Discovery of 3-Amino-1 H -pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family.

Autor: Amrhein JA; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Berger LM; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Tjaden A; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Krämer A; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany., Elson L; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Tolvanen T; Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Solnavägen 1, 17177 Solna, Sweden., Martinez-Molina D; Pelago Bioscience AB, Scheeles Väg 1, 17165 Solna, Sweden., Kaiser A; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany., Schubert-Zsilavecz M; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany., Müller S; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany., Hanke T; Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Nov 27; Vol. 23 (23). Date of Electronic Publication: 2022 Nov 27.
DOI: 10.3390/ijms232314834
Abstrakt: The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N -myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N -(1 H -pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d , which exhibited high cellular potency for CDK16 (EC 50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20-120 nM and 50-180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2/M phase cell cycle arrest at all tested concentrations for 43d , caused by inhibition of CDK16.
Databáze: MEDLINE
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