Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε
Original language description
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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
<a href="/en/project/GX19-28347X" target="_blank" >GX19-28347X: Molecular and functional analysis of casein kinase 1 biology</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of Medicinal Chemistry
ISSN
0022-2623
e-ISSN
1520-4804
Volume of the periodical
68
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
25
Pages from-to
506-530
UT code for WoS article
001387025600001
EID of the result in the Scopus database
2-s2.0-85213475598