Design, synthesis and mechanism studies of novel dual PARP1/BRD4 inhibitors against pancreatic cancer.

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 PARP1/2 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.

Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer.

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.

Efficacy of percutaneous intervertebral foramen and TLIF in treatment of extreme lateral lumbar disc herniation / 局解手术学杂志

Objective To evaluate the clinical effect of percutaneous intervertebral foramen and TLIF in the treatment of extreme lateral lumbar disc herniation and the SF-36 score.Methods A total of 90 patients with extreme lateral lumbar disc herniation admitted in our hos-pital from March 2015 to March 2017 were selected as the subjects,who were divided into the control group ( traditional therapy) and the study group(percutaneous intervertebral foramen treatment), according to the different surgical methods,45 cases in each group.The treat-ment,pain,SF-36 score and other indicators of two groups were observed.Results The rate of excellence and good was 97.78% in the study group and 86.67% in the control group,the difference was significant(P<0.05).The blood loss was (46.83 ± 3.64)mL in the study group and (79.32 ±5.47)mL in the control group,the difference was significant(P<0.05).There was no significant difference in the scores of SF-36 and JOA between the two groups(P>0.05).After treatment,the two groups were significantly improved(P<0.05),the improvement rate of the study group was more obvious (P<0.05).After treatment,TNF-α,IL-6 and CRP levels were significantly better than those in the control group (P<0.05).Conclusion Percutaneous intervertebral foramen treatment of extreme lateral lumbar disc herniation can reduce the intraoperative blood loss and improve the quality of life