Inducing the deficiency of homologous recombination (HR) repair is an effective strategy to broaden the indication of PARP inhibitors in pancreatic cancer treatment. Repression of BRD4 has been reported to significantly elevate HR deficiency and sensitize cancer cells to PARP inhibitors. Inspired by the concept of synthetic lethality, we designed, synthetized and optimized a dual PARP1/BRD4 inhibitor III-7, with a completely new structure and high selectivity against both targets. III-7 repressed the expression and activity of PARP1 and BRD4 to synergistically inhibit the malignant growth of pancreatic cancer cells in vitro and in vivo. Based on the results of bioinformatic analysis, we found that Olaparib induced the acceleration of mitosis and recovery of DNA repair to cause the generation of drug resistance. III-7 reversed Olaparib-induced adaptive resistance and induced cell cycle arrest and DNA damage by perturbing PARP1 and BRD4-involved signaling pathways. We believe that the PARP1/BRD4 dual inhibitors are novel and promising antitumor agents, which provide an efficient strategy for pancreatic cancer treatment.

诱导同源重组 (HR) 修复缺陷是扩大 PARP 抑制剂在胰腺癌治疗中的适应症的有效策略。据报道，抑制 BRD4 可显着提高 HR 缺陷并使癌细胞对 PARP 抑制剂敏感。受合成杀伤力概念的启发，我们设计、合成和优化了 PARP1/BRD4 双抑制剂III-7，具有全新的结构和对两个靶点的高选择性。III-7通过抑制PARP1和BRD4的表达和活性协同抑制胰腺癌细胞在体内外的恶性生长. 基于生物信息学分析结果，我们发现奥拉帕尼诱导有丝分裂加速和DNA修复恢复，从而引起耐药性的产生。III-7通过扰乱 PARP1 和 BRD4 参与的信号通路逆转了奥拉帕尼诱导的适应性抗性和诱导的细胞周期停滞和 DNA 损伤。我们相信PARP1/BRD4双重抑制剂是一种新型且有前景的抗肿瘤药物，为胰腺癌的治疗提供了一种有效的策略。