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.,Journal of Medicinal Chemistry

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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-22 , DOI: 10.1021/acs.jmedchem.0c00917
Chen-Xi Wang ₁ , Zi-Lin Zhang ₁ , Qi-Kun Yin ₁ , Jia-Li Tu ₁ , Jia-En Wang ₁ , Yao-Hao Xu ₁ , Yong Rao ₁ , Tian-Miao Ou ₁ , Shi-Liang Huang ₁ , Ding Li ₁ , Hong-Gen Wang ₁ , Qing-Jiang Li ₁ , Jia-Heng Tan ₁ , Shuo-Bin Chen ₁ , Zhi-Shu Huang ₁

Affiliation

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, compound 9h exhibited nanomolar inhibitory activity and binding affinity for BLM. 9h could effectively disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited 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.

中文翻译：

新的喹唑啉酮衍生物的设计，合成和评估，该衍生物可抑制Bloom综合征蛋白（BLM）解旋酶，在端粒区域引发DNA损伤，并与PARP抑制剂协同作用。

DNA损伤反应（DDR）通路对于癌细胞的生存至关重要，并且是癌症治疗的诱人靶标。Bloom综合征蛋白（BLM）是一种DNA解旋酶，在DDR途径中起重要作用。我们以前的研究通过筛选试验发现了一种有效的新型BLM抑制剂和喹唑啉酮骨架。在这里，为了更好地理解BLM抑制剂的结构活性关系（SAR）和生物学作用，基于该支架设计，合成和评估了一系列新的衍生物。其中，化合物9h表现出纳摩尔抑制活性和对BLM的结合亲和力。9h可有效破坏BLM向细胞DNA募集。再说9小时通过显着触发端粒区域的DNA损伤并诱导凋亡，可抑制结直肠细胞系HCT116的增殖，特别是与聚（ADP-核糖）聚合酶（PARP）抑制剂联用时。该结果表明在DDR途径中，BLM和PARP抑制剂之间具有合成的致命作用。

更新日期：2020-09-10

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