Biochemical Barriers on the Path to Ocean Anoxia?

Declining ocean oxygen associated with global warming and climate change is impacting marine ecosystems across scales from microscopic planktonic communities to global fisheries. We report a fundamental dichotomy in the affinities of enzymes for oxygen—the terminal proteins catalyzing respiration are active at much lower oxygen concentrations than oxygenase enzymes involved in organic matter catabolism.

New Biological Targets in Fungi and Novel Molecule under Development: A Review

Antifungal therapeutics is confronted today with the challenge of drug resistance of most fungal germs to current antifungal drugs. Faced with this situation, the search for new and more efficient antifungal molecules that avoid the phenomenon of drug resistance becomes an urgent task. The design of new antifungal drugs acting on new biological targets and/or by innovative mechanisms of action is essential in the fight against fungal infections. Current advances in molecular biology have identified new targets for the development of new antifungal therapy. Several biological targets for the development of new antifungal agents are currently being explored. Amongst these, the most promising are BET (Bromodomain and Extra-Terminal) proteins, Homoserine transacetylase (HTA), mannan cell wall, Glycosylphosphatidylinositols (GPI) anchor biosynthesis, Histone deacetylases, Sphingolipid biosynthesis, D9 fatty acid desaturase and Chitin biosynthesis. This review summarizes the new biological targets and their inhibitors under development as potential new antifungal drugs.

Trichostatin A downregulates bromodomain and extra-terminal proteins to suppress osimertinib resistant non-small cell lung carcinoma

Background The third-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown significant therapeutic effects on patients with non-small cell lung carcinoma (NSCLC) who carry active EGFR mutations, as well as those who have developed acquired resistance to the first-generation of EGFR-TKIs due to the T790M mutation. However, most patients develop drug resistance after 8–10 months of treatment. Currently, the mechanism has not been well clarified, and new therapeutic strategies are urgently needed. Methods Osimertinib resistant cell lines were established by culturing sensitive cells in chronically increasing doses of osimertinib. The anticancer effect of reagents was examined both in vitro and in vivo using the sulforhodamine B assay and a xenograft mouse model. The molecular signals were detected by western blotting. The combination effect was analyzed using CompuSyn software. Results We found that bromodomain and extra-terminal proteins (BETs) were upregulated in osimertinib resistant (H1975-OR) cells compared with those in the paired parental cells (H1975-P), and that knockdown of BETs significantly inhibited the growth of H1975-OR cells. The BET inhibitor JQ1 also exhibited stronger growth-inhibitory effects on H1975-OR cells and a greater expression of BETs and the downstream effector c-Myc than were observed in H1975-P cells. The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) showed stronger growth suppression in H1975-OR cells than in H1975-P cells, but vorinostat, another HDAC inhibitor, showed equal inhibitory efficacy in both cell types. Consistently, downregulation of BET and c-Myc expression was greater with TSA than with vorinostat. TSA restrained the growth of H1975-OR and H1975-P xenograft tumors. The combination of TSA and JQ1 showed synergistic growth-inhibitory effects in parallel with decreased BET and c-Myc expression in both H1975-OR and H1975-P cells and in xenograft nude mouse models. BETs were not upregulated in osimertinib resistant HCC827 cells compared with parental cells, while TSA and vorinostat exhibited equal inhibitory effects on both cell types. Conclusion Upregulation of BETs contributed to the osimertinib resistance of H1975 cells. TSA downregulated BET expression and enhanced the growth inhibitory effect of JQ1 both in vitro and in vivo. Our findings provided new strategies for the treatment of osimertinib resistance.

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

ObjectivesBinding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription in many fibrotic diseases. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in scleroderma (SSc).MethodsDermal fibroblasts were isolated from biopsies from healthy subjects or patients with diffuse cutaneous (dc)SSc. Fibroblasts were treated with pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. Knockdown of BETs was achieved by siRNA transfection. The in vivo anti-fibrotic efficacy of JQ1 was determined in a bleomycin-induced skin fibrosis mouse model. T-test or ANOVA were used to compare differences between groups, and a p-value of <0.05 was considered significant.ResultsBET inhibitor JQ1 dose-dependently downregulated pro-fibrotic genes in dcSSc fibroblasts, and inhibited cell migration and gel contraction. It suppressed proliferation by inducing cell cycle arrest. The anti-fibrotic effects of JQ1 were also observed in TGFβ-treated normal fibroblasts. JQ1 prevented bleomycin-induced skin fibrosis in mice. The anti-fibrotic effect of JQ1 was mediated by inhibition of BRD4, as specific blockade or knockdown of BRD4 led to downregulation of fibrotic markers and inhibition of myofibroblast properties, while inhibition or knockdown of BRD2 or BRD3 had minimal effects in dcSSc fibroblasts.ConclusionsBET inhibition showed promising anti-fibrotic effects in SSc both in vitro and in vivo. Specifically, we showed that BRD4 plays a critical role in SSc fibrosis and that targeting BRD4 might be a novel therapeutic option for this disease.Significance statementBlockade of histone readers bromodomain extra-terminal proteins (BETs) shows potent anti-fibrotic properties in SSc dermal fibroblasts and bleomycin-induced skin fibrosis model. Among the BETs, BRD4 appears to regulate essential processes involved in SSc fibrosis. Results from this study provide the scientific foundation for the use of BET or BRD4 inhibitors in treating SSc.

Drug Discovery of Acetophenone Derivatives as BRD4 Inhibitors

Background: The bromodomain and extra-terminal proteins (BET), in particular BRD4, has recently emerged as a potential therapeutic target for the treatment of many human disorders such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more attention to discover potent BRD4 inhibitors in the past years. In this article, we described the discovery process of an entirely new chemotype of BRD4 inhibitors. Methods: A fragment-based drug discovery strategy was employed in attempting to find a novel chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized based on the interaction revealed by the docking study and the Structure-Activity Relationship (SAR). Results: A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4 with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM, LE > 0.5) based on virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragmentbased drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit nanomolar potency in biochemical assays (IC50 = 0.18 μM). Conclusion: The title compounds displayed potent inhibitory activity to BRD4, implying acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new chemotype may be promising for developing novel BRD4 inhibitors.