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
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Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription
Martina Minisini,Eros Di Giorgio,Emanuela Kerschbamer,Emiliano Dalla,Massimo Faggiani,Elisa Franforte,Franz-Josef Meyer-Almes,Rino Ragno,Lorenzo Antonini,A. Maio,Francesco Fiorentino,Dante Rotili,M. Chinellato,Stefano Perin,Laura Cendron,Christian X. Weichenberger,Alessandro Angelini,Claudio Brancolini +17 more
TL;DR: Although NKL54 cannot outcompete MEF2 from binding to class IIa HDACs, it supportsMEF2-dependent transcription through several actions, including potentiation of chromatin binding.
Journal ArticleDOI
HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells
TL;DR: It is observed that the class I/II HDAC inhibitor trichostatin A robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures, suggesting that class I HDACs are positive, not negative, regulators of FshB expression in vitro.
Journal ArticleDOI
Genetic and epigenetic strategies for advancing ovarian cancer immunotherapy
TL;DR: In this review, immunotherapy response in OC will be evaluated in the context of disease genetics and epigenetics, with a focus on checkpoint blockade and novel genetic and epigenetic therapies that show synergistic potential with current immunotherapies.
Journal ArticleDOI
Structure-based design of selective histone deacetylase 6 zinc binding groups.
TL;DR: An interesting benzimidazole fragment was selected from the in silico studies and presented as potential zing binding group for the development of novel HDAC6 selective inhibitors.
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.