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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Inhibition of Class IIa HDACs improves endothelial barrier function in endotoxin-induced acute lung injury
Anita Kovacs-Kasa,Laszlo Kovacs,Mary Cherian-Shaw,Vijay Patel,Mary L Meadows,David J. Fulton,Yunchao Su,Alexander D. Verin +7 more
TL;DR: The data strongly suggest that Class IIa HDACs are involved in LPS‐induced ALI in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization.
Journal ArticleDOI
Expression of DHA-Metabolizing Enzyme Alox15 is Regulated by Selective Histone Acetylation in Neuroblastoma Cells.
Christabel Fung-Yih Ho,Claire Poh-Ee Bon,Yee-Kong Ng,Deron R. Herr,Jui-Sheng Wu,Teng-Nan Lin,Teng-Nan Lin,Wei-Yi Ong +7 more
TL;DR: Results indicate regulation of Alox15 mRNA expression in neuroblastoma cells by histone modifications, and increasing Alox 15 expression in differentiating neurons.
Journal ArticleDOI
Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodelling
Nishimori S,OMeara Mj,Castro Cd,Noda H,Cetinbas M,da Silva Martins J,Ayturk U,Brooks Dj,Michael Bruce,Nagata M,Ono W,Janton Cj,Bouxsein Ml,Foretz M,Berdeaux R,Sadreyev Ri,Gardella T,Juppner H,Kronenberg Hm,Marc N. Wein +19 more
TL;DR: It is established that SIK inhibition is central to PTH1R action in bone development and remodeling and highlights the key role of cAMP-regulated SIKs downstream of GPCR action.
Journal ArticleDOI
The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs
Chung-Pu Wu,Chung-Pu Wu,Sabrina Lusvarghi,Jyun-Cheng Wang,Sung-Han Hsiao,Yang-Hui Huang,Tai-Ho Hung,Tai-Ho Hung,Suresh V. Ambudkar +8 more
TL;DR: It is revealed that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs.
Journal ArticleDOI
Induced CAR-Macrophages as a Novel Therapeutic Cell Type for Cancer Immune Cell Therapies
Siyu Su,Anhua Lei,Xudong Wang,Hengxing Lu,Shuhang Wang,Yuqiong Yang,Ning Li,Yi Zhang,Jin Zhang +8 more
TL;DR: In this review, the current state of development of human CAR-macrophages is listed and an overview of the crucial functions of humanCAR- macrophages in the field of tumor immune cell therapy is provided.
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.