| Literature DB >> 33576627 |
Olasunkanmi O Olaoye1,2, Paris R Watson3, Nabanita Nawar1,2, Mulu Geletu1, Abootaleb Sedighi1, Shazreh Bukhari1,2, Yasir S Raouf1,2, Pimyupa Manaswiyoungkul1,2, Fettah Erdogan1,2, Ayah Abdeldayem1,2, Aaron D Cabral1,2, Muhammad Murtaza Hassan1,2, Krimo Toutah1, Andrew E Shouksmith1, Justyna M Gawel1, Johan Israelian1,2, Tudor B Radu1,2, Niyati Kachhiyapatel1, Elvin D de Araujo1, David W Christianson3, Patrick T Gunning1,2.
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.Entities:
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Year: 2021 PMID： 33576627 PMCID： PMC8063965 DOI： 10.1021/acs.jmedchem.0c01922
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446