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

Olasunkanmi O. Olaoye, Paris R. Watson, Nabanita Nawar, Mulu Geletu, Abootaleb Sedighi, Shazreh Bukhari, Yasir S. Raouf, Pimyupa Manaswiyoungkul, Fettah Erdogan, Ayah Abdeldayem, Aaron D. Cabral, Muhammad Murtaza Hassan, Krimo Toutah, Andrew E. Shouksmith, Justyna M. Gawel, Johan Israelian, Tudor B. Radu, Niyati Kachhiyapatel, Elvin D. De Araujo, David W. ChristiansonPatrick T. Gunning

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2691-2704
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number5
DOIs
Publication statusPublished - Mar 11 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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