2. Academic Validation
  3. Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype

Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype

  • J Med Chem. 2021 Mar 11;64(5):2691-2704. doi: 10.1021/acs.jmedchem.0c01922.
Olasunkanmi O Olaoye 1 2,  Paris R Watson 3,  Nabanita Nawar 1 2,  Mulu Geletu 1,  Abootaleb Sedighi 1,  Shazreh Bukhari 1 2,  Yasir S Raouf 1 2,  Pimyupa Manaswiyoungkul 1 2,  Fettah Erdogan 1 2,  Ayah Abdeldayem 1 2,  Aaron D Cabral 1 2,  Muhammad Murtaza Hassan 1 2,  Krimo Toutah 1,  Andrew E Shouksmith 1,  Justyna M Gawel 1,  Johan Israelian 1 2,  Tudor B Radu 1 2,  Niyati Kachhiyapatel 1,  Elvin D de Araujo 1,  David W Christianson 3,  Patrick T Gunning 1 2
Affiliations

Affiliations

  • 1 Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Ontario L5L 1C6, Canada.
  • 2 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • 3 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
PMID: 33576627 DOI: 10.1021/acs.jmedchem.0c01922
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.

Figures