Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F25%3A00140747" target="_blank" >RIV/00216224:14310/25:00140747 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.4c02201" target="_blank" >https://doi.org/10.1021/acs.jmedchem.4c02201</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.4c02201" target="_blank" >10.1021/acs.jmedchem.4c02201</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Popis výsledku v původním jazyce

Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 (37) targeting CK1 delta and CK1 epsilon with excellent selectivity over the highly related CK1 alpha isoform. The developed PROTAC, AH078 (37) selectively degraded CK1 delta and CK1 epsilon with a DC50 of 200 nM. Characterization of AH078 (37) revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 (37) represents a versatile chemical tool to study CK1 delta and CK1 epsilon function in cellular systems.

Název v anglickém jazyce

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Popis výsledku anglicky

Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 (37) targeting CK1 delta and CK1 epsilon with excellent selectivity over the highly related CK1 alpha isoform. The developed PROTAC, AH078 (37) selectively degraded CK1 delta and CK1 epsilon with a DC50 of 200 nM. Characterization of AH078 (37) revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 (37) represents a versatile chemical tool to study CK1 delta and CK1 epsilon function in cellular systems.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/GX19-28347X" target="_blank" >GX19-28347X: Molekulární a funkční analýza biologie kasein kinázy 1</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>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

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

68

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

25

Strana od-do

506-530

Kód UT WoS článku

001387025600001

EID výsledku v databázi Scopus

2-s2.0-85213475598