Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
journal contributionposted on 19.02.2016, 00:06 by Xiaozhang Zheng, Paul Bauer, Timm Baumeister, Alexandre J. Buckmelter, Maureen Caligiuri, Karl H. Clodfelter, Bingsong Han, Yen-Ching Ho, Nikolai Kley, Jian Lin, Dominic J. Reynolds, Geeta Sharma, Chase C. Smith, Zhongguo Wang, Peter S. Dragovich, Janet Gunzner-Toste, Bianca M. Liederer, Justin Ly, Thomas O’Brien, Angela Oh, Leslie Wang, Weiru Wang, Yang Xiao, Mark Zak, Guiling Zhao, Po-wai Yuen, Kenneth W. Bair
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.
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BCcompoundNamptplasma protein bindingmouse PK properties10 nMcancer cell linesHTU 251 mouse xenograft modelADME propertiesAdditional modificationsPCHCTinhibitorbiaryl sulfoneInhibitorsCrystal structuressulfonamide motifs2780 cell proliferation IC 50nicotinamide phosphoribosyltransferase9.0 nMCLhepatocyte stabilityMDCK permeability