BRD4 as an emerging epigenetic therapeutic target for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder, mainly comprising two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). IBD, featured by recurrent symptoms and significant morbidity, poses a significant threat to global health and has an adverse impact on quality of life. Currently, there is no curative therapy for IBD, and the available medications are only for managing the disease condition, likely owing to the insufficient understanding of the underlying pathophysiology processes involved in IBD, and the lack of safe and effective medicines.

An updated patent review of BRD4 degraders.

Introduction: Bromodomain-containing protein 4 (BRD4), an important epigenetic reader, is closely associated with the pathogenesis and development of many diseases, including various cancers, inflammation, and infectious diseases. Targeting BRD4 inhibition or protein elimination with small molecules represents a promising therapeutic strategy, particularly for cancer therapy.

Areas Covered: The recent advances of patented BRD4 degraders were summarized.

Questionnaire survey of risk factors for recurrence of ocular inflammation in patients with uveitis after SARS-CoV-2 infection.

Introduction: During the COVID-19 pandemic in China, the proportion of patients with uveitis who were infected with SARS-CoV-2 increased greatly. The impact of SARS-CoV-2 infection on patients with uveitis has not been fully described.

Methods: A questionnaire on SARS-CoV-2 infection was sent to patients with uveitis to assess ocular and systemic conditions before and after infection.

IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors.

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes.

RIPTACs: A groundbreaking approach to drug discovery.

Regulated induced proximity targeting chimeras (RIPTACs), a new class of heterobifunctional molecules, show promise in specifically targeting and eliminating cancer cells while leaving healthy cells unharmed. As a groundbreaking drug discovery approach, RIPTACs work by forming a stable complex with two proteins, one specifically found in cancer cells (target protein, TP) and the other pan-essential for cell survival (effector protein, EP), selectively disrupting the function of the EP in cancer cells and causing cell death. Interestingly, the TPs need not be linked to disease progression, broadening the spectrum of potential drug targets.

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2).

Nuclear receptor binding SET domain proteins (NSDs) catalyze the mono- or dimethylation of histone 3 lysine 36 (H3K36me1 and H3K36me2), using -adenosyl-l-methionine (SAM) as a methyl donor. As a key member of the NSD family of proteins, NSD2 plays an important role in the pathogenesis and progression of various diseases such as cancers, inflammations, and infectious diseases, serving as a promising drug target. Developing potent and specific NSD2 inhibitors may provide potential novel therapeutics.

Bromodomain-containing protein 4 (BRD4): a key player in inflammatory bowel disease and potential to inspire epigenetic therapeutics.

Introduction: Inflammatory bowel diseases (IBDs) are debilitating chronic inflammatory disorders with increasing prevalence worldwide. Epigenetic regulator bromodomain-containing protein 4 (BRD4) is critical in controlling gene expression of IBD-associated inflammatory cytokine networks. BRD4 as a promising therapeutic target is also tightly associated with many other diseases, such as airway inflammation and fibrosis, cancers, infectious diseases and central nervous system disorders.

Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity.

Aldehyde dehydrogenase 1A1 (ALDH1A1) plays vital physiological and toxicological functions in many areas, such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of ALDH1A1 has been disclosed to play an important role in obesity, diabetes and other diseases, indicating the potential need for the identification and development of small molecule ALDH1A1 inhibitors. Herein, a series of benzimidazole derivatives was designed, synthesized and evaluated.

Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy.

As a newly emerged technology, PROTAC (proteolysis targeting chimera) is a promising therapeutic strategy for varieties of diseases. Unlike small molecule inhibitors, PROTACs catalytically induce target proteins degradation, including currently "undruggable" target proteins. In addition, PROTACs can be a potentially successful strategy to overcome drug resistance.

Discovery and development of selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors.

ALDH1A1, one important member of 19 ALDHs, can metabolize reactive aldehydes to their corresponding carboxylic acid derivatives and play important physiological and toxicological roles in many areas, including CNS, metabolic disorders, and cancers. Overexpression of ALDH1A1 correlates with poor prognosis and tumor aggressiveness, is associated with drug resistance in traditional chemotherapy for cancer treatment and contributes to obesity, diabetes, and inflammation. So, inhibition of ALDH1A1 may offer new therapeutic options for patients with cancer, obesity, diabetes, and inflammation.

Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery.

As epigenetic readers of the histone code, BRD4 is the most extensively and thoroughly studied member of BET family, which plays a critical role in many human diseases including cancer, inflammation, HIV infections, CNS disorders, and cardiovascular diseases and has been proved to be a promising therapeutic target for these diseases. To date, many small-molecule BRD4 inhibitors have been discovered, and some of them are in clinical trials for the treatment of different diseases. Due to the lack of selectivity of these small molecules for BRD4 BD1, BRD4 BD2 and/or other BET proteins, they exert some toxic side effects, including dizziness, nausea, and vomit.

Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity.

LDH1A1, one of 19 NAD(P)-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1.

Chemical constituents from plant endophytic fungus .

Five new natural compounds (-) along with four known ones, involving dibenzo--pyrone derivatives, a benzo--pyrone derivative and an amide-type compound were obtained from , an endophyte isolated from The structures of these isolates were elucidated by intensive analysis of spectroscopic data including NMR, HRMS (ESI and EI), UV and IR spectra. Compounds (-) were evaluated for their cytotoxicities against five selected human tumourtumour cell lines (A-549, MDA-MB-231, MCF-7, KB and KB-VIN), and compound exhibited activities against MDA-MB-231and MCF-7 with IC values of 20.1 M and 32.

Development of Novel Anticancer Agents with a Scaffold of Tetrahydropyrido[4,3-]pyrimidine-2,4-dione.

ONC201 is a small molecular anticancer agent currently in multiple Phase II clinical trials. Based on the pharmacophore of ONC201, a series of small molecular compounds with a core structure of tetrahydropyrido[4,3-]pyrimidine-2,4-dione were designed and synthesized. Preliminary mechanism studies of these compounds indicated that they can inhibit the phosphorylation of AKT and ERK, induce the dephosphorylation of Foxo3a, and promote the expression of TRAIL and the enhancement of activating transcription factor 4 (ATF4) in PC-3 cells.

Lack of Association Found between Helicobacter pylori Infection and Diarrhea-Predominant Irritable Bowel Syndrome: A Multicenter Retrospective Study.

Aims. The association between Helicobacter pylori (H. pylori) infection and diarrhea-predominant irritable bowel syndrome (IBS-D) is still controversial.

Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant.

The epidermal growth factor receptor (EGFR) T790M mutant is found in approximately 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). Here, a series of novel aminopyrimidines bearing a hydrazone moiety were identified as potent and selective EGFR inhibitors. Compounds 14a, 15g, and 15i potently inhibited all EGFR mutants including EGFR T790M/L858R, EGFR T790M/delE746_A750, and EGFR T790M while they showed weak effects on the wild type (WT) EGFR.

Synthesis and Anti-Hepatitis B Virus Evaluation of 7-Methoxy-3-heterocyclic quinolin-6-ols.

A series of novel 7-methoxy-3-heterocyclic quinolin-6-ol derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in the HepG2.2.15 cell line.

Polyacrylonitrile fibers efficiently loaded with tamoxifen citrate using wet-spinning from co-dissolving solution.

Tamoxifen citrate (TAM)-loaded polyacrylonitrile (PAN) fibers were prepared using an improved wet-spinning technique. TAM was used as a model drug to evaluate the potential application of the loaded fiber system for drug delivery. PAN was first homogeneously dissolved in the N,N-dimethylacetamide (DMAc) solution containing TAM and then the co-dissolving solution was solidified to prepare the fibers using a wet-spinning method.

Microencapsulation of tamoxifen: application to cotton fabric.

Tamoxifen microcapsules and drug loaded medicated fabrics were investigated. The microcapsules were prepared using a complex coacervation procedure involving gelatin B and acacia gum. The morphology, particle size, drug loading capacity and in vitro release characteristics of the drug microcapsules were optimized for coating tamoxifen microcapsules onto the cotton fabrics.