Identification of a new class of highly selective inhibitors
of casein kinase 1
Paula Martín Moyano[a], Václav Němec[a], [b], Prashant Khirsariya[a], [b], Pavlína Janovská[c], Petra Lesáková[c], Pavlína
Kebková[c], Benedict-Tilman Berger[d], Apirat Chaikuad[d], Stefan Knapp[d], Vítězslav Bryja[c], and Kamil Paruch*[a], [b]
[a] Department of Chemistry, Masaryk University, Kamenice 5, Brno 625 00 (Czech Republic)
[b] International Clinical Research Centre, St. Anne´s University Hospital, Pekařská 53, Brno, 656 91 (Czech Republic)
[c] Department of Experimental Biology, Masaryk University, Kamenice 5, Brno 625 00 (Czech Republic)
[d] Institute for Pharmaceutical Chemistry, Structural Genomics Consortium, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 15,
Frankfurt am Main, 60438 (Germany)
*paruch@chemi.muni.cz
Recently, we identified potent and highly selective inhibitors of casein kinase 1 (CK1). Individual
isoforms of CK1 play pivotal roles in some key cellular signaling pathways. Thus, they have been
recently recognized as attractive targets for pharmacological inhibition, especially in the context
of the treatment of acute myeloid leukemia (AML)[1,2]
and chronic lymphocytic leukemia (CLL).[3]
In the preparation of our imidazole-based inhibitors, we typically utilized the van Leusen
cyclization.[4]
However, some compounds could not be made via this methodology and we had
to use alternative approaches., e.g. organocatalyzed construction of the imidazole core.[5]
Overall, we prepared and tested >200 compounds, which allowed for thorough mapping of the
structure-activity relationship (SAR) around the central azaindole-imidazole pharmacophore,
and identification of potent and highly selective inhibitors of CK1 α, δ and ε isoforms. The series
of the inhibitors has been patented and served as the basis for establishing of the spin-off
company CasInvent Pharma a.s.
References
[1] P. Janovská, E. Normant, H. Miskin, V. Bryja, Int. J. Mol. Sci. 2020, 21, 9026.
[2] 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.
[3] P. Janovska, J. Verner, J. Kohoutek, L. Bryjova, M. Gregorova, M. Dzimkova, H. Skabrahova, T.
Radaszkiewicz, P. Ovesna, O. Vondalova Blanarova, T. Nemcova, Z. Hoferova, K. Vasickova, L.
Smyckova, A. Egle, S. Pavlova, L. Poppova, K. Plevova, S. Pospisilova, V. Bryja, Blood 2018, 131, 1206–
1218.
[4] A. M. Van Leusen, J. Wildeman, O. H. Oldenziel, J. Org. Chem. 1977, 42, 1153–1159.
[5] J. A. Murry, D. E. Frantz, A. Soheili, R. Tillyer, E. J. J. Grabowski, P. J. Reider, J. Am. Chem. Soc. 2001,
123, 9696–9697.