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

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

  • Bioorg Med Chem Lett. 2014 Feb 1;24(3):954-62. doi: 10.1016/j.bmcl.2013.12.062.
Peter S Dragovich 1,  Guiling Zhao 2,  Timm Baumeister 3,  Brandon Bravo 2,  Anthony M Giannetti 2,  Yen-Ching Ho 3,  Rongbao Hua 4,  Guangkun Li 4,  Xiaorong Liang 2,  Xiaolei Ma 2,  Thomas O'Brien 2,  Angela Oh 2,  Nicholas J Skelton 2,  Chengcheng Wang 5,  Weiru Wang 2,  Yunli Wang 4,  Yang Xiao 2,  Po-wai Yuen 4,  Mark Zak 2,  Qiang Zhao 5,  Xiaozhang Zheng 3
Affiliations

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dragovich.peter@gene.com.
  • 2 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 3 Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
  • 4 Pharmaron Beijing, Co. Ltd., 6 Taihe Road, BDA, Beijing 100176, PR China.
  • 5 Crown Bioscience, Science & Technology Innovation Park, No.6 Beijing West Road, Taicang City, Jiangsu Province, PR China.
PMID: 24433859 DOI: 10.1016/j.bmcl.2013.12.062
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.

Keywords

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

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