Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F23%3A00079773" target="_blank" >RIV/00159816:_____/23:00079773 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14310/23:00130385

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/10.1002/anie.202217532" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1002/anie.202217532</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/anie.202217532" target="_blank" >10.1002/anie.202217532</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity

Popis výsledku v původním jazyce

Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1 alpha, delta and epsilon. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1 delta or dual inhibition of CK1 delta/epsilon in cells. The compound MU1742 also efficiently inhibits CK1 alpha and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38 alpha, as exemplified by the compound MU1299.

Název v anglickém jazyce

Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity

Popis výsledku anglicky

Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1 alpha, delta and epsilon. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1 delta or dual inhibition of CK1 delta/epsilon in cells. The compound MU1742 also efficiently inhibits CK1 alpha and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38 alpha, as exemplified by the compound MU1299.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

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Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Angewandte Chemie-International Edition

ISSN

1433-7851

e-ISSN

1521-3773

Svazek periodika

62

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

7

Strana od-do

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Kód UT WoS článku

000924089800001

EID výsledku v databázi Scopus

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