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Discovery of novel thiophene[3,2-d]pyrimidine-based tubulin inhibitors with enhanced antitumor efficacy for combined use with anti-pd-l1 immunotherapy in melanoma

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资源类型：
Pubmed体系：
作者：
Xu Chenglong[1] * ; Wu Chengyong[2] * ; Li Ling[3] * ; Zhao Huiting[1] ; Liu Jin[4] ; Peng Xiaopeng[5] ; Wang Yuxi[2,6,*2] ; Chen Jianjun[1,*1] ;
机构： [1]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China [2]Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China [3]The Eighth Affiliated Hospital Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, 518000, China [4]Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228, China [5]College of Pharmacy, Gannan Medical University, Ganzhou, 314000, China [6]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China
出处：
DOI： 10.1016/j.ejmech.2024.116791
ISSN：

关键词： 2-methylthieno[3 2-d]pyrimidine Tubulin inhibitors Anti-cancer Combination therapy

摘要：
Herein, we designed and synthesized a series of novel 2-methylthieno [3,2-d]pyrimidine analogues as tubulin inhibitors with antiproliferative activities at low nanomolar levels. Among them, compound DPP-21 displayed the most potent anti-proliferative activity against six cancer cell lines with an average IC50 of ∼6.23 nM, better than that of colchicine (IC50 = 9.26 nM). DPP-21 exerted its anti-cancer activity by suppressing the polymerization of tubulin with an IC50 of 2.4 μM. Furthermore, the crystal structure of DPP-21 in complex with tubulin was solved by X-ray crystallography to 2.94 Å resolution, confirming the direct binding of DPP-21 to the colchicine site. Moreover, DPP-21 arrested the cell cycle in the G2/M phase of mitosis, subsequently inducing tumor cell apoptosis. Additionally, DPP-21 was able to effectively inhibit the migration of cancer cells. Besides, DPP-21 exhibited significant in vivo anti-tumor efficacy in a B16-F10 melanoma tumor model with a TGI of 63.3 % (7 mg/kg) by intraperitoneal (i.p.) injection. Notably, the combination of DPP-21 with NP-19 (a PD-L1-targeting small molecule inhibitor reported by our group before) demonstrated enhanced anti-cancer efficacy in vivo. These results suggest that DPP-21 is a promising lead compound deserving further investigation as a potential anti-cancer agent.Copyright © 2024 Elsevier Masson SAS. All rights reserved.

基金：
This work was supported by National Natural Science Foundation of China (No. #82173668; #82373706), and Guangdong Basic and Applied Basic Research Foundation (2023A1515012967).
语种：
外文
PubmedID：
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出版当年[2024]版：
无
最新[2023]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]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China
共同第一作者：
通讯作者：
通讯机构： [1]School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China [2]Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China [6]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China [*1]School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. [*2]West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
推荐引用方式(GB/T 7714)：
Xu Chenglong,Wu Chengyong,Li Ling,et al.Discovery of novel thiophene[3,2-d]pyrimidine-based tubulin inhibitors with enhanced antitumor efficacy for combined use with anti-pd-l1 immunotherapy in melanoma[J].European Journal Of Medicinal Chemistry.2024,277:116791.doi:10.1016/j.ejmech.2024.116791.
APA：
Xu Chenglong,Wu Chengyong,Li Ling,Zhao Huiting,Liu Jin...&Chen Jianjun.(2024).Discovery of novel thiophene[3,2-d]pyrimidine-based tubulin inhibitors with enhanced antitumor efficacy for combined use with anti-pd-l1 immunotherapy in melanoma.European Journal Of Medicinal Chemistry,277,
MLA：
Xu Chenglong,et al."Discovery of novel thiophene[3,2-d]pyrimidine-based tubulin inhibitors with enhanced antitumor efficacy for combined use with anti-pd-l1 immunotherapy in melanoma".European Journal Of Medicinal Chemistry 277.(2024):116791

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