title: Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15 nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50 = 0.93 ± 0.29 nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents.
authors.affiliation: Department of Pharmacology.
authors.forename: Tian-Ying
authors.initials: TY
authors.lastname: Xu
authors.affiliation: Department of Pharmacology.
authors.forename: Sai-Long
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Dong
authors.affiliation: Department of Pharmacology.
authors.forename: Xin-Zhu
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology.
authors.forename: Xiao-Qun
authors.initials: XQ
authors.lastname: Lv
authors.affiliation: Eastern Hepatobiliary Surgical Hospital &Institute, Second Military Medical University, Shanghai, China.
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Qian
authors.affiliation: Department of Pharmacology.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Chun-Quan
authors.initials: CQ
authors.lastname: Sheng
authors.affiliation: Department of Pharmacology.
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Miao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D054409:Nicotinamide Phosphoribosyltransferase