학술논문
Structure-BasedDiscovery of Novel Amide-ContainingNicotinamide Phosphoribosyltransferase (Nampt) Inhibitors.
Document Type
Article
Author
Zheng, Xiaozhang; Bauer, Paul; Baumeister, Timm; Buckmelter, Alexandre J.; Caligiuri, Maureen; Clodfelter, Karl H.; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Lin, Jian; Reynolds, Dominic J.; Sharma, Geeta; Smith, Chase C.; Wang, Zhongguo; Dragovich, Peter S.; Gunzner-Toste, Janet; Liederer, Bianca M.; Ly, Justin; O’Brien, Thomas; Oh, Angela
Source
Subject
*DRUG development
*NICOTINAMIDE
*PHOSPHORIBOSYLTRANSFERASES
*ENZYME inhibitors
*CRYSTAL structure
*THIOUREA
*DRUG design
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Language
ISSN
0022-2623
Abstract
Crystal structures of several urea-and thiourea-derived compoundsin complex with the nicotinamide phosphoribosyltransferase (Nampt)protein were utilized to design a potent amide-containing inhibitorbearing an aza-indole moiety (7, Nampt BC IC50= 9.0 nM, A2780 cell proliferation IC50= 10 nM). TheNampt–7cocrystal structure was subsequently obtainedand enabled the design of additional amide-containing inhibitors whichincorporated various other fused 6,5-heterocyclic moieties and biarylsulfone or sulfonamide motifs. Additional modifications of these moleculesafforded many potent biaryl sulfone-containing Nampt inhibitors whichalso exhibited favorable in vitro ADME properties (microsomal andhepatocyte stability, MDCK permeability, plasma protein binding).An optimized compound (58) was a potent inhibitor ofmultiple 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 aU251 mouse xenograft model. [ABSTRACT FROM AUTHOR]