Novel pyridazinone derivatives bind to KSRP: Synthesis, anti-tumor biological evaluations and modelling insights.

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.

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.

miR­873 inhibits colorectal cancer cell proliferation by targeting TRAF5 and TAB1.

MicroRNA-873 (miR­873) has been reported to be dysregulated in a variety of malignancies, however, the biological function and underlying molecular mechanism of miR­873 in colorectal cancer (CRC) remain unclear. In the present study we found that the expression levels of miR­873 were markedly decreased in CRC cell lines and tissues from patients. Statistical analysis revealed that miR­873 expression was inversely correlated with the disease stage of CRC. Kaplan­Meier survival analysis revealed that patients with CRC with lower miR­873 expression had shorter overall survival rates. Additionally, downregulation of miR­873 enhanced the proliferation of CRC cells, while upregulation of miR­873 reduced this proliferation. Furthermore, we found that tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and TGF­ß activated kinase 1 (MAP3K7) binding protein 1 (TAB1) were direct targets of miR­873 in CRC cells. A luciferase assay revealed that ectopic expression of miR­873 significantly reduced nuclear factor κB (NF­κB) luciferase activity, while ectopic expression of miR­873 inhibitor enhanced luciferase activity, suggesting that downregulation of miR­873 can activate NF­κB signaling. Therefore, our findings established a tumor-suppressive role for miR­873 in the inhibition of CRC progression, which may be employed as a novel prognostic marker and as an effective therapeutic target for CRC.