Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.

在我们以前的工作中，通过PARP / PI3K双重抑制剂共同靶向PARP和PI3K已被认为是治疗三阴性乳腺癌（TNBC）的有前途的化疗策略。为了进一步探索新颖和更有效的PARP / PI3K双重抑制剂，设计，合成和评估了一系列化合物的药理特性，从而产生了候选化合物12，这是一种有效且高度选择性的PARP / PI3K双重抑制剂。与Olaparib相比，化合物12对BRCA熟练的MDA-MB-468细胞表现出优异的抗增殖特性。在MDA-MB-468细胞衍生的异种移植模型中，化合物12在50 mg / kg的剂量下显示出优异的抗肿瘤功效，比单次服用Olaparib或BKM120更有效。此外，化合物12显示出良好的代谢稳定性和高安全性。综上所述，这些结果表明作为新型PARP / PI3K双重抑制剂的化合物12值得进一步研究。