Structure-Based Design of Potent Nicotinamide Phosphoribosyltransferase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

Jinhong Bai, Chenzhong Liao, Yanghan Liu, Xiaochu Qin, Jiaxuan Chen, Yatao Qiu, Dongguang Qin, Zheng Li, Zheng Chao Tu, Sheng Jiang

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) has the potential to directly limit NAD production in cancer cells and is an effective strategy for cancer treatment. Using a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of NAMPT. Several designed compounds showed promising antiproliferative activities in vitro. (E)-N-(5-((4-(((2-(1H-Indol-3-yl)ethyl)(isopropyl)amino)methyl)phenyl)amino)pentyl)-3-(pyridin-3-yl)acrylamide, 30, bearing an indole moiety, has an IC50 of 25.3 nM for binding to the NAMPT protein and demonstrated promising inhibitory activities in the nanomolar range against several cancer cell lines (MCF-7 GI50 = 0.13 nM; MDA-MB-231 GI50 = 0.15 nM). Triple-negative breast cancer is the most malignant subtype of breast cancer with no effective targeted treatments currently available. Significant antitumor efficacy of compound 30 was achieved (TGI was 73.8%) in an orthotopic MDA-MB-231 triple-negative breast cancer xenograft tumor model. This paper reports promising lead molecules for the inhibition of NAMPT which could serve as a basis for further investigation.

Original languageEnglish (US)
Pages (from-to)5766-5779
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number12
DOIs
StatePublished - Jun 23 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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