Substrate-Guided Development of HDAC11-Selective Inhibitors Featuring α-Amino Amide Zinc-Binding Groups

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00640809" target="_blank" >RIV/86652036:_____/25:00640809 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1021/acsomega.5c08195" target="_blank" >https://doi.org/10.1021/acsomega.5c08195</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acsomega.5c08195" target="_blank" >10.1021/acsomega.5c08195</a>

Result language
angličtina
Original language name
Substrate-Guided Development of HDAC11-Selective Inhibitors Featuring α-Amino Amide Zinc-Binding Groups
Original language description
Histone deacetylases (HDACs) play a pivotal role in various biological pathways and represent interesting drug targets. Therefore, HDAC inhibitors (HDACi) with high isoform selectivity and a zinc-binding group different from hydroxamic acid, because of its low metabolic stability, are required. HDAC11, as a highly potent defatty-acylase, differs from other HDACs in its substrate preference. Starting from this finding, we developed specific inhibitors for HDAC11 based on a peptide containing a fatty-acylated lysine side chain as the selectivity tail. The introduction of different heteroatoms at the fatty acyl residue was used to generate potent zinc-binding groups in combination with the scissile amide bond, as well as to suppress substrate properties of the resulting compounds. Further optimization resulted in a highly potent and selective HDAC11 inhibitor 31, which exhibits low nanomolar inhibition against HDAC11 without targeting other HDACs and is active in cells. The data presented here may help expand the range of zinc-binding groups utilized in HDAC inhibitors. Furthermore, the concept of the selectivity tail was demonstrated to facilitate straightforward access to selective defatty-acylase inhibitors.
Czech name
—
Czech description
—

Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10608 - Biochemistry and molecular biology

Project
<a href="/en/project/GA24-12155S" target="_blank" >GA24-12155S: Elucidating functions of histone deacetylase 11 throughout the kingdoms of life</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Similar results(10)