Discovery of Isaindigotone Derivatives as Novel Bloom's Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair
Discovery of Isaindigotone Derivatives as Novel Bloom's Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair
复制标题
发现伊桑靛酮衍生物作为新型布卢姆氏综合征蛋白 (BLM) 解旋酶抑制剂，可破坏 BLM/DNA 相互作用并调节同源重组修复
DOI：
10.1021/acs.jmedchem.9b00083
复制
发表时间：
2019
影响因子：
7.3
通讯作者：
Huang Zhi-Shu
中科院分区：
文献类型：
--
作者：
Yin Qi-Kun;Wang Chen-Xi;Wang Yu-Qing;Guo Qian-Liang;Zhang Zi-Lin;Ou Tian-Miao;Huang Shi-Liang;Li Ding;Wang Hong-Gen;Tang Jia-Heng;Chen Shuo-Bin;Huang Zhi-Shu
同源重组修复（HRR）是DNA损伤修复的重要途径，是肿瘤治疗和药物设计的重要靶点。Bloom综合征蛋白（Bloom syndrome protein，BLM）是一种3′-5′端DNA解旋酶，在HRR调控中起重要作用。然而，有关BLM抑制剂及其生物学效应的研究报道有限。本文通过合成、筛选和评价，确定了一类新的BLM抑制剂靛地酮衍生物。其中，化合物29是一种有效的BLM抑制剂，具有很高的结合亲和力，对BLM有很好的抑制作用。细胞评价表明，29有效地破坏了BLM在DNA双链断裂位点的募集，促进了RAD 51的积累，并调节了HRR过程。同时，29能显著诱导癌细胞DNA损伤反应，以及细胞凋亡和增殖停滞。我们的发现提供了一个潜在的抗癌策略的基础上通过小分子干扰BLM。
Homologous recombination repair (HRR), a crucial approach in DNA damage repair, is an attractive target in cancer therapy and drug design. The Bloom syndrome protein (BLM) is a 3′–5′ DNA helicase that performs an important role in HRR regulation. However, limited studies about BLM inhibitors and their biological effects have been reported. Here, we identified a class of isaindigotone derivatives as novel BLM inhibitors by synthesis, screening, and evaluating. Among them, compound29was found as an effective BLM inhibitor with a high binding affinity and good inhibitory effect on BLM. Cellular evaluation indicated that29effectively disrupted the recruitment of BLM at DNA double-strand break sites, promoted an accumulation of RAD51, and regulated the HRR process. Meanwhile,29significantly induced DNA damage responses, as well as apoptosis and proliferation arrest in cancer cells. Our finding provides a potential anticancer strategy based on interfering with BLM via small molecules.