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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA24-12155S" target="_blank" >GA24-12155S: Studium funkce histon deacetylázy 11 napříč říšemi života</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Omega

ISSN

2470-1343

e-ISSN

2470-1343

Svazek periodika

10

Číslo periodika v rámci svazku

42

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

50577-50587

Kód UT WoS článku

001593131100001

EID výsledku v databázi Scopus

2-s2.0-105019951843