Crystal structure-based comparison of two NAMPT inhibitors

• 来源期刊: 中国药理学报（英文版）
• 关键词: nicotinamide phosphoribosyltransferase (NAMPT) FK866 MSO anticancer drugs antiproliferation crystal structure binding mode
• 年，卷（期）: 2018,（2）
• 页码范围: 294-301
• 页数: 8页
• 语种: 英文
• DOI: 10.1038/aps.2017.80

摘要

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a novel strategy for cancer therapy,but only two inhibitors of NAMPT (FK866 and CHS828) have progressed into clinical trials.This study seeks to compare a novel potent NAMPT inhibitor,MSO,with a classical inhibitor FK866 in their biological activity and molecular binding mode,thereby contributing to future chemical optimization and a further understanding of the action mode of NAMPT inhibitors.The IC50values of MSO and FK866 in inhibition of recombinant human NAMPT activity were 9.08±0.90 and 1.60±0.32 nmol/L,respectively.Consistently,FK866 exerted better antiproliferation in 6 human cancer cell lines (HepG2,A2780,95-D,A549,U20S and U266) than MSO with IC50 values nearly 12-fold to 225-fold lower than those of MSO.Co-crystal structures of wild-type human NAMPT complexed with MSO or FK866 were elucidated,which revealed that MSO did not interact with Ser241.The hydrogen bond mediated by crystallographic water between MSO and His191 or Val350 of NAMPT did not exist in FK866.Instead,FK866 exhibited hydrophobic interactions with Arg349.Based on the activity assays and crystal structure analyses,we elaborate the reason why the antiproliferation activity of MSO was not as good as that of FK866,which would contributes to the current understanding of the mode of action of NAMPT inhibitors and will also contribute to further development of anticancer drugs in the future.