Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer

• Published in: European journal of medicinal chemistry 2021-05, Vol.217, p.113357, Article 113357
• Main Authors: Wu, Zhengyang, Bai, Ying, Jin, Jiaming, Jiang, Teng, Shen, Hui, Ju, Qiurong, Zhu, Qihua, Xu, Yungen
• Format: Article
• Language: English
• Subjects: Cancer; Dual inhibitors; PARP; PI3K; Synergistic cytotoxic effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113357

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: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 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. [Display omitted] •A series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities.•Compounds 9a and 23a exhibited strong PARP/PI3K inhibitory activities.•9a and 23a showed considerablei antitumor efficacy in vitro and in vivo.•23a possessed promising kinase selectivity and low cardiotoxicity.