The discovery of the potent aurora inhibitor MK-0457 (VX-680)

The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) containing the T315I mutation.

Graphical abstractThe identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR, which led to the discovery of MK-0457 (VX-680), is described.Figure optionsDownload full-size imageDownload as PowerPoint slide