Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer
Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer
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7-((7H-吡咯并[2,3-d]嘧啶-4-基)氧基)-2,3-二氢-1H-茚-1-酮衍生物的设计、合成和生物学评价作为有效的FAK抑制剂
DOI：
10.1016/j.ejmech.2021.113978
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发表时间：
2022
影响因子：
6.7
通讯作者：
Luoting Yu
中科院分区：
文献类型：
--
作者：
Wei Wei;Zhanzhan Feng;Zhihao Liu;Xinyue Li;Hualong He;Kai Ran;Yaojie Shi;Yongxia Zhu;Tinghong Ye;Chao Gao;Ningyu Wang;Luoting Yu
粘着斑激酶（FAK）通过细胞内信号转导和基因表达及蛋白质周转的调节促进肿瘤进展，其是包括卵巢癌在内的各种癌症类型的引人注目的治疗靶点。然而，FAK抑制剂的临床反应仍然不令人满意。在这里，我们描述了FAK抑制剂的发现使用支架跳跃策略。构效关系（SAR）研究表明36是一种有效的FAK抑制剂，在体外对FAK信号转导具有抑制活性。36处理后PA-1细胞的迁移和侵袭能力明显降低，MMP-2和MMP-9的表达也明显降低。在体内实验中，36对肿瘤的生长和转移均有抑制作用，未见明显不良反应。这些结果揭示了FAK caseor 36治疗卵巢癌的潜力。
Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure–activity relationship (SAR) exploration identified36as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signalingin vitro. Treatment with36not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover,36inhibited tumor growth and metastasis, and no obvious adverse effects were observed during thein vivostudy. These results revealed the potential of FAK inhibitor36for treatment of ovarian cancer.