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Selective inhibition of histone deacetylase 10: hydrogen bonding to the gatekeeper residue is implicated

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine de...

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Hauptverfasser: Géraldy, Magalie (VerfasserIn) , Morgen, Michael (VerfasserIn) , Ridinger, Johannes (VerfasserIn) , Oehme, Ina (VerfasserIn) , Witt, Olaf (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: April 9, 2019
In: Journal of medicinal chemistry
Year: 2019, Jahrgang: 62, Heft: 9, Pages: 4426-4443
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.8b01936
Online-Zugang:Verlag, Pay-per-use, Volltext: https://doi.org/10.1021/acs.jmedchem.8b01936
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Verfasserangaben:Magalie Géraldy, Michael Morgen, Peter Sehr, Raphael R. Steimbach, Davide Moi, Johannes Ridinger, Ina Oehme, Olaf Witt, Mona Malz, Mauro S. Nogueira, Oliver Koch, Nikolas Gunkel, and Aubry K. Miller
Beschreibung
Zusammenfassung:The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
Beschreibung:Gesehen am 01.08.2019
Beschreibung:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.8b01936

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