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Structure-guided design of potent tetrazolo[1,5-a]pyrimidine-based tubulin inhibitors with in vivo antitumor activity

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资源类型：
Pubmed体系：
作者：
Guo Yaolin[1] * ; Yu Quanwei[3,5] * ; Guo Cuiyu[1] * ; Wu Chengyong[1] ; Tan Lun[1] ; Zhang Ruofei[1] ; He Yang[2,5] ; Tong Aiping[1,4] ; Wang Yuxi[1,2] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China [3]Heilongjiang Institute for Drug Control, Harbin, 150088, China [4]State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China [5]Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
出处：
DOI： 10.1016/j.ejmech.2025.118288
ISSN：

关键词： Tubulin Colchicine-binding site inhibitor Structure-based drug design High-throughput virtual screening Crystal structure

摘要：
Inhibitors targeting the colchicine-binding site of tubulin (CBSIs) represent a promising class of antitumor agents, offering the potential to overcome multidrug resistance. Through high-throughput virtual screening (HTVS) via molecular docking (Glide) followed by structural optimization, a novel hit compound Q1 (tetrazolo[1,5-a]pyrimidine scaffold; SKOV3 IC50 = 2.20 ± 0.05 μM) was identified from the ChemDiv library. Molecular dynamics (MD) simulations revealed that the cyclohexane moiety of Q1 exhibited high flexibility, which was identified as a key factor limiting its potency. Three stages of structural modification (Parts A-C) yielded 66 derivatives. The racemic lead compound rac-Q31 (hereinafter referred to as Q31 for brevity), which bears an optimized 3,5-dimethylphenyl group, exhibited potent antitumor activity with an IC50 of 24.6 ± 1.4 nM against SKOV3 cells. A co-crystal structure (PDB: 9LSE) confirmed that Q31 binds stably within the colchicine site, forming a hydrogen bond with α-Thr179 and key hydrophobic interactions, including those with α-Leu240 and β-Ile316. (S)-Q31 showed enhanced activity (SKOV3 IC50 = 17.2 ± 1.8 nM). In an SKOV3 xenograft model, (S)-Q31 exhibited significant antitumor efficacy (tumor growth inhibition, TGI = 74.12 % at 4 mg/kg, i.v.) with good tolerability. Mechanistically, (S)-Q31 inhibited microtubule polymerization, arrested the cell cycle at the G2/M phase, and induced apoptosis. This study establishes (S)-Q31 as a promising CBSI lead compound and provides structural insights for novel microtubule inhibitor development.Copyright © 2025 Elsevier Masson SAS. All rights reserved.

基金：
Ministry of Science and Technology of China (MoST) (2022YFC2303700), the National Natural Science Foundation of China (82473782), the Natural Science Foundation of Sichuan Province of China (2025ZNSFSC1869).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
最新[2025]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China [4]State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China
推荐引用方式(GB/T 7714)：
Guo Yaolin,Yu Quanwei,Guo Cuiyu,et al.Structure-guided design of potent tetrazolo[1,5-a]pyrimidine-based tubulin inhibitors with in vivo antitumor activity[J].European Journal Of Medicinal Chemistry.2025,302(Pt 1):118288.doi:10.1016/j.ejmech.2025.118288.
APA：
Guo Yaolin,Yu Quanwei,Guo Cuiyu,Wu Chengyong,Tan Lun...&Wang Yuxi.(2025).Structure-guided design of potent tetrazolo[1,5-a]pyrimidine-based tubulin inhibitors with in vivo antitumor activity.European Journal Of Medicinal Chemistry,302,(Pt 1)
MLA：
Guo Yaolin,et al."Structure-guided design of potent tetrazolo[1,5-a]pyrimidine-based tubulin inhibitors with in vivo antitumor activity".European Journal Of Medicinal Chemistry 302..Pt 1(2025):118288

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