Discovery of 1,5-diaryl-1,2,4-triazole derivatives as myoferlin inhibitors and their antitumor effects in pancreatic cancer.

Aim: The first inhibitor targeting myoferlin (MYOF), WJ460, bears poor metabolic stability and water solubility. Therefore, this study aimed to improve the drug-like properties of WJ460. Materials & methods: The authors synthesized an array of 1,5-diaryl-1,2,4-triazole analogs and appraised the binding activities with MYOF and their antiproliferative and antimigratory activities against pancreatic cancer cells. Results: Molecular docking and surface plasmon resonance results showed that E4 was directly bound to the MYOF-C2D domain. E4 effectively inhibited the proliferation and migration of pancreatic cancer cells in vitro. An in silico study suggested that the water solubility of E4 was improved by about 22-times than that of WJ460. Conclusion: The findings suggested that the druglike ability of E4 was significantly improved.

A potent and selective small molecule inhibitor of myoferlin attenuates colorectal cancer progression.

As a pivotal vesicular trafficking protein, Myoferlin (MYOF) has become an attractive target for cancer therapy. However, the roles of MYOF in colorectal cancer invasion remain enigmatic, and MYOF-targeted therapy in this malignancy has not been explored. In the present study, we provided the first functional evidence that MYOF promoted the cell invasion of colorectal cancer. Furthermore, we identified a novel small molecule inhibitor of MYOF (named YQ456) that showed high binding affinity to MYOF (KD  = 37 nM) and excellent anti-invasion capability (IC50  = 110 nM). YQ456 was reported for the first time to interfere with the interactions between MYOF and Ras-associated binding (Rab) proteins at low nanomolar levels. This interference disrupted several vesicle trafficking processes, including lysosomal degradation, exosome secretion, and mitochondrial dynamics. Further, YQ456 exhibited excellent inhibitory effects on the growth and invasiveness of colorectal cancer. As the first attempt, the anticancer efficacy of YQ456 in the patient-derived xenograft (PDX) mouse model indicated that targeting MYOF may serve as a novel and practical therapeutic approach for colorectal cancer.

microRNA-32-5p targets KLF2 to promote gastric cancer by activating PI3K/AKT signaling pathway.

Krüppel-like factor 2 (KLF2) is a member of the zinc finger family, which is considered a potential tumor suppressor gene due to its reduced expression in gastric cancer. MicroRNAs (miRNAs) are a class of short non-coding single-stranded RNAs that are closely related to the development of gastric cancer. The purpose of this study was to investigate the miRNAs that regulate KLF2 and explore its specific mechanism in gastric cancer. Bioinformatics software Targetscan identified that microRNA-32-5p (miRNA-32-5p) may bind to KLF2 mRNA to regulate its expression. In order to verify the regulatory effect of miRNA-32-5p on KLF2, the proliferation and migration assays were performed in both KLF2 overexpression and KLF2 knockdown gastric cancer cells. Dual-Luciferase reporter assay proved that KLF2 could bind to the PTEN promoter to induce its expression. Moreover, research on molecular mechanisms indicated that both miRNA-32-5p and shKLF2 downregulated the expression of PTEN and activated the PI3K/AKT signaling to promote the development of gastric cancer. Targeting miRNA-32-5p and KLF2 is expected to provide new sign and target for gastric cancer treatment.