Crystal structure-based comparison of two NAMPT inhibitors

doi:10.1038/aps.2017.80

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	Crystal structure-based comparison of two NAMPT inhibitors
	Zhang, Sai-long 3; Xu, Tian-ying 3; Yang, Zhen-lin 1; Han, Shuo 1; Zhao, Qiang1 ; Miao, Chao-yu 2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2018-02
卷号	39 期号:2 页码:294-301
关键词	nicotinamide phosphoribosyltransferase (NAMPT) FK866 MS0 anticancer drugs antiproliferation crystal structure binding mode
ISSN号	1671-4083
DOI	10.1038/aps.2017.80
文献子类	Article
英文摘要	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, MS0, 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 IC50 values of MS0 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, U2OS and U266) than MS0 with IC50 values nearly 12-fold to 225-fold lower than those of MS0. Co-crystal structures of wild-type human NAMPT complexed with MS0 or FK866 were elucidated, which revealed that MS0 did not interact with Ser241. The hydrogen bond mediated by crystallographic water between MS0 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 MS0 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.
资助项目	National Natural Science Foundation of China[81130061] ; National Natural Science Foundation of China[81373414] ; Shanghai Municipal Science and Technology Project[16431901400] ; Shanghai Municipal Science and Technology Project[16140904500]
WOS关键词	NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE NAMPT ; COLONY-ENHANCING FACTOR ; IN-VITRO ; PHASE-I ; CHS 828 ; IDENTIFICATION ; CELLS ; BIOSYNTHESIS ; RESISTANCE ; FK866
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:6163695
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000423868000015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279937]
专题	药物靶标结构与功能中心
通讯作者	Zhao, Qiang; Miao, Chao-yu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Beijing Inst Brain Disorders, Ctr Stroke, Beijing 100069, Peoples R China 3.Second Mil Med Univ, Dept Pharmacol, Shanghai 200433, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Sai-long,Xu, Tian-ying,Yang, Zhen-lin,et al. Crystal structure-based comparison of two NAMPT inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2018,39(2):294-301.
APA	Zhang, Sai-long,Xu, Tian-ying,Yang, Zhen-lin,Han, Shuo,Zhao, Qiang,&Miao, Chao-yu.(2018).Crystal structure-based comparison of two NAMPT inhibitors.ACTA PHARMACOLOGICA SINICA,39(2),294-301.
MLA	Zhang, Sai-long,et al."Crystal structure-based comparison of two NAMPT inhibitors".ACTA PHARMACOLOGICA SINICA 39.2(2018):294-301.