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Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound is a<3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC of 3 μM after 6 h.

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BackgroundAbnormal microRNA expression is closely related to cancer occurrence and development. miR-365a-3p plays an oncogenic role in skin cancer, but its role in lung cancer remains unclear. In this study, we aimed to investigate its role and underlying molecular mechanisms in lung cancer.MethodsWestern blot and real-time quantitative PCR (qPCR) were used to detect the expression of miR-365a-3p in lung adenocarcinoma and lung cancer cell lines. The effects of miR-365a-3p on lung cancer cell proliferation, migration, and invasion were also explored in vitro. The potential miR-365a-3p that targets USP33 was determined by dual luciferase reporter assay and verified by qPCR and western blot analysis. miR-365a-3p acts as an oncogene by promoting lung carcinogenesis via the downregulation of the miR-365a/USP33/SLIT2/ROBO1 axis based on western blot analysis. Subcutaneous tumourigenesis further demonstrated that miR-365a-3p promotes tumour formation in vivo.ResultsmiR-365a-3p was upregulated in lung adenocarcinoma and lung cancer cell lines. Overexpression of miR-365a-3p promoted and inhibition of miR-365a-3p suppressed the proliferation, migration, and invasion of lung cancer cells. We identified USP33 as the downstream target of miR-365a-3p and observed a negative correlation between miR-365a-3p and USP33 expression in lung adenocarcinoma patients. The miR-365/USP33/SLIT2/ROBO1 axis, a new mechanism, was reported to inhibit the invasion and metastasis of lung cancer. A nude mouse model of lung cancer further verified these findings.ConclusionsIn summary, miR-365a-3p acts as an oncogene by promoting lung carcinogenesis via the downregulation of the USP33/SLIT2/ROBO1 signalling pathway, making the miR-365/USP33/SLIT2/ROBO1 axis a new mechanism of lung cancer promotion and a novel therapeutic target for predicting prognosis and response to gene therapy.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0563-6) contains supplementary material, which is available to authorized users.

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Myocardial infarction (MI) remains a severe cardiac disease because of its high incidence and mortality worldwide. A growing body of recent investigations have confirmed that LINC00961 acts as a tumor suppressor in diverse malignancies. However, the biological significance of LINC00961 and its molecular mechanism in MI are still elusive. Hypoxia is the leading cause of MI and induces myocardial injury. In this study, we found the upregulated expression of LINC00961 in cardiomyocytes H9c2 after hypoxia treatment.Knockdown of LINC00961 ameliorated hypoxia-induced cell injury by facilitating cell viability while repressing cell apoptosis. The significant increase of signal transducer and activator of transcription 1 (STAT1) expression and phosphorylation levels was observed in hypoxia-induced cells and proved to exacerbate hypoxia injury. In addition, STAT1 transcriptionally activated LINC00961 by binding to LINC00961 promoter. Furthermore, our results validated that suppressing LINC00961 contributed to the remarkable diminution in the phosphorylation levels of phosphoinositide 3-kinases (PI3K), AKT, and glycogen synthase kinase-3β (GSK3β). Inhibition of PI3K/AKT signaling or GSK3β pathway rescued the effects of LINC00961 knockdown on the hypoxiainduced injury of cardiomyocytes. Namely, we concluded that STAT1-avtiviated LINC00961 accelerated MI via the PI3K/AKT/GSK3β pathway, which may provide clues for the treatment of patients with MI.