6vnq
Crystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Bishydroxamic Acid Based InhibitorCrystal Structure of Danio rerio Histone Deacetylase 10 in Complex with Bishydroxamic Acid Based Inhibitor
Structural highlights
FunctionHDA10_DANRE Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Has a very weak lysine deacetylase, if any (PubMed:28516954).[1] Publication Abstract from PubMedWe report the synthesis and evaluation of a class of selective multi-target agents for the inhibition of HDAC6, HDAC8 and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N -benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity on HDAC6, HDAC8 and HDAC10, while retaining selectivity over HDAC1, HDAC2 and HDAC3. The best substance inhibited viability of the SK-N-BE(2)C neuroblastoma cell line with an IC 50 value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes proof of concept for such hybrid molecules and may serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors. Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.,Miller AK, Morgen M, Steimbach RR, Geraldy M, Hellweg L, Sehr P, Ridinger J, Witt O, Oehme I, Herbst-Gervasoni CJ, Osko JD, Porter NJ, Christianson DW, Gunkel N ChemMedChem. 2020 Apr 29. doi: 10.1002/cmdc.202000149. PMID:32348628[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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