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
Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases.
TL;DR: In this paper, a review of the progress in the field of non-hydroxamic histone deacetylases (HDACis) in the time period from 2015 to present is presented.
Journal ArticleDOI
FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells
Makoto Usami,Shohei Kikuchi,Kohichi Takada,Michihiro Ono,Yusuke Sugama,Yohei Arihara,Naotaka Hayasaka,Hajime Nakamura,Yuuki Ikeda,Masahiro Hirakawa,Makoto Yoshida,Koji Miyanishi,Masayoshi Kobune,Junji Kato +13 more
TL;DR: Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.
Journal ArticleDOI
The important role of histone deacetylases in modulating vascular physiology and arteriosclerosis.
TL;DR: The present knowledge of the cellular and molecular basis of HDACs in mediating the biological function of vascular cells and related pharmacologic interventions in vascular disease is discussed.
Journal ArticleDOI
Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery.
TL;DR: Proteolysis-targeting chimeras (PROTACs) have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation as mentioned in this paper .
Journal ArticleDOI
Turning enemies into allies-reprogramming tumor-associated macrophages for cancer therapy.
Martina Molgora,Marco Colonna +1 more
TL;DR: Molgora et al. as discussed by the authors reviewed approaches that are currently being evaluated to convert immunosuppressive TAM into immunostimulatory macrophages that promote T cell responses and tumor elimination.
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.