Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy
Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy
复制标题
发现 4-羟基喹唑啉衍生物作为小分子 BET/PARP1 抑制剂，可诱导缺陷同源重组并导致三阴性乳腺癌治疗的综合致死率
DOI：
10.1021/acs.jmedchem.2c00135
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发表时间：
2022-05-12
影响因子：
7.3
通讯作者：
Ouyang, Liang
中科院分区：
文献类型：
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作者：
Zhang, Jifa;Yang, Chengcan;Ouyang, Liang
聚腺苷二磷酸核糖聚合酶(PARP)抑制剂的有效效力和耐药性限制了它们的应用。在这里，我们开发了一种新的范例，模拟乳腺癌易感基因(BRCA)突变的影响，以触发合成致死的可能性，基于先前发现的溴域包含蛋白4(BRD4)和PARP1之间的潜在合成致死效应。因此，本研究描述了对BRD4和PARP1具有高选择性的化合物BP44。幸运的是，BP44抑制了三阴性乳腺癌(TNBC)中的同源重组，并触发了合成致命性，从而导致细胞周期停滞和DNA损伤。综上所述，我们在前人研究的基础上对BRD4-PARP1抑制剂进行了优化，有望成为未来治疗TNBC的候选药物。这一战略旨在扩大PARPI在BRCA胜任的TNBC中的使用，提出一种创新的方法来解决未得到满足的肿瘤学需求
The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here,we exploit a new paradigm that mimics the effects of breast cancersusceptibility genes (BRCA) mutations to trigger the possibility ofsynthetic lethality, based on the previous discovery of a potentialsynthetic lethality effect between bromodomain-containing protein 4(BRD4) and PARP1. Consequently, the present study describescompoundBP44with high selectivity for BRD4 and PARP1.Fortunately,BP44inhibits the homologous recombination in triple-negative breast cancer (TNBC) and triggers synthetic lethality, thusleading to cell cycle arrest and DNA damage. In conclusion, weoptimized the BRD4-PARP1 inhibitor based on previous studies,and we expect it to become a candidate drug for the treatment ofTNBC in the future. This strategy aims to expand the use of PARPi in BRCA-competent TNBC, making an innovative approach to address unmet oncology needs