Structural and in Vivo Characterization of Tubastatin A, a Widely Used Histone Deacetylase 6 Inhibitor

Shen, Sida; Svoboda, Michal; Zhang, Guangming; Cavasin, Maria A.; Motlova, L.; McKinsey, Timothy A.; Eubanks, James H.; Bařinka, Cyril; Kozikowski, Alan P.

doi:10.1021/acsmedchemlett.9b00560

Cited by 56 publications

(58 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since no highly selective HDAC10 probes have been reported yet according to ChemicalProbes.org, our data designates TH65, with at least 30-fold selectivity (limit of our assay) over other HDACs, as novel promising chemical probe for HDAC10. Interestingly, we found the HDAC6 inhibitor Tubastatin A to be the second most selective HDAC10 inhibitor (CATDS = 0.67), contrasting the original and recent reports 34,35 but agreeing with results of in-cell nano-BRET binding assays 36 . Furthermore, the pan-HDAC inhibitor Abexinostat had the highest HDAC10 a nity in the panel of drugs (pK d app HDAC10 = 7.8 vs.…”

Section: Resultssupporting

confidence: 62%

“…The pro ling data for the 53 drugs targeting HDACs and metallohydrolases is a rich resource for chemical biologists and medicinal chemists that we make available here and in ProteomicsDB for further interrogation by the scienti c community. The study not only substantially extends the available chemoproteomic data beyond the 16 HDACis previously analysed in a conceptually similar way 17 , it also compares favourably to the hitherto largest studies using other pro ling technologies 34,35 . This extensive scope enabled analyses not possible in small data sets and revealed a number of surprises.…”

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Lechner

Malgapo

Grätz

et al. 2021

Preprint

View full text Add to dashboard Cite

HDAC drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a chemical proteomics assay using three promiscuous chemotypes and quantitative mass spectrometry that we deployed to establish the target landscape of 53 drugs. The results highlight 14 direct targets, including 9 out of the 11 human zinc-dependent HDACs, question the reported selectivity of widely-used molecules, notably for HDAC6, and delineate how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent target of hydroxamate drugs. This ill-annotated palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. Both enzymatic inhibition and knocking down the protein led to the accumulation of extracellular vesicles. Given the importance of exosome biology in neurological diseases or cancer, this HDAC-independent drug effect creates the incentive for considering MBLAC2 as a target for drug discovery.

show abstract

Section: Resultssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 58%

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Lechner

Malgapo

Grätz

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Besides, TubA and its analogs were also reported to have anti-inflammatory effects through enhancing the immunosuppressive activity of Foxp3 + Tregs [26], as well as anti-rheumatic [81] and anti-hepatitis C viral activities [82]. Recently, the crystal structure of drHDAC6-CD2/TubA complex had been solved, giving the molecular basis of ligand-protein interaction [83]. TubA had become a starting point for structural optimization, and several subsequent works were carried out based on its analogs.…”

Section: Aromatic Hydroxamic Acid-derived Inhibitorsmentioning

confidence: 99%

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

Xiao

Zhang

2020

Future Drug. Discov.

View full text Add to dashboard Cite

Histone deacetylase 6 (HDAC6) is a unique isozyme in the HDAC family with various distinguished characters. HDAC6 is predominantly localized in the cytoplasm and has several specific nonhistone substrates, such as α-tubulin, cortactin, Hsp90, tau and peroxiredoxins. Accumulating evidence reveals that targeting HDAC6 may serve as a promising therapeutic strategy for the treatment of cancers, neurological disorders and immune diseases, making the development of HDAC6 inhibitors particularly attractive. Recently, multitarget drug design and proteolysis targeting chimera technology have also been applied in the discovery of novel small molecular modulators targeting HDAC6. In this review, we briefly describe the structural features and biological functions of HDAC6 and discuss the recent advances in HDAC6 modulators, including selective inhibitors, chimeric inhibitors and proteolysis targeting chimeras for multiple therapeutic purposes.

show abstract

“…The protonation states at pH 7.0 were predicted using the Epik-tool in Schrödinger. 84,97 The structures were finally subjected to a restrained energy minimization step (rmsd of the atom displacement for terminating the minimization was 0.3 Å)…”

Section: Molecular Dockingmentioning

confidence: 99%

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

Herp¹,

Ridinger²,

Robaa³

et al. 2020

Preprint

View full text Add to dashboard Cite

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

show abstract

Structural and in Vivo Characterization of Tubastatin A, a Widely Used Histone Deacetylase 6 Inhibitor

Cited by 56 publications

References 42 publications

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

Contact Info

Product

Resources

About