Fragment-based discovery of a potent NAMPT inhibitor. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Korepanova, Alla; Longenecker, Kenton L.; Pratt, Steve D.; Panchal, Sanjay C.; Clark, Richard F.; Lake, Marc; Gopalakrishnan, Sujatha M.; Raich, Diana; Sun, Chaohong; Petros, Andrew M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 3(2018)
• Page Start: 437
• Page End: 440
• Publication Date: 2018-02-01
• Subjects: NMR -- Fragment-based -- FBDD -- FBLD -- NAMPT; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.12.023
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor.