Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Acta Pharmaceutica Sinica B

Bo Liu¹  Jie Liu²  Liang Ouyang²  Yanmei Chen³  Kai Zhang³  Danfeng Shi³  Guan Wang³  Huidan Tan³  Xiaosa Chang³  Dejuan Sun³ 

[1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China;Corresponding authors. Tel./fax: [phone] (Jie Liu), [phone] (Bo Liu), [phone] (Liang Ouyang).;State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China;

关键词: BRD4;    PARP1;    Dual-target inhibitor;    Synthetic lethality;    Quinazolin-4(3H)-one derivatives;   

DOI  :  

来源: DOAJ

【 摘 要 】

This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

【 授权许可】

Unknown