奥拉帕尼
PARP1
PARP抑制剂
胰腺癌
合成致死
癌症研究
聚ADP核糖聚合酶
化学
DNA修复
溴尿嘧啶
同源重组
DNA损伤
BRD4
癌症
细胞周期
癌细胞
细胞
组蛋白
DNA
生物
生物化学
内科学
医学
聚合酶
作者
Shu-Ping Wang,Yu Li,Shihui Huang,Shiqi Wu,Ling-Li Gao,Qin Sun,Qianwen Lin,Lei Huang,Liu-Qiong Meng,Yi Zou,Qihua Zhu,Yungen Xu
标识
DOI:10.1021/acs.jmedchem.1c01535
摘要
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.
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