title: Fragment-based identification of amides derived from trans-2-(pyridin-3-yl)cyclopropanecarboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
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.
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Bravo
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Eric
authors.initials: E
authors.lastname: Cheng
authors.forename: Lisa
authors.initials: L
authors.lastname: Crocker
authors.forename: Yezhen
authors.initials: Y
authors.lastname: Feng
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Rongbao
authors.initials: R
authors.lastname: Hua
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Youming
authors.initials: Y
authors.lastname: Shen
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Wang
authors.forename: Leslie
authors.initials: L
authors.lastname: Wang
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Po-wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D003521:Cyclopropanes; C587724:N-(4-((1-propyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-(pyridin-3-yl)cyclopropanecarboxamide; D011725:Pyridines; D013450:Sulfones; D054409:Nicotinamide Phosphoribosyltransferase