Structural basis for potent inhibition of the Aurora kinases and a T3151 multi-drug resistant mutant form of Abl kinase by VX-680

The small molecule inhibitor of the Aurora-family of protein kinases VX-680 or MK-0457, demonstrates potent anticancer activity in multiple in vivo models and has recently entered phase 11 clinical trials. Although VX-680 shows a high degree of enzyme selectivity against multiple kinases, it unexpectedly inhibits both Flt-3 and Abl kinases at low nanomolar concentrations. Furthermore VX-680 potently inhibits Abl and the Imatinib resistant mutant (T315I) that is commonly expressed in refractory CML and ALL. We describe here the crystal structure of VX-680 bound to Aurora-A and show that this inhibitor exploits a centrally located hydrophobic pocket in the active site that is only present in an inactive or closed kinase conformation. A tight association of VX-680 with this hydrophobic pocket explains its high affinity for the Aurora kinases and also provides an explanation for its selectivity profile, including its ability to inhibit Ab1 and the Imatinib-resistant mutant (T315I). (C) 2006 Elsevier Ireland Ltd. All rights reserved.