학술논문
Fragment-Based Identificationof Amides Derived from trans-2-(Pyridin-3-yl)cyclopropanecarboxylicAcid as PotentInhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT).
Document Type
Article
Author
Giannetti, Anthony M.; Zheng, Xiaozhang; Skelton, Nicholas J.; Wang, Weiru; Bravo, Brandon J.; Bair, Kenneth W.; Baumeister, Timm; Cheng, Eric; Crocker, Lisa; Feng, Yezhen; Gunzner-Toste, Janet; Ho, Yen-Ching; Hua, Rongbao; Liederer, Bianca M.; Liu, Yongbo; Ma, Xiaolei; O’Brien, Thomas; Oeh, Jason; Sampath, Deepak; Shen, Youming
Source
Subject
*CARBOXYLIC acids
*NICOTINAMIDE
*PHOSPHORIBOSYLTRANSFERASES
*IN vitro studies
*LABORATORY mice
*XENOGRAFTS
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Language
ISSN
0022-2623
Abstract
Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containinginhibitors of the human nicotinamide phosphoribosyltransferase(NAMPT) enzyme were identified using fragment-based screening andstructure-based design techniques. Multiple crystal structures wereobtained of initial fragment leads, and this structural informationwas utilized to improve the biochemical and cell-based potency ofthe associated molecules. Many of the optimized compounds exhibitednanomolar antiproliferative activities against human tumor lines inin 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 cellculture IC50= 0.000 49 μM) which demonstratedencouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model. [ABSTRACT FROM AUTHOR]