title: Structure-based discovery of novel amide-containing nicotinamide phosphoribosyltransferase (nampt) inhibitors.
abstract: Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model.
authors.affiliation: Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, Massachusetts 02472, United States. xzheng@formatherapeutics.com
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Paul
authors.initials: P
authors.lastname: Bauer
authors.forename: Timm
authors.initials: T
authors.lastname: Baumeister
authors.forename: Alexandre J
authors.initials: AJ
authors.lastname: Buckmelter
authors.forename: Maureen
authors.initials: M
authors.lastname: Caligiuri
authors.forename: Karl H
authors.initials: KH
authors.lastname: Clodfelter
authors.forename: Bingsong
authors.initials: B
authors.lastname: Han
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kley
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Reynolds
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.forename: Chase C
authors.initials: CC
authors.lastname: Smith
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Leslie
authors.initials: L
authors.lastname: Wang
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase