Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China.
Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China; School of Biological and Food Engineering, Huanghuai University, Zhumadian 463000, China.
Bioorg Med Chem. 2024 Nov 1;113:117936. doi: 10.1016/j.bmc.2024.117936. Epub 2024 Oct 5.
PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a-14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在 BRCA 突变型三阴性乳腺癌（TNBC）的临床治疗中显示出显著的潜在疗效。然而，大多数 TNBC 患者不携带 BRCA 突变，因此不能从 PARPi 中获益。先前关于源自 PARPi 或 RAF-RAF 通路抑制剂的多靶点分子的研究为开发新型抗 TNBC 药物提供了另一种方法。因此，为了拓宽 PARP 抑制剂在 BRCA 野生型 TNBC 患者中的应用，通过将奥拉帕利（Olaparib，Ola）和 rigosertib 的关键药效团整合到一个单一实体中，构建了一系列双靶点分子。随后的研究表明，所得化合物 13a-14c 对 BRCA 缺陷或野生型 TNBC 细胞表现出潜在的抗增殖活性。其中，一种最佳的化合物 13b 对 PARP-1 表现出良好的抑制活性，在 MDA-MB-231 细胞中的抑制活性比奥拉帕利高约 34 倍，并且发挥多种功能机制诱导细胞凋亡。此外，13b 显示出优于奥拉帕利（TGI，38.5%）、11b（TGI，51.8%）或甚至它们联合给药（TGI，56.7%）的抗肿瘤疗效（TGI，61.3%），但没有显示出明显的系统毒性。这些发现表明，13b 可能是 BRCA 野生型 TNBC 的潜在候选药物。
