Last update 01 Nov 2024

HDAC7 x HDAC5 x HDAC9

Last update 01 Nov 2024

Basic Info

Related Targets

HDAC7HDAC5HDAC9

Drugs associated with HDAC7 x HDAC5 x HDAC9

TMP269

Target

HDAC5 x HDAC7 x HDAC9

Mechanism

HDAC5 modulators [+2]

Active Org.-

Originator Org.

GSK Plc

Active Indication-

Inactive Indication-

Drug Highest Phase-

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HDAC7 x HDAC5 x HDAC9

100 Translational Medicine associated with HDAC7 x HDAC5 x HDAC9

0 Patents (Medical) associated with HDAC7 x HDAC5 x HDAC9

Literatures (Medical) associated with HDAC7 x HDAC5 x HDAC9

01 May 2024·Journal of Molecular Biology

Folding of Class IIa HDAC Derived Peptides into α-helices Upon Binding to Myocyte Enhancer Factor-2 in Complex with DNA

Article

Author: Biondi, Barbara ; Lastella, Luana ; Borsato, Giuseppe ; Perin, Stefano ; Angelini, Alessandro ; Cendron, Laura ; Brancolini, Claudio ; Chinellato, Monica ; Carli, Alberto ; Di Giorgio, Eros

Interaction of transcription factor myocyte enhancer factor-2 (MEF2) family members with class IIa histone deacetylases (HDACs) has been implicated in a wide variety of diseases. Though considerable knowledge on this topic has been accumulated over the years, a high resolution and detailed analysis of the binding mode of multiple class IIa HDAC derived peptides with MEF2D is still lacking. To fulfil this gap, we report here the crystal structure of MEF2D in complex with double strand DNA and four different class IIa HDAC derived peptides, namely HDAC4, HDAC5, HDAC7 and HDAC9. All class IIa HDAC derived peptides form extended amphipathic α-helix structures that fit snugly in the hydrophobic groove of MEF2D domain. Binding mode of class IIa HDAC derived peptides to MEF2D is very similar and occur primarily through nonpolar interactions mediated by highly conserved branched hydrophobic amino acids. Further studies revealed that class IIa HDAC derived peptides are unstructured in solution and appear to adopt a folded α-helix structure only upon binding to MEF2D. Comparison of our peptide-protein complexes with previously characterized structures of MEF2 bound to different co-activators and co-repressors, highlighted both differences and similarities, and revealed the adaptability of MEF2 in protein-protein interactions. The elucidation of the three-dimensional structure of MEF2D in complex with multiple class IIa HDAC derived peptides provide not only a better understanding of the molecular basis of their interactions but also have implications for the development of novel antagonist.

22 Sep 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington’s Disease Pathology

Q1 · MEDICINE

Article

Author: Doherty, Elizabeth M. ; Eznarriaga, Maria ; McAllister, George ; Ladduwahetty, Tammy ; Vogt, Thomas F. ; Strijbosch, Annelieke ; Clissold, Cole ; Heaphy, Patrick ; Williams, Rachel ; Wilkinson, Hilary A. ; Esmieu, William ; Blackaby, Wesley ; Vater, Huw ; Matthews, Kim ; Beaumont, Vahri ; Mangette, John E. ; Lazari, Ovadia ; Stafford, Douglas G. ; Jarvis, Rebecca ; Dominguez, Celia ; Macabuag, Natsuko ; Van de Bospoort, Rhea ; Breccia, Perla ; Wang, Hong-Jun ; Urbonas, Liudvikas

Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin (HTT) gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan. To further investigate the role of HDAC4 in cellular models of HD, we have developed bifunctional degraders of the protein and report the first potent and selective degraders of HDAC4 that show an effect in multiple cell lines, including HD mouse model-derived cortical neurons. These degraders act via the ubiquitin-proteasomal pathway and selectively degrade HDAC4 over other class IIa HDAC isoforms (HDAC5, HDAC7, and HDAC9).

01 Sep 2022·Biomedicine & Pharmacotherapy

Radix polygoni multiflori protects against hippocampal neuronal apoptosis in diabetic encephalopathy by inhibiting the HDAC4/JNK pathway

Article

Author: Chen, Gang ; Li, Haizhi ; Pan, Wei ; Xu, Yongjie ; Zhu, Liying ; Yang, Tingting ; Wei, Sijia ; Huang, Changyudong ; Lin, Hairong ; Zhao, Shuyun ; Qian, Wen ; Li, Xing

With an poorly characterized pathogenesis, Diabetic encephalopathy (DE), one of the main chronic complications of diabetes, would require further studies. Recent studies have proven that DE developing in conjunction with neuronal apoptosis, which is tightly regulated by a variety of processes and involved with histone acetylation and molecular signaling or so on. Though the histone deacetylase 4 (HDAC4), HDAC5, HDAC7, and HDAC9 form class IIa of the HDAC superfamily have been found participating in multiple neurodegenerative diseases, while JNK signaling pathway activation was hypothesized as a key cause leading to cell apoptosis, the correlation between HDAC4 and JNK signaling pathway remains unknown. Studies have found that Radix Polygoni Multiflori (RPM) contains a variety of ingredients, such as TSG and Emodin, could exert antioxidant effects, scavenge free radicals, inhibit cell apoptosis and provide neuroprotection, but the underlying mechanism has not fully elucidated yet. In the present study, we further explored the mechanism by which RPM improves the cognitive function of diabetic rats. Simultaneously, TSG and Emodin were used to stimulate HT-22 hippocampal neurons treated with high glucose. After RPM extracts or TSG, Emodin treatments, the cognitive functions of DE rats improved while the hippocampal neurons arranged tighter and increased. Meanwhile, the expression level of HAT, HDAC, HDAC4 and JNK signaling pathway and apoptosis related genes were decreased. Our finds indicates that RPM and Emodin would inhibit HDAC4 expression, curb the activation of the JNK pathway, reduce hippocampal neuron apoptosis and ultimately meliorate the cognitive function from diabetes. Additionally, the markedly inhibitory effects of the RPM and Emodin on HAT and HDAC was identified for the first time in this study, which provides a basis for future drug targeting histones acetylation development and application.

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