A novel series of non-hydroxamate HDAC inhibitors (HDACi) showing a uracil group at the left and a 2-aminoanilide/2-aminoanilide-like portion at the right head have been reported. In particular, the new compounds incorporating a 2-aminoanilide moiety behaved as class I-selective HDACi. Compound 8, the most potent and class I-selective, showed weak apoptosis (higher than MS-275) joined to cytodifferentiating activity on U937 cells. Surprisingly, the highest differentiation was observed with 13, through an effect that seems to be unrelated to HDAC inhibition.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1016/j.bmcl.2008.03.055 | DOI Listing |
J Med Chem
October 2024
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
In this work, we have synthesized a set of peptoid-based histone deacetylase inhibitors (HDACi) with a substituted hydrazide moiety as zinc-binding group. Subsequently, all compounds were evaluated in biochemical HDAC inhibition assays and for their antiproliferative activity against native and cisplatin-resistant cancer cell lines. The hydrazide derivatives with a propyl or butyl substituent (compounds and ) emerged as the most potent class I HDAC selective inhibitors (HDAC1-3).
View Article and Find Full Text PDFJ Med Chem
December 2023
Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
Histone deacetylases (HDACs) have emerged as powerful epigenetic modifiers of histone/non-histone proteins via catalyzing the deacetylation of ε--acetyl lysines. The dysregulated activity of these Zn-dependent hydrolases has been broadly implicated in disease, notably cancer. Clinically, the recurring dose-limiting toxicities of first-generation HDACi sparked a paradigm shift toward safer isoform-specific molecules.
View Article and Find Full Text PDFJCI Insight
September 2023
Department of Molecular Medicine, Scripps Research, La Jolla, California, USA.
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds.
View Article and Find Full Text PDFBlood Adv
October 2023
Division of Hematologic Malignancies and Hematopoetic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA.
Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options.
View Article and Find Full Text PDFCell Signal
October 2023
Department of Nutrition, The University of Nevada Reno, Reno, NV 89557, United States of America; Cellular and Molecular Biology, The University of Nevada Reno, Reno, NV 89557, United States of America; Center of Biomedical Research Excellence for Molecular and Cellular Signal Transduction in the Cardiovascular System, The University of Nevada Reno, Reno, NV 89557, United States of America. Electronic address:
Skeletal muscle atrophy is defined by wasting or decrease in muscle mass owing to injury, aging, malnutrition, chronic disuse, or physical consequences of chronic illness. Under normal physiological conditions, a network of signal transduction pathways serves to balance muscle protein synthesis and proteolysis; however, metabolic shifts occur from protein synthesis to protein degradation that leads to a reduction in cross-sectional myofibers and can result in loss of skeletal muscle mass (atrophy) over time. Recent evidence highlights posttranslational modifications (PTMs) such as acetylation and phosphorylation in contractile dysfunction and muscle wasting.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!