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- Title
Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase.
- Authors
Xu, Tian-Ying; Zhang, Sai-Long; Dong, Guo-Qiang; Liu, Xin-Zhu; Wang, Xia; Lv, Xiao-Qun; Qian, Qi-Jun; Zhang, Ruo-Yu; Sheng, Chun-Quan; Miao, Chao-Yu
- 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 ± 1.15nM) 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.
- Subjects
SMALL molecules; CHEMICAL inhibitors; NICOTINAMIDE; PHOSPHORIBOSYLTRANSFERASES; ANTINEOPLASTIC agents; CANCER cells
- Publication
Scientific Reports, 2015, p10043
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep10043