Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2021 May 5;217:113357. doi: 10.1016/j.ejmech.2021.113357. Epub 2021 Mar 10.
PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC = 1.57 nM, 23a: IC = 0.91 nM) and PI3Kα (9a: IC = 2.0 nM, 23a: IC = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在携带有 BRCA 突变的癌症中取得了巨大成功，但只有一小部分患者携带 BRCA 突变，这导致其适应症范围较窄。最近，新出现的证据表明，PARP 和 PI3K 抑制剂的联合使用可以在各种癌症中引发意想不到的协同效应，甚至包括 BRCA 功能正常的癌症。在这项工作中，设计、合成了一系列 PARP/PI3K 双重抑制剂，并对其生物活性进行了评估。结果发现，化合物 9a 和 23a 对 PARP-1（9a：IC=1.57 nM，23a：IC=0.91 nM）和 PI3Kα（9a：IC=2.0 nM，23a：IC=1.5 nM）具有优异的抑制活性，并对 BRCA 缺陷型（HCT-116、HCC-1937）和 BRCA 功能正常型（SW620、MDA-MB-231/468）肿瘤细胞均表现出良好的抗增殖活性。9a 和 23a 在 MDA-MB-468 异种移植小鼠模型中也表现出相当的体内抗肿瘤疗效，TGI 值分别为 56.39%和 48.77%。此外，23a 具有较高的激酶选择性和较低的心脏毒性等良好特性。总体而言，这项工作表明 9a 和 23a 可能是用于癌症治疗的潜在 PARP/PI3K 双重抑制剂，值得进一步研究。
