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Molecular basis of human angiotensin-1 converting enzyme inhibition by a series of diprolyl-derived compounds.
FEBS J
January 2025
Department of Life Sciences, University of Bath, UK.
Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment of hypertension, inflammation and fibrosis. It consists of two homologous N and C catalytic domains, nACE and cACE, respectively. Unfortunately, the current clinically available ACE inhibitors produce undesirable side effects due to the nonselective inhibition of these domains.
View Article and Find Full Text PDFDiscovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.
J Med Chem
December 2024
China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported.
View Article and Find Full Text PDFStructure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.
J Med Chem
December 2023
GSK, Medicines Research Centre, Stevenage SG1 2NY, Hertfordshire, U.K.
Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series.
View Article and Find Full Text PDFRecent progress and structural analyses of domain-selective BET inhibitors.
Med Res Rev
July 2023
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.
Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine-ε-N-acetylation (K ), bromodomains serve as recognition modules ("readers") of this activating epigenetic mark and competition of the bromodomain-K interaction with small-molecule inhibitors is an attractive strategy to control aberrant bromodomain-mediated gene expression.
View Article and Find Full Text PDFValosin-containing protein (VCP/p97) inhibition reduces viral clearance and induces toxicity associated with muscular damage.
Cell Death Dis
December 2022
Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
Valosin-containing protein (VCP)/p97 has emerged as a central regulator of the ubiquitin-proteasome system by connecting ubiquitylation and degradation. The development of CB-5083, an ATPase D2-domain-selective and orally bioavailable inhibitor of VCP/p97, allows targeting of the ubiquitin-proteasome system in human diseases. In this study, we evaluated the effect of CB-5083 on the immune response in mice by using the lymphocytic choriomeningitis virus (LCMV) as an infection model.
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