Fragment-based discovery of a potent NAMPT inhibitor

Abstract NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragmentscreens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragmentsbound to NAMPT while for the other four fragmentsforce-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragmentposes to that of bound FK866 we were able to synthetically elaborate one of the fragmentsinto a potent NAMPT inhibitor.