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

J 2023

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

NĚMEC, Václav, PrashantKumar KHIRSARIYA, Pavlína JANOVSKÁ, Paula MARTÍN MOYANO, Lukáš MAIER et. al.

Basic information

Original name

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

Authors

NĚMEC, Václav (203 Czech Republic, belonging to the institution), PrashantKumar KHIRSARIYA (356 India, belonging to the institution), Pavlína JANOVSKÁ (203 Czech Republic, belonging to the institution), Paula MARTÍN MOYANO (724 Spain, belonging to the institution), Lukáš MAIER (203 Czech Republic, belonging to the institution), Petra PROCHÁZKOVÁ (203 Czech Republic, belonging to the institution), Pavlína KEBKOVÁ (203 Czech Republic, belonging to the institution), Tomáš GYBEĽ (703 Slovakia, belonging to the institution), Benedict-Tilman BERGER, Apirat CHAIKUAD, Maria REINECKE, Bernhard KUSTER, Stefan KNAPP, Vítězslav BRYJA (203 Czech Republic, belonging to the institution) and Kamil PARUCH (203 Czech Republic, belonging to the institution)

Edition

Angewandte Chemie International Edition, Wiley-VCH GmbH, 2023, 1433-7851

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10400 1.4 Chemical sciences

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 16.600 in 2022

RIV identification code

RIV/00216224:14310/23:00130385

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1002/anie.202217532

UT WoS

000924089800001

Keywords in English

CK1; Chemical Probe; Inhibitor; Isoform Selectivity; Wnt Pathway

Abstract

V originále

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 CK1α, δ and ϵ. 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 CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α 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. p38α, as exemplified by the compound MU1299.

Links

EF16_025/0007381, research and development project

Name: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou

GX19-28347X, research and development project

Name: Molekulární a funkční analýza biologie kasein kinázy 1

Investor: Czech Science Foundation

LM2018130, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1209/2022, interní kód MU

Name: Molekuly, komplexy, makrocykly a xerogely

Investor: Masaryk University, Molecules, complexes, macrocycles, and xerogels

Citovat

NĚMEC, Václav, PrashantKumar KHIRSARIYA, Pavlína JANOVSKÁ, Paula MARTÍN MOYANO, Lukáš MAIER, Petra PROCHÁZKOVÁ, Pavlína KEBKOVÁ, Tomáš GYBEĽ, Benedict-Tilman BERGER, Apirat CHAIKUAD, Maria REINECKE, Bernhard KUSTER, Stefan KNAPP, Vítězslav BRYJA and Kamil PARUCH. Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity. Angewandte Chemie International Edition. Wiley-VCH GmbH, 2023, vol. 62, No 11, p. 1-7. ISSN 1433-7851. Available from: https://dx.doi.org/10.1002/anie.202217532.

@article{2262757,
   author = {Němec, Václav and Khirsariya, PrashantKumar and Janovská, Pavlína and Martín Moyano, Paula and Maier, Lukáš and Procházková, Petra and Kebková, Pavlína and Gybeľ, Tomáš and Berger, BenedictandTilman and Chaikuad, Apirat and Reinecke, Maria and Kuster, Bernhard and Knapp, Stefan and Bryja, Vítězslav and Paruch, Kamil},
   article_number = {11},
   doi = {http://dx.doi.org/10.1002/anie.202217532},
   keywords = {CK1; Chemical Probe; Inhibitor; Isoform Selectivity; Wnt Pathway},
   language = {eng},
   issn = {1433-7851},
   journal = {Angewandte Chemie International Edition},
   title = {Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity},
   url = {https://doi.org/10.1002/anie.202217532},
   volume = {62},
   year = {2023}
}

TY  - JOUR
ID  - 2262757
AU  - Němec, Václav - Khirsariya, PrashantKumar - Janovská, Pavlína - Martín Moyano, Paula - Maier, Lukáš - Procházková, Petra - Kebková, Pavlína - Gybeľ, Tomáš - Berger, Benedict-Tilman - Chaikuad, Apirat - Reinecke, Maria - Kuster, Bernhard - Knapp, Stefan - Bryja, Vítězslav - Paruch, Kamil
PY  - 2023
TI  - Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity
JF  - Angewandte Chemie International Edition
VL  - 62
IS  - 11
SP  - 1-7
EP  - 1-7
PB  - Wiley-VCH GmbH
SN  - 14337851
KW  - CK1
KW  - Chemical Probe
KW  - Inhibitor
KW  - Isoform Selectivity
KW  - Wnt Pathway
UR  - https://doi.org/10.1002/anie.202217532
N2  - 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 CK1α, δ and ϵ. 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 CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α 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. p38α, as exemplified by the compound MU1299.
ER  -

NĚMEC, Václav, PrashantKumar KHIRSARIYA, Pavlína JANOVSKÁ, Paula MARTÍN MOYANO, Lukáš MAIER, Petra PROCHÁZKOVÁ, Pavlína KEBKOVÁ, Tomáš GYBEĽ, Benedict-Tilman BERGER, Apirat CHAIKUAD, Maria REINECKE, Bernhard KUSTER, Stefan KNAPP, Vítězslav BRYJA and Kamil PARUCH. Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity. \textit{Angewandte Chemie International Edition}. Wiley-VCH GmbH, 2023, vol.~62, No~11, p.~1-7. ISSN~1433-7851. Available from: https://dx.doi.org/10.1002/anie.202217532.

Detailed Information on Publication Record