The successful use of PARP1 inhibitors like olaparib (Loparza®) in the treatment of BRCA1/2-deficient breast cancer has provided clinical proof-of-concept for applying personalized medicine based on synthetic lethality to the treatment of cancer. Unfortunately, all marketed PARP1 inhibitors act by competing with the cofactor NAD⁺ and resistance is already developing to this anticancer mechanism. Allosteric PARP1 inhibitors could provide a means of overcoming this resistance. A high throughput screen performed by Tulin et al. identified 5F02 as an allosteric PARP inhibitor that acts by preventing the enzymatic activation of PARP1 by histone H4. 5F02 demonstrated anticancer activity in several cancer cell lines and was more potent than olaparib and synergistic with olaparib in these assays. In the present study, we explored the structure–activity relationship of 5F02 by preparing analogs that possessed structural variation in four regions of the chemical scaffold. Our efforts led to lead molecule 7, which demonstrated potent anti-clonogenic activity against BRCA-deficient NALM6 leukemia cells in culture and a therapeutic index for the BRCA-deficient cells over their BRCA-proficient isogenic counterparts.

中文翻译：

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新型变构PARP1抑制剂，用于治疗BRCA缺陷型白血病

PARP1抑制剂（如olaparib（Loparza®））在BRCA1 / 2缺乏型乳腺癌的治疗中的成功应用为将基于合成致死性的个性化药物应用于癌症治疗提供了临床概念证明。不幸的是，所有上市的PARP1抑制剂都通过与辅因子NAD ⁺竞争而发挥作用对这种抗癌机制已经产生了抗药性。变构PARP1抑制剂可以提供克服这种耐药性的手段。Tulin等人进行的高通量筛选。鉴定出5F02是一种变构PARP抑制剂，它通过阻止组蛋白H4对PARP1的酶促活化而起作用。5F02在几种癌细胞系中显示出抗癌活性，在这些试验中比olaparib更有效，并且与olaparib协同作用。在本研究中，我们通过制备在化学支架的四个区域具有结构变异的类似物探索了5F02的构效关系。我们的努力导致了铅分子7，其在培养物中对BRCA缺陷型NALM6白血病细胞表现出有效的抗克隆活性，并且相对于BRCA缺陷型同基因对应物，BRCA缺陷型细胞的治疗指数更高。