Last update 01 Nov 2024

SIRT2 x HDAC6

Last update 01 Nov 2024

Basic Info

Related Targets

SIRT2HDAC6

Drugs associated with SIRT2 x HDAC6

Mz325

Target

HDAC6 x SIRT2

Mechanism

HDAC6 inhibitors [+1]

Active Org.

Universität Leipzig

Originator Org.

Universität Leipzig

Active Indication

Ovarian Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SIRT2 x HDAC6

100 Translational Medicine associated with SIRT2 x HDAC6

0 Patents (Medical) associated with SIRT2 x HDAC6

Literatures (Medical) associated with SIRT2 x HDAC6

01 Jan 2024·International Journal of Medical Sciences

The Protein Acetylation after Traumatic Spinal Cord Injury: Mechanisms and Therapeutic Opportunities

Review

Author: Li, Hong-Wei ; Zhang, Hai-Hong

Spinal cord injury (SCI) leads to deficits of various normal functions and is difficult to return to a normal state. Histone and non-histone protein acetylation after SCI is well documented and regulates spinal cord plasticity, axonal growth, and sensory axon regeneration. However, our understanding of protein acetylation after SCI is still limited. In this review, we summarize current research on the role of acetylation of histone and non-histone proteins in regulating neuron growth and axonal regeneration in SCI. Furthermore, we discuss inhibitors and activators targeting acetylation-related enzymes, such as α-tubulin acetyltransferase 1 (αTAT1), histone deacetylase 6 (HDAC6), and sirtuin 2 (SIRT2), to provide promising opportunities for recovery from SCI. In conclusion, a comprehensive understanding of protein acetylation and deacetylation in SCI may contribute to the development of SCI treatment.

09 Nov 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation

Q1 · MEDICINE

Article

Author: Jung, Manfred ; Hansen, Finn K. ; Gross, Olaf ; Zhang, Lin ; Neuwirt, Emilia ; König, Philipp ; Gaitzsch, Lena ; Toy, Lara ; Tararina, Margarita A. ; Schutkowski, Mike ; Zhai, Shiyang ; Romier, Christophe ; Colcerasa, Arianna ; Schiedel, Matthias ; Sinatra, Laura ; Christianson, David W. ; Vogelmann, Anja ; Yesiloglu, Talha Z. ; Einsle, Oliver ; Papenkordt, Niklas ; Hilscher, Sebastian ; Friedrich, Florian ; Sippl, Wolfgang ; Bendas, Gerd

Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.

08 May 2023·Translational neurodegeneration

Microtubule acetylation dyshomeostasis in Parkinson's disease

Review

Author: Vora, Lalitkumar K. ; Tryphena, Kamatham Pushpa ; Samim, Khan Sabiya ; Singh, Shashi Bala ; Naren, Padmashri ; Khatri, Dharmendra Kumar ; Srivastava, Saurabh

A review.The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system.This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse.Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, resp.Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs.Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan.The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimers disease and Parkinsons disease (PD).PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels.Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD.The enzymic regulators of MT acetylation along with their synthetic modulators have also been briefly explored.Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurol. conditions that lack it.Graphical abstract: [graphic not available: see fulltext].

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