Fragment-based discovery of a potent NAMPT inhibitor

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Korepanova, Alla¹  Longenecker, Kenton L.¹  Pratt, Steve D.¹  Panchal, Sanjay C.¹  Clark, Richard F.¹  Lake, Marc¹  Gopalakrishnan, Sujatha M.¹  Raich, Diana¹  Sun, Chaohong¹  Petros, Andrew M.¹ 

[1] Res & Dev AbbVie, 1 North Waukegan Rd, N Chicago, IL 60064 USA

关键词: NMR;    Fragment-based;    FBDD;    FBLD;    NAMPT;   

DOI  :  10.1016/j.bmcl.2017.12.023

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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