Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 64(5): 2691-2704, 2021 03 11.
Article in English | MEDLINE | ID: mdl-33576627

ABSTRACT

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure-activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (Ki = 0.7 nM) and inhibits the enzyme function (IC50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.


Subject(s)
Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Sulfonamides/pharmacology , Animals , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/metabolism , Histone Deacetylase Inhibitors/pharmacokinetics , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/metabolism , Hydroxamic Acids/pharmacokinetics , Male , Mice, Inbred BALB C , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Zebrafish , Zebrafish Proteins/antagonists & inhibitors , Zebrafish Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...