通过抑制 ROR1 发现 3-(2-氨基苯并[d]噻唑-5-基)苯甲酰胺衍生物作为强效抗癌剂

IF 3.3 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fang Luo , Jie Liu , Rongtao Wang, Huiyin Yang, Ting Zhong, Mingzhi Su, Yanhua Fan
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引用次数: 0

摘要

受体酪氨酸激酶样孤儿受体1(ROR1)是受体酪氨酸激酶家族的成员,在非小细胞肺癌(NSCLC)中过度表达,对细胞增殖、迁移和侵袭至关重要。最近,越来越多的证据表明,ROR1 在维持 Src 生存通路和 p38 细胞凋亡通路之间的平衡方面发挥着关键作用。因此,ROR1 被认为是开发抗癌药物的一个有吸引力的治疗靶点。然而,到目前为止,只有少数小分子 ROR1 抑制剂被报道。本文以先导化合物 9a 为基础,通过生物异构和简化策略,设计并合成了一系列 3-(2-氨基苯并[d]噻唑-5-基)苯甲酰胺衍生物。MTT 试验表明,化合物 7h 的抗癌性能最佳,对 A549、PC9 和 H1975 细胞的 IC50 值分别为 18.16、8.11 和 3.5 μM。同时,化合物 7h 对 H1975 细胞的选择性指数(SI)为 22.86,而先导化合物 9a 的选择性指数为 1.83,比先导化合物 9a 高出至少 12 倍,这表明 7h 具有良好的安全性。此外,分子对接、CETSA 和 DARTS 分析表明,化合物 7h 可能是一种新型小分子 ROR1 抑制剂。更重要的是,化合物 7h 通过阻断 Src 生存通路和重新激活 p38 细胞凋亡通路,显著抑制了体外 H1975 细胞的迁移和侵袭,并诱导 H1975 细胞周期停滞在 G1 期。总之,我们的研究表明,ROR1抑制剂7h可能是治疗NSCLC的一种新型候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition

Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, which was overexpressed in non-small cell lung cancer (NSCLC) and essential for cell proliferation, migration and invasion. Recently, accumulating evidences indicated that ROR1 played a critical role in maintaining the balance between the Src survival pathway and the p38 apoptotic pathway. Hence, ROR1 was considered as an attractive therapeutic target for the development of anticancer drugs. However, only a few small molecule ROR1 inhibitors were reported until now. Herein, a series of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives were designed and synthesized via bioisosterism and simplification strategy guided by the lead compound 9a. MTT assay showed that compound 7h exhibited the best anti-cancer properties with IC50 values of 18.16, 8.11 and 3.5 μM against A549, PC9 and H1975 cells, respectively. Meanwhile, the selectivity index (SI) of compound 7h for H1975 cells was 22.86 compared to that of the lead compound 9a of 1.83, which is at least 12 fold higher than that of lead compound 9a, suggesting that 7h had a favorable safety profile. In addition, the molecular docking, CETSA and DARTS assays suggested that compound 7h might be a novel small molecule ROR1 inhibitor. More importantly, compound 7h significantly suppressed the migration and invasion of H1975 cells in vitro by blocking Src survival pathway and reactivating the p38 apoptotic pathway, and induced H1975 cell cycle arrest in G1 phase. Collectively, our work suggested that the ROR1 inhibitor 7h might be a novel drug candidate for NSCLC treatment.
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来源期刊
Bioorganic & Medicinal Chemistry
Bioorganic & Medicinal Chemistry 医学-生化与分子生物学
CiteScore
6.80
自引率
2.90%
发文量
413
审稿时长
17 days
期刊介绍: Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.
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