein MCL1, such as TP53-deficient hepatocellular carcinoma and TP53/RB1-deficient small cell lung cancer (SCLC). Because they do not inhibit the non-canonical (non-mitotic) functions of AURKA, they exhibit a wider therapeutic window compared to conventional inhibitors and can be administered continuously without significant toxicity to normal cells.

Other names

kinase sparing TPX2-tethering Aurora kinase A ligands