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

J 2025

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

HAAG, Adrian; Vaclav NEMEC; Pavlína JANOVSKÁ; Jana BARTOŠÍKOVÁ; Bikash ADHIKARI et al.

Základní údaje

Originální název

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

Autoři

Vydání

Journal of Medicinal Chemistry, Washington, American Chemical Society, 2025, 0022-2623

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30107 Medicinal chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.800 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

Assays; Degradation; Inhibitors; Mixtures; Peptides and proteins

Štítky

14314010, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 5. 2025 11:24, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

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.

Návaznosti

GX19-28347X, projekt VaV

Název: Molekulární a funkční analýza biologie kasein kinázy 1

Investor: Grantová agentura ČR, Molekulární a funkční analýza biologie kasein kinázy 1

90252, velká výzkumná infrastruktura

Název: CZ-OPENSCREEN IV

Citovat

HAAG, Adrian; Vaclav NEMEC; Pavlína JANOVSKÁ; Jana BARTOŠÍKOVÁ; Bikash ADHIKARI; Juliane MUELLER; Martin P SCHWALM; Štěpán ČADA; Uli OHMAYER; Henrik DAUB; Yeojin KIM; Florian BORN; Elmar WOLF; Vítězslav BRYJA a Stefan KNAPP. Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε. Journal of Medicinal Chemistry. Washington: American Chemical Society, 2025, roč. 68, č. 1, s. 506-530. ISSN 0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.4c02201.

@article{2481764,
   author = {Haag, Adrian and Nemec, Vaclav and Janovská, Pavlína and Bartošíková, Jana and Adhikari, Bikash and Mueller, Juliane and Schwalm, Martin P and Čada, Štěpán and Ohmayer, Uli and Daub, Henrik and Kim, Yeojin and Born, Florian and Wolf, Elmar and Bryja, Vítězslav and Knapp, Stefan},
   article_location = {Washington},
   article_number = {1},
   doi = {https://doi.org/10.1021/acs.jmedchem.4c02201},
   keywords = {Assays; Degradation; Inhibitors; Mixtures; Peptides and proteins},
   language = {eng},
   issn = {0022-2623},
   journal = {Journal of Medicinal Chemistry},
   title = {Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε},
   url = {https://doi.org/10.1021/acs.jmedchem.4c02201},
   volume = {68},
   year = {2025}
}

TY  - JOUR
ID  - 2481764
AU  - Haag, Adrian - Nemec, Vaclav - Janovská, Pavlína - Bartošíková, Jana - Adhikari, Bikash - Mueller, Juliane - Schwalm, Martin P - Čada, Štěpán - Ohmayer, Uli - Daub, Henrik - Kim, Yeojin - Born, Florian - Wolf, Elmar - Bryja, Vítězslav - Knapp, Stefan
PY  - 2025
TI  - Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε
JF  - Journal of Medicinal Chemistry
VL  - 68
IS  - 1
SP  - 506-530
EP  - 506-530
PB  - American Chemical Society
SN  - 00222623
KW  - Assays
KW  - Degradation
KW  - Inhibitors
KW  - Mixtures
KW  - Peptides and proteins
UR  - https://doi.org/10.1021/acs.jmedchem.4c02201
N2  - 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.
ER  -

HAAG, Adrian; Vaclav NEMEC; Pavlína JANOVSKÁ; Jana BARTOŠÍKOVÁ; Bikash ADHIKARI; Juliane MUELLER; Martin P SCHWALM; Štěpán ČADA; Uli OHMAYER; Henrik DAUB; Yeojin KIM; Florian BORN; Elmar WOLF; Vítězslav BRYJA a Stefan KNAPP. Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε. \textit{Journal of Medicinal Chemistry}. Washington: American Chemical Society, 2025, roč.~68, č.~1, s.~506-530. ISSN~0022-2623. Dostupné z: https://doi.org/10.1021/acs.jmedchem.4c02201.

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