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
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 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.