Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT)

  • J Med Chem. 2014 Feb 13;57(3):770-92. doi: 10.1021/jm4015108.
Anthony M Giannetti  1 ,  Xiaozhang Zheng ,  Nicholas J Skelton ,  Weiru Wang ,  Brandon J Bravo ,  Kenneth W Bair ,  Timm Baumeister ,  Eric Cheng ,  Lisa Crocker ,  Yezhen Feng ,  Janet Gunzner-Toste ,  Yen-Ching Ho ,  Rongbao Hua ,  Bianca M Liederer ,  Yongbo Liu ,  Xiaolei Ma ,  Thomas O'Brien ,  Jason Oeh ,  Deepak Sampath ,  Youming Shen ,  Chengcheng Wang ,  Leslie Wang ,  Hongxing Wu ,  Yang Xiao ,  Po-wai Yuen ,  Mark Zak ,  Guiling Zhao ,  Qiang Zhao ,  Peter S Dragovich
Affiliations
  • 1. Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 24405419 DOI: 10.1021/jm4015108
Abstract

Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro Cell Culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 Cell Culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.