Journal ArticleDOI
Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group
Mercedes Lobera,Kevin P. Madauss,Denise T Pohlhaus,Quentin G. Wright,Mark Trocha,Darby Schmidt,Erkan Baloglu,Ryan P. Trump,Martha S. Head,Glenn A. Hofmann,Monique F. Murray-Thompson,Benjamin Schwartz,Subhas J. Chakravorty,Zining Wu,Palwinder K. Mander,Laurens Kruidenier,Robert A. Reid,William Burkhart,Brandon J. Turunen,James X Rong,James X Rong,Craig D. Wagner,Mary B. Moyer,Carrow I. Wells,Xuan Hong,John T. Moore,Jon D. Williams,Dulce Soler,Shomir Ghosh,Michael A. Nolan +29 more
TLDR
The discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates is reported.Abstract:
In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.read more
Citations
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Journal ArticleDOI
TGF-β1-Dependent Downregulation of HDAC9 Inhibits Maturation of Human Osteoblasts
TL;DR: Characterizing the expression changes of different HDACs in hOBs following recombinant human TGF-β1 treatment and investigating the effect of the alteredHDACs on both the proliferation and maturation of hobs and osteogenic cell lines found HDAC9 an interesting therapeutic target to support fracture healing and bone metabolisms.
DissertationDOI
Studies on the role of two proteins in breast cancer - histone deacetylase 11 in estrogen receptor positive breast cancer and the redox protein memo in metastasis and tumorigenesis
TL;DR: The finding that HDAC11 has oncogenic potential in ER-positive breast cancer and therefore might be a new target for therapy is shown, and Memo has prognostic value for patients who received endocrine therapy.
Journal ArticleDOI
Binding Free Energy (BFE) Calculations and Quantitative Structure-Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors.
Conrad V. Simoben,Ehab Ghazy,Patrik Zeyen,Salma Darwish,Matthias Schmidt,Christophe Romier,Dina Robaa,Wolfgang Sippl +7 more
TL;DR: In this paper, the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni (smHDAC) were explored using molecular docking and binding free energy (BFE) calculations.
Patent
Compounds and methods
ホッグセット、アンダース,ヨハンセン、パル +1 more
TL;DR: This method may be used to stimulate an immune response, also in various therapies or prophylaxis, and Pharmaceutical composition or kit comprising components for use in this method, the cells produced in this way, and also their use in the treatment and prevention form an aspect of the present invention.
Journal ArticleDOI
Latest Research Trends in Agrochemical Fungicides: Any Learnings for Pharmaceutical Antifungals?
TL;DR: The research-based agrochemical industry has proven that these requirements can be fulfilled by a constant flow of novel fungicidal modes of action and the design of resistance-breaking active ingredients in an established fungicidal mode of action class, if the molecular structure of the mutated fungal strain is known.
References
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Journal ArticleDOI
The Cambridge Structural Database: a quarter of a million crystal structures and rising
TL;DR: The Cambridge Structural Database now contains data for more than a quarter of a million small-molecule crystal structures, and projections concerning future accession rates indicate that the CSD will contain at least 500,000 crystal structures by the year 2010.
Journal ArticleDOI
Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
Chunaram Choudhary,Chanchal Kumar,Florian Gnad,Michael L. Nielsen,Michael Rehman,Tobias C. Walther,Jesper V. Olsen,Matthias Mann +7 more
TL;DR: A proteomic-scale analysis of protein acetylation suggests that it is an important biological regulatory mechanism and the regulatory scope of lysine acetylations is broad and comparable with that of other major posttranslational modifications.
Journal ArticleDOI
Substrate and Functional Diversity of Lysine Acetylation Revealed by a Proteomics Survey
Sung Chan Kim,Robert Sprung,Yue Chen,Yingda Xu,Haydn L. Ball,Jimin Pei,Tzuling Cheng,Yoonjung Kho,Hao Xiao,Lin Xiao,Nick V. Grishin,Michael A. White,Xiang-Jiao Yang,Yingming Zhao +13 more
TL;DR: This study reveals previously unappreciated roles for lysine acetylation in the regulation of diverse cellular pathways outside of the nucleus, including many longevity regulators and metabolism enzymes.
Journal ArticleDOI
Epigenetic protein families: a new frontier for drug discovery
Cheryl H. Arrowsmith,C. Bountra,Paul V. Fish,Kevin Lee,Kevin Lee,Matthieu Schapira,Matthieu Schapira +6 more
TL;DR: The key protein families that mediate epigenetic signalling through the acetylation and methylation of histones are reviewed, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones.
Journal ArticleDOI
Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy
Chun Li Zhang,Timothy A. McKinsey,Shurong Chang,Christopher L. Antos,Joseph A. Hill,Eric N. Olson +5 more
TL;DR: It is shown that class II HDACs are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions, and act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.