Discovery of Inhibitors of <i>Schistosoma mansoni</i> HDAC8 by Combining Homology Modeling, Virtual Screening, and in Vitro Validation

Kannan, Srinivasaraghavan; Melesina, Jelena; Hauser, Alexander‐Thomas; Chakrabarti, Alokta; Heimburg, Tino; Schmidtkunz, Karin; Walter, Alexandra; Marek, Martin; Pierce, Raymond J.; Romier, Christophe; Jung, Manfred; Sippl, Wolfgang

doi:10.1021/ci5004653

Cited by 59 publications

(90 citation statements)

References 53 publications

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“…This conformation creates a larger active site which should accommodate larger inhibitors compared to human HDAC8 and, therefore, offers the possibility for organism-specific inhibition. Indeed, smHDAC8 has been inhibited by the traditional HDACi SAHA and M344, as well as bulky ‘linkerless’ hydroxamate inhibitors (Kannan, et al, 2014; Heimburg, et al, 2016). …”

Section: Resultsmentioning

confidence: 99%

Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Tabackman

Frankson

Marsan

et al. 2016

Journal of Structural Biology

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Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/ or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

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Section: Resultsmentioning

confidence: 99%

Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Tabackman

Frankson

Marsan

et al. 2016

Journal of Structural Biology

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“…It has been shown that, in many cases, IC 50 values are very similar but may differ with different substrates by up to 20-fold in potency for certain inhibitors [42].…”

Section: Reviewmentioning

confidence: 99%

HDAC8: a multifaceted target for therapeutic interventions

Chakrabarti

Oehme

Witt

et al. 2015

Trends in Pharmacological Sciences

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232

163

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Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.

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“…So far, only a few series of Sm HDAC8 inhibitors have been reported, and most were only moderately effective against the parasite or showed no effect (Figure ). Based on virtual screening and structure‐guided optimization of a co‐crystallized hit ( J1038 , Figure ), we recently described a benzamidohydroxamic acid TH65 (Figure ) as an Sm HDAC8 inhibitor that is able to kill S. mansoni larvae in culture …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis

et al. 2018

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Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prepared as potential inhibitors of Schistosoma mansoni histone deacetylase 8 (SmHDAC8). The crystal structures of SmHDAC8 with four inhibitors provided insight into the binding mode and orientation of molecules in the binding pocket as well as the orientation of its flexible amino acid residues. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs. The most promising compounds were further investigated for their activity toward the major human HDAC isotypes. The most potent inhibitors were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Two of the compounds showed significant, dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.

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Discovery of Inhibitors of Schistosoma mansoni HDAC8 by Combining Homology Modeling, Virtual Screening, and in Vitro Validation

Cited by 59 publications

References 53 publications

Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

HDAC8: a multifaceted target for therapeutic interventions

Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis

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