Discovery and development of MP529, a new effective and selective inhibitor of Aurora A kinase.

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3261 Genetic instability can lead to tumorigenesis, creating the need for cells to develop mechanisms and checkpoints to ensure faithful replication and division of genetic material. These mechanisms and checkpoints remain intact in normal cells, but are often disrupted or lost in cancer cells. Aurora kinases have mitotic regulatory functions and are important proteins in the maintenance of genetic stability, especially during mitosis. Aurora A localizes to the centrosomes during mitosis and is required for spindle assembly; atypical amounts of Aurora A in cells cause abnormal spindle formation and disruption of the spindle-assembly checkpoint. Overexpression of Aurora has been observed in several types of human cancers including breast, colorectal, prostate, ovarian, and pancreas. Aurora A represents a logical target because of its implication in tumorigenesis and, being a kinase, lends itself to small molecule inhibition. We have developed new small molecule inhibitors, the MP529 series, which demonstrate both activity and specificity for Aurora A kinase. These compounds were developed using our proprietary CLIMB drug discovery process which involves physical screening of much fewer compounds than traditional methods, (less than one hundred versus several million), and produces superior results. The crystal structure of Aurora A kinase was used as a substrate for docking to generate a subset of leads from our large virtual library of compounds; this subset of leads was selected based on calculated binding energies. The lead compounds were then subjected to a number of in silico physiochemical and ADMET prediction algorithms to determine which were most likely to be “drug-like”. This computational screen produced a group of candidates of the substituted (4-p-tolylsulfamoyl-phenyl) amide class, the MP529 series. These compounds demonstrate nanomolar activity against Aurora-A kinase in biochemical enzyme based assays, while exhibiting little to no activity versus Aurora B. In cell based assays the MP529 series induced phenotypes indicative of Aurora A inhibition, and these compounds have been extended into in vivo studies. This series of compounds has been evaluated in in vivo xenograft models and shows efficacy while maintaining desirable pharmacokinetic properties and a large therapeutic window. The MP529 series is a unique set of compounds that demonstrate improved activity and selectivity for the Aurora A target, and is currently undergoing late-stage preclinical development.