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Design, synthesis and biological evaluation of a new class of 7H-pyrrolo[2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer

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收录情况： ◇ SCIE

作者：
Li Xinyue[1] * ; Wei Wei[1] * ; Tao Longyue[1] ; Zeng Jun[1] ; Zhu Yongxia[2] ; Yang Tianqiong[1] ; Wang Qiwei[1] ; Tang Minhai[1] ; Liu Zhihao[1] ; Yu Luoting[1] ;
机构： [1]Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherqpy/ Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China [2]Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China
出处：
DOI： 10.1016/j.ejmech.2022.114887
ISSN：

摘要：
Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure-activity relationship (SAR) revealed that 12 is a potent Mps1 inhibitor (IC50 = 29 nM), which inhibited phosphorylation of Mps1 in vitro and in vivo. Treatment with 12 not only impeded proliferation of breast cancer cell lines, but also induced cell cycle arrest and apoptosis of MCF-7 and 4T1 cells. 12 suppressed tumor growth in vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 inhibitor 12 for the treatment of breast cancer.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

基金：
This study was supported by National Natural Science Foundation of China, China (81903441), Natural Science Foundation of Sichuan Province, China (2022NSFSC1396) and Science and Technology Pro￾gram of Sichuan Province (2021YFH0145).
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外文
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中科院(CAS)分区：
出版当年[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
JCR分区：
出版当年[2023]版：
Q1 CHEMISTRY, MEDICINAL
最新[2023]版：
Q1 CHEMISTRY, MEDICINAL

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]Laboratory of Emergency Medicine, Department of Emergency Medicine, State Key Laboratory of Biotherqpy/ Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Li Xinyue,Wei Wei,Tao Longyue,et al.Design, synthesis and biological evaluation of a new class of 7H-pyrrolo[2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer[J].EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.2023,245:doi:10.1016/j.ejmech.2022.114887.
APA：
Li Xinyue,Wei Wei,Tao Longyue,Zeng Jun,Zhu Yongxia...&Yu Luoting.(2023).Design, synthesis and biological evaluation of a new class of 7H-pyrrolo[2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,245,
MLA：
Li Xinyue,et al."Design, synthesis and biological evaluation of a new class of 7H-pyrrolo[2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 245.(2023)

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