Yuan Zigao, Chen Shaopeng, Sun Qinsheng, Wang Ning, Li Dan, Miao Shuangshuang, Gao Chunmei, Chen Yuzong, Tan Chunyan, Jiang Yuyang
Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Bioorg Med Chem. 2017 Aug 1;25(15):4100-4109. doi: 10.1016/j.bmc.2017.05.058. Epub 2017 May 31.
Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivatives of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compounds showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC values in the nanomolar range. Furthermore, compound P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compounds targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
奥拉帕利是首个被美国食品药品监督管理局（FDA）批准用于治疗携带BRCA基因突变的卵巢癌患者的PARP抑制剂。近期研究表明，奥拉帕利与组蛋白去乙酰化酶（HDAC）抑制剂联合治疗具有增强的抗癌效果。在此，基于合理药物设计策略，构建了奥拉帕利的异羟肟酸衍生物作为PARP和HDAC双重抑制剂。这些杂合化合物对PARP1/2和HDAC1/6显示出强效抑制活性，IC值处于纳摩尔范围。此外，化合物P1在所选人类癌细胞系中表现出广谱抗增殖活性。特别地，P1在癌细胞MDA-MB-231、HCC1937和Raji中显示出比奥拉帕利和伏立诺他更强的活性，并且与伏立诺他相比，对正常细胞MCF-10A的细胞毒性低4.1倍。进一步的机制研究表明，P1可诱导PARP的裂解和组蛋白的高度乙酰化，增加DNA损伤生物标志物γ-H2AX的表达，降低BRCA1和RAD51的水平，并通过调节线粒体和死亡受体介导的途径来调控肿瘤细胞的生长和凋亡。因此，我们的研究表明，同时靶向PARP和HDAC的化合物可能是一种切实可行的癌症治疗方法。
