Development of a Potent and Selective HDAC8 Inhibitor.

A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.

[1]  Hening Lin,et al.  HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. , 2016, ACS chemical biology.

[2]  O. Witt,et al.  HDAC8: a multifaceted target for therapeutic interventions. , 2015, Trends in pharmacological sciences.

[3]  O. Wiest,et al.  Variable active site loop conformations accommodate the binding of macrocyclic largazole analogues to HDAC8. , 2015, Biochemistry.

[4]  R. Johnstone,et al.  Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders , 2015, Nature Reviews Drug Discovery.

[5]  Ted Natoli,et al.  An Unbiased Approach To Identify Endogenous Substrates of “Histone” Deacetylase 8 , 2014, ACS chemical biology.

[6]  M. Deardorff,et al.  Compromised Structure and Function of HDAC8 Mutants Identified in Cornelia de Lange Syndrome Spectrum Disorders , 2014, ACS chemical biology.

[7]  O. Wiest,et al.  Inhibition and Mechanism of HDAC8 Revisited , 2014, Journal of the American Chemical Society.

[8]  I. Krantz,et al.  Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. , 2014, Human molecular genetics.

[9]  K. Shirahige,et al.  Design, Synthesis, and Biological Activity of NCC149 Derivatives as Histone Deacetylase 8‐Selective Inhibitors , 2014, ChemMedChem.

[10]  E. Toone,et al.  Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. , 2013, Journal of medicinal chemistry.

[11]  Amanda J. Guise,et al.  The functional interactome landscape of the human histone deacetylase family , 2013, Molecular systems biology.

[12]  D. E. Olson,et al.  Discovery of the first histone deacetylase 6/8 dual inhibitors. , 2013, Journal of medicinal chemistry.

[13]  C. Fierke,et al.  HDAC8 substrates: Histones and beyond. , 2013, Biopolymers.

[14]  Hiroki Tsumoto,et al.  Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries. , 2012, Journal of medicinal chemistry.

[15]  Gabriele Gillessen-Kaesbach,et al.  HDAC8 mutations in Cornelia de Lange Syndrome affect the cohesin acetylation cycle , 2012, Nature.

[16]  P. Buglyó,et al.  Suberoylanilide hydroxamic acid, a potent histone deacetylase inhibitor; its X-ray crystal structure and solid state and solution studies of its Zn(II), Ni(II), Cu(II) and Fe(III) complexes. , 2011, Journal of inorganic biochemistry.

[17]  S. Schreiber,et al.  Discovery of histone deacetylase 8 selective inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[18]  James E. Bradner,et al.  Chemical Phylogenetics of Histone Deacetylases , 2010, Nature chemical biology.

[19]  V. Fokin,et al.  Copper(I)-catalyzed cycloaddition of organic azides and 1-iodoalkynes. , 2010, Angewandte Chemie.

[20]  Walter Cabri,et al.  Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors , 2009, ChemMedChem.

[21]  Wayne W. Hancock,et al.  Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells , 2009, Nature Reviews Drug Discovery.

[22]  Christopher B. Harrison,et al.  Structural origin of selectivity in class II-selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.

[23]  J. Buggy,et al.  Interferon-α is able to maintain complete molecular remission induced by imatinib after its discontinuation , 2008, Leukemia.

[24]  S. Grünewald,et al.  Factors affecting the substrate specificity of histone deacetylases. , 2007, Biochemical and biophysical research communications.

[25]  Eric Verdin,et al.  Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[26]  Li-Huei Tsai,et al.  Recovery of learning and memory is associated with chromatin remodelling , 2007, Nature.

[27]  Michele Pallaoro,et al.  HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics , 2007, Cell Research.

[28]  J. Porco,et al.  Synthesis of 1,4,5-Trisubstituted-1,2,3-triazoles by Copper-Catalyzed Cycloaddition-Coupling of Azides and Terminal Alkynes. , 2006 .

[29]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[30]  R. De Francesco,et al.  Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Schreiber,et al.  Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. , 2001, Organic letters.

[32]  M. Pirrung,et al.  A Convenient Procedure for the Preparation of Amino Acid Hydroxamates from Esters. , 1996 .