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Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062. Epub 2013 Dec 21.

Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Author information

  • 1Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dragovich.peter@gene.com.
  • 2Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • 4Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
  • 5Crown Bioscience, Science & Technology Innovation Park, No.6 Beijing West Road, Taicang City, Jiangsu Province, PR China.

Abstract

The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Fragment-based design; NAMPT; Nicotinamide phosphoribosyltransferase; Structure-based design; Surface plasmon resonance; X-ray crystal structure

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