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

. 2023 Mar 06 ; 62 (11) : e202217532. [epub] 20230202

Language English Country Germany Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

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.

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F. Ardito, M. Giuliani, D. Perrone, G. Troiano, L. Lo Muzio, Int. J. Mol. Med. 2017, 40, 271-280.

E. D. G. Fleuren, L. Zhang, J. Wu, R. J. Daly, Nat. Rev. Cancer 2016, 16, 83-98.

M. M. Attwood, D. Fabbro, A. V. Sokolov, S. Knapp, H. B. Schiöth, Nat. Rev. Drug Discovery 2021, 20, 839-861.

M. I. Davis, J. P. Hunt, S. Herrgard, P. Ciceri, L. M. Wodicka, G. Pallares, M. Hocker, D. K. Treiber, P. P. Zarrinkar, Nat. Biotechnol. 2011, 29, 1046-1051.

C. Škuta, M. Popr, T. Müller, J. Jindřich, M. Kahle, D. Sedlák, D. Svozil, P. Bartůněk, Nat. Methods 2017, 14, 759-760;

R. M. Garbaccio, E. R. Parmee, Cell Chem. Biol. 2016, 23, 10-17;

R. A. M. Serafim, J. M. Elkins, W. J. Zuercher, S. A. Laufer, M. Gehringer, J. Med. Chem. 2022, 65, 1132-1170;

https://www.thesgc.org/chemical-probes, accessed 14. 3. 2022.

M. E. Berginski, N. Moret, C. Liu, D. Goldfarb, P. K. Sorger, S. M. Gomez, Nucleic Acids Res. 2021, 49, D529-D535.

P. Janovská, E. Normant, H. Miskin, V. Bryja, Int. J. Mol. Sci. 2020, 21, 9026-9044.

C. Du, H. Yang, F. Feng, W. Liu, Y. Chen, H. Sun, Future Med. Chem. 2021, 13, 505-528.

U. Knippschild, M. Krüger, J. Richter, P. Xu, B. García-Reyes, C. Peifer, J. Halekotte, V. Bakulev, J. Bischof, Front. Oncol. 2014, 4, 96.

S. Jiang, M. Zhang, J. Sun, X. Yang, Cell Commun. Signaling 2018, 16, 23.

B. Schittek, T. Sinnberg, Mol. Cancer 2014, 13, 231.

W. Minzel, A. Venkatachalam, A. Fink, E. Hung, G. Brachya, I. Burstain, M. Shaham, A. Rivlin, I. Omer, A. Zinger, S. Elias, E. Winter, P. E. Erdman, R. W. Sullivan, L. Fung, F. Mercurio, D. Li, J. Vacca, N. Kaushansky, L. Shlush, M. Oren, R. Levine, E. Pikarsky, I. Snir-Alkalay, Y. Ben-Neriah, Cell 2018, 175, 171-185.

B. L. Ebert, J. Krönke, N. Engl. J. Med. 2018, 379, 1873-1874.

P. Janovská, J. Verner, J. Kohoutek, L. Bryjová, M. Gregorová, M. Dzimková, H. Škabrahová, T. Radaszkiewicz, P. Ovesná, O. Vondálová Blanařová, T. Němcová, Z. Hoferova, K. Vašíčková, L. Smyčková, A. Egle, S. Pavlová, L. Poppová, K. Plevová, Š. Pospíšilová, V. Bryja, Blood 2018, 131, 1206-1218.

V. Němec, M. Hylsová, L. Maier, J. Flegel, S. Sievers, S. Ziegler, M. Schröder, B.-T. Berger, A. Chaikuad, B. Valčíková, S. Uldrijan, S. Drápela, K. Souček, H. Waldmann, S. Knapp, K. Paruch, Angew. Chem. Int. Ed. 2019, 58, 1062-1066;

Angew. Chem. 2019, 131, 1074-1078.

L. Xing, J. Klug-Mcleod, B. Rai, E. A. Lunney, Bioorg. Med. Chem. 2015, 23, 6520-6527;

R. Bouley, H. V. Waldschmidt, M. C. Cato, A. Cannavo, J. Song, J. Y. Cheung, X. Q. Yao, W. J. Koch, S. D. Larsen, J. J. G. Tesmer, Mol. Pharmacol. 2017, 92, 707-717;

K. Kusakabe, N. Ide, Y. Daigo, T. Itoh, T. Yamamoto, E. Kojima, Y. Mitsuoka, G. Tadano, S. Tagashira, K. Higashino, Y. Okano, Y. Sato, M. Inoue, M. Iguchi, T. Kanazawa, Y. Ishioka, K. Dohi, Y. Kido, S. Sakamoto, S. Ando, M. Maeda, M. Higaki, H. Yoshizawa, H. Murai, Y. Nakamura, Bioorg. Med. Chem. 2015, 23, 2247-2260.

A. M. Van Leusen, J. Wildeman, O. H. Oldenziel, J. Org. Chem. 1977, 42, 1153-1159.

J. L. Adams, J. C. Boehm, T. F. Gallagher, S. Kassis, E. F. Webb, R. Hall, M. Sorenson, R. Garigipati, D. E. Griswold, J. C. Lee, Bioorg. Med. Chem. Lett. 2001, 11, 2867-2870;

M. J. Graneto, R. G. Kurumbail, M. L. Vazquez, H.-S. Shieh, J. L. Pawlitz, J. M. Williams, W. C. Stallings, L. Geng, A. S. Naraian, F. J. Koszyk, M. A. Stealey, X. D. Xu, R. M. Weier, G. J. Hanson, R. J. Mourey, R. P. Compton, S. J. Mnich, G. D. Anderson, J. B. Monahan, R. Devraj, J. Med. Chem. 2007, 50, 5712-5719.

D. E. Frantz, L. Morency, A. Soheili, J. A. Murry, E. J. J. Grabowski, R. D. Tillyer, Org. Lett. 2004, 6, 843-846.

H. B. Jalani, E. Venkateswararao, M. Manickam, S.-H. Jung, Bull. Korean Chem. Soc. 2016, 37, 1966-1970.

J. K. Cheong, N. T. Hung, H. Wang, P. Tan, P. M. Voorhoeve, S. H. Lee, D. M. Virshup, Oncogene 2011, 30, 2558-2569.

C. Liu, Y. Li, M. Semenov, C. Han, G.-H. Baeg, Y. Tan, Z. Zhang, X. Lin, X. He, Cell 2002, 108, 837-847.

T. Radaszkiewicz, M. Nosková, K. Gömöryová, O. Vondálová Blanářová, K. A. Radaszkiewicz, M. Picková, R. Víchová, T. Gybeľ, K. Kaiser, L. Demková, L. Kučerová, T. Bárta, D. Potěšil, Z. Zdráhal, K. Souček, V. Bryja, eLife 2021, 10, e65759.

M. Reinecke, B. Ruprecht, S. Poser, S. Wiechmann, M. Wilhelm, S. Heinzlmeir, B. Kuster, G. Médard, ACS Chem. Biol. 2019, 14, 655-664.

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