PUBLICATION
Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype
- Authors
- Olaoye, O.O., Watson, P.R., Nawar, N., Geletu, M., Sedighi, A., Bukhari, S., Raouf, Y.S., Manaswiyoungkul, P., Erdogan, F., Abdeldayem, A., Cabral, A.D., Hassan, M.M., Toutah, K., Shouksmith, A.E., Gawel, J.M., Israelian, J., Radu, T.B., Kachhiyapatel, N., de Araujo, E.D., Christianson, D.W., Gunning, P.T.
- ID
- ZDB-PUB-210213-19
- Date
- 2021
- Source
- Journal of medicinal chemistry 64(5): 2691-2704 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Hydroxamic Acids/chemical synthesis
- Hydroxamic Acids/metabolism
- Hydroxamic Acids/pharmacokinetics
- Hydroxamic Acids/pharmacology*
- Molecular Structure
- Histone Deacetylase 6/antagonists & inhibitors*
- Histone Deacetylase 6/metabolism
- Catalytic Domain
- Cell Proliferation/drug effects
- Histone Deacetylase Inhibitors/chemical synthesis
- Histone Deacetylase Inhibitors/metabolism
- Histone Deacetylase Inhibitors/pharmacokinetics
- Histone Deacetylase Inhibitors/pharmacology*
- Zebrafish
- Mice, Inbred BALB C
- Structure-Activity Relationship
- Cell Line, Tumor
- Sulfonamides/chemical synthesis
- Sulfonamides/metabolism
- Sulfonamides/pharmacokinetics
- Sulfonamides/pharmacology*
- Molecular Docking Simulation
- Animals
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/metabolism
- Protein Binding
- Humans
- Male
- PubMed
- 33576627 Full text @ J. Med. Chem.
Citation
Olaoye, O.O., Watson, P.R., Nawar, N., Geletu, M., Sedighi, A., Bukhari, S., Raouf, Y.S., Manaswiyoungkul, P., Erdogan, F., Abdeldayem, A., Cabral, A.D., Hassan, M.M., Toutah, K., Shouksmith, A.E., Gawel, J.M., Israelian, J., Radu, T.B., Kachhiyapatel, N., de Araujo, E.D., Christianson, D.W., Gunning, P.T. (2021) Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype. Journal of medicinal chemistry. 64(5):2691-2704.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping