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
Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
TL;DR: The development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic are highlighted.
Journal ArticleDOI
New and emerging HDAC inhibitors for cancer treatment.
TL;DR: The influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis is discussed and HDAC inhibitors targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents are examined.
Journal ArticleDOI
Targeting macrophages: therapeutic approaches in cancer.
TL;DR: The state of the art of TAM-targeting strategies is evaluated, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms.
Journal ArticleDOI
HDACs and HDAC Inhibitors in Cancer Development and Therapy
Yixuan Li,Edward Seto +1 more
TL;DR: The role of HDACs in cancer and the therapeutic potential ofHDAC inhibitors (HDACi) as emerging drugs in cancer treatment are discussed.
Journal ArticleDOI
Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.
TL;DR: Four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications are summarized as a guide to discover additional HDAC inhibitor-based therapies with greater therapeutic utility.
References
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Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflammation
TL;DR: Different and even competing responses are demonstrated at the level of macrophage cytokine production with implications for their respective roles in inflammation, including a possible dampening or suppressive role for M-CSF in certain circumstances.
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Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases.
Armin Lahm,Chantal Paolini,Michele Pallaoro,Maria Chiara Nardi,Philip Jones,Petra Neddermann,Sonia Sambucini,Matthew J. Bottomley,P. Lo Surdo,Andrea Carfi,Uwe Koch,R. De Francesco,Christian Steinkühler,Paola Gallinari +13 more
TL;DR: Evidence is presented supporting the view that vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
Journal ArticleDOI
Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5
TL;DR: The studies suggest that 14-3-3 binding toHDAC5 is required for CaMK-dependent disruption of MEF2-HDAC complexes and nuclear export of HDAC5, and implicate 14- 3-3 as a signal-dependent regulator of muscle cell differentiation.
Journal ArticleDOI
Defining GM-CSF– and Macrophage-CSF–Dependent Macrophage Responses by In Vitro Models
Derek Lacey,Adrian Achuthan,Andrew J. Fleetwood,Hang Dinh,John Roiniotis,Glen M. Scholz,Melody W. Chang,Sandra K Beckman,Andrew D. Cook,John A. Hamilton +9 more
TL;DR: Care needs to be exercised when drawing definitive conclusions from a particular in vitro system about the roles of GM- CSF and M-CSF in macrophage lineage biology, as evidence of “competition” at the level of gene expression was observed.
Journal ArticleDOI
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
Céline Bellenguez,Steve Bevan,Andreas Gschwendtner,Spencer Cca.,Annette I. Burgess,Matti Pirinen,Caroline A. Jackson,Matthew Traylor,Amy Strange,Zhan Su,P D Syme,Rainer Malik,Joanna Pera,N. Bo,Robin Lemmens,Robin Lemmens,Colin Freeman,R. Schanz,T James,D Poole,Lee Murphy,Helen Segal,L Cortellini,Cheng Y-C.,Daniel Woo,Mike A. Nalls,Bertram Müller-Myhsok,Christa Meisinger,Udo Seedorf,Helen Ross-Adams,Steven Boonen,D. Wloch-Kopec,V Valant,Julia Slark,Karen L. Furie,Hossein Delavaran,Cordelia Langford,Panos Deloukas,Sarah Edkins,Sarah E. Hunt,Emma Gray,Serge Dronov,Leena Peltonen,Solveig Gretarsdottir,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Kari Stefansson,Kari Stefansson,Giorgio B. Boncoraglio,Eugenio Parati,John Attia,Elizabeth G. Holliday,Christopher R Levi,Franzosi M-G.,Anuj Goel,Anna Helgadottir,Anna Helgadottir,Jenefer M. Blackwell,Jenefer M. Blackwell,Elvira Bramon,Matthew A. Brown,Juan P. Casas,Juan P. Casas,Aiden Corvin,Audrey Duncanson,Janusz Jankowski,Janusz Jankowski,Christopher G. Mathew,Palmer Cna.,Robert Plomin,Anna Rautanen,Stephen Sawcer,Richard C. Trembath,Ananth C. Viswanathan,Nicholas W. Wood,B. B. Worrall,Steven J. Kittner,Steven J. Kittner,Braxton D. Mitchell,Brett M. Kissela,James F. Meschia,Vincent Thijs,Vincent Thijs,Arne Lindgren,Mary Joan MacLeod,Agnieszka Slowik,Matthew Walters,Jonathan Rosand,Jonathan Rosand,Pankaj Sharma,Martin Farrall,Sudlow Clm.,Peter M. Rothwell,Martin Dichgans,Peter Donnelly,Hugh S. Markus +96 more
TL;DR: A new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 is identified, which suggests distinct genetic architectures for different stroke subtypes.