Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation
- 8 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (11), 5956-5971
- https://doi.org/10.1021/acs.jmedchem.0c00230
Abstract
AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g. JT86, IC50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines and up to 70-fold less toxicity in normal human cells. JT86 was 9-fold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modelling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefit in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.Keywords
Funding Information
- National Health and Medical Research Council (1093378, 1117017)
- Australian Research Council (CE140100011)
This publication has 96 references indexed in Scilit:
- Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophagesProceedings of the National Academy of Sciences, 2012
- Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenibJournal of Hepatology, 2012
- Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomasThe Laryngoscope, 2011
- Efficacy of novel histone deacetylase inhibitor, AR42, in a mouse model of, human T-lymphotropic virus type 1 adult T cell lymphomaLeukemia Research, 2011
- Highly Enantioselective Direct Alkylation of Arylacetic Acids with Chiral Lithium Amides as Traceless AuxiliariesJournal of the American Chemical Society, 2011
- Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagyProceedings of the National Academy of Sciences of the United States of America, 2011
- Toward the estimation of the absolute quality of individual protein structure modelsBioinformatics, 2010
- Trans-regulation of Histone Deacetylase Activities through AcetylationJournal of Biological Chemistry, 2009
- The many roles of histone deacetylases in development and physiology: implications for disease and therapyNature Reviews Genetics, 2009
- HDAC inhibitors as anti‐inflammatory agentsBritish Journal of Pharmacology, 2007