Bromodomain-containing protein 4 (BRD4) and histone deacetylases
(HDAC) are both attractive epigenetic targets in cancer and other
chronic diseases. Based on the integrated fragment-based drug design,
synthesis, and in vitro and in vivo evaluations, a series of novel
thieno[2,3-d]pyrimidine-based hydroxamic acid derivatives
are discovered as selective BRD4–HDAC dual inhibitors. Compound 17c is the most potent inhibitor for BRD4 and HDAC with IC50 values at nanomolar levels, as well as the expression level
of c-Myc, and increases the acetylation of histone H3. Moreover, 17c presents inhibitory effects on the proliferation of colorectal
carcinoma (CRC) cells via inducing autophagic cell death. It also
has a good pharmacokinetic profile in rats and oral bioavailability
of 40.5%. In the HCT-116 xenograft in vivo models, 17c displays potent inhibitory efficiency on tumor growth by inducing
autophagic cell death and suppressing IL6–JAK–STAT signaling
pathways. Our results suggest that the BRD4–HDAC dual inhibition
might be an attractive therapeutic strategy for CRC.
Aim
Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy. Accumulating studies have reported metabolites that are significantly associated with the development of GDM. However, studies on the metabolism of placenta, the most important organ of maternal‐fetal energy and material transport, are extremely rare. This study aimed to identify and discuss the relationship between differentially expressed metabolites (DEM) and clinical parameters of the mothers and newborns.
Methods
In this study, metabolites from 63 placenta tissues (32 GDM and 31 normal controls) were assayed by ultra‐performance liquid chromatography‐high resolution mass spectrometry (UPLC‐HRMS).
Results
A total of 1297 annotated metabolites were detected, of which 87 significantly different in GDM placenta. Lipids and lipid‐like molecules accounted for 62.1% of DEM as they were significantly enriched via the “biosynthesis of unsaturated fatty acids” and “fatty acid biosynthesis” pathways. Linoleic acid and α‐linolenic acid appeared to be good biomarkers for the prediction and diagnosis of GDM. In addition, the level of PC(14:0/18:0) was negatively correlated with neonatal weight. 14 metabolites significantly different in male and female offspring, with the most increase in female newborns.
Conclusion
Even if maternal blood glucose level is well controlled, there are still metabolic abnormalities in GDM. Lipids and lipid‐like molecules were the main differential metabolites, especially unsaturated fatty acids.
In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/ GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.
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