机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.[2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University, and Collaborative Innovation Center of Biotherapy , Chengdu , Sichuan 610041 , China.四川大学华西医院[3]Department of Structural Biology , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 , United States.[4]Affiliated Cancer Hospital and Institute of Guangzhou Medical University , Guangzhou , Guangdong 511436 , China.
Colchicine binding site inhibitors (CBSIs) hold great potential in developing new generations of antimitotic drugs. Unlike existing tubulin inhibitors such as paclitaxel, they are generally much less susceptible to resistance caused by the overexpression of drug efflux pumps. The 3,4,5-trimethoxyphenyl (TMP) moiety is a critical component present in many CBSIs, playing an important role in maintaining suitable molecular conformations of CBSIs and contributing to their high binding affinities to tubulin. Previously reported modifications to the TMP moiety in a variety of scaffolds of CBSIs have usually resulted in reduced antiproliferative potency. We previously reported a potent CBSI, VERU-111, that also contains the TMP moiety. Herein, we report the discovery of a VERU-111 analogue 13f that is significantly more potent than VERU-111. The X-ray crystal structure of 13f in complex with tubulin confirms its direct binding to the colchicine site. In addition, 13f exhibited a strong inhibitory effect on tumor growth in vivo.
基金：
This work is supported by NIH/NCI grant R01CA148706 to
W.L. and D.D.M and NIH grants 1S10OD010678-01 and
1S10RR026377-01 and the Guangzhou key medical discipline
construction project to W.L. Its contents are solely the
responsibility of the authors and do not necessarily represent
the official views of the NIH. Additional support was from the
University of Tennessee College of Pharmacy Drug Discovery
Center. We thank Dr. Lei Yang at St. Jude Children’s Research
Hospital for the metabolic stability evaluation for new VERU-
111 analogues. We also thank Dr. Benoît
Gigant (Institute for
Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ.
Paris-Sud, Université Paris-Saclay, France) and Dr. Michel O.
Steinmetz (Paul Scherrer Institute, Switzerland) for kindly
providing the plasmids of RB3-SLD and TTL. The X-ray work
was supported by National Natural Science Foundation of
China (No. 81703553), China Postdoctoral Science Foundation
(No. 2017M610607), and Postdoctoral Science Foundation
of Sichuan University (No. 2017SCU12045). G.K. and
S.W.W. acknowledge the support of American Lebanese Syrian
Associated Charities (ALSAC).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|2 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States.[4]Affiliated Cancer Hospital and Institute of Guangzhou Medical University , Guangzhou , Guangdong 511436 , China.
推荐引用方式(GB/T 7714)：
Wang Qinghui,Arnst Kinsie E,Wang Yuxi,et al.Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities.[J].Journal of medicinal chemistry.2018,61(17):7877-7891.doi:10.1021/acs.jmedchem.8b00827.
APA：
Wang Qinghui,Arnst Kinsie E,Wang Yuxi,Kumar Gyanendra,Ma Dejian...&Li Wei.(2018).Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities..Journal of medicinal chemistry,61,(17)
MLA：
Wang Qinghui,et al."Structural Modification of the 3,4,5-Trimethoxyphenyl Moiety in the Tubulin Inhibitor VERU-111 Leads to Improved Antiproliferative Activities.".Journal of medicinal chemistry 61..17(2018):7877-7891
医学