Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
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抑制布卢姆综合征蛋白 (BLM) 解旋酶、触发端粒区域 DNA 损伤并与 PARP 抑制剂协同作用的新型喹唑啉酮衍生物的设计、合成和评估
DOI：
10.1021/acs.jmedchem.0c00917
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发表时间：
2020
影响因子：
7.3
通讯作者：
Huang Zhi-Shu
中科院分区：
文献类型：
--
作者：
Wang Chen-Xi;Zhang Zi-Lin;Yin Qi-Kun;Tu Jia-Li;Wang Jia-En;Xu Yao-Hao;Rao Yong;Ou Tian-Miao;Huang Shi-Liang;Li Ding;Wang Hong-Gen;Li Qing-Jiang;Tan Jia-Heng;Chen Shuo-Bin;Huang Zhi-Shu
DNA损伤反应（DDR）途径对于癌细胞的存活至关重要，并且是癌症治疗的有吸引力的靶点。布卢姆综合征蛋白（Bloom syndrome protein，BLM）是一种DNA解旋酶，在DDR途径中发挥重要作用。我们以前的研究发现了一个有效的新的BLM抑制剂与喹唑啉酮支架通过筛选试验。因此，为了更好地理解BLM抑制剂的构效关系（SAR）和生物学作用，基于该支架设计、合成和评价了一系列新的衍生物。其中，化合物9 hex抑制纳摩尔抑制活性和对BLM. 9 h的结合亲和力可以有效地破坏BLM向细胞中DNA的募集。此外，9通过显著触发端粒区域的DNA损伤和诱导凋亡来抑制结肠直肠细胞系HCT 116的增殖，特别是与聚（ADP-核糖）聚合酶（PARP）抑制剂组合。这一结果表明，在DDR途径中BLM和PARP抑制剂之间存在合成致死效应。
DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay. Herein, to better understand the structure–activity relationship (SAR) and biological roles of the BLM inhibitor, a series of new derivatives were designed, synthesized, and evaluated based on this scaffold. Among them, compound9hexhibited nanomolar inhibitory activity and binding affinity for BLM.9hcould effectively disrupt BLM recruitment to DNA in cells. Furthermore,9hinhibited the proliferation of the colorectal cell line HCT116 by significantly triggering DNA damage in the telomere region and inducing apoptosis, especially in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor. This result suggested a synthetic lethal effect between the BLM and PARP inhibitors in DDR pathways.