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Discovery of 3-Amin...
Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family
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Amrhein, JA (author)
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Berger, LM (author)
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Tjaden, A (author)
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Kramer, A (author)
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Elson, L (author)
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Tolvanen, T (author)
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Martinez-Molina, D (author)
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Kaiser, A (author)
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Schubert-Zsilavecz, M (author)
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Muller, S (author)
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Knapp, S (author)
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Hanke, T (author)
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- 2022-11-27
- 2022
- English.
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In: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:23
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https://doi.org/10.3...
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Abstract
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- 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-(1H-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 (EC50 = 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.
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- By the author/editor
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Amrhein, JA
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Berger, LM
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Tjaden, A
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Kramer, A
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Elson, L
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Tolvanen, T
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show more...
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Martinez-Molina, ...
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Kaiser, A
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Schubert-Zsilave ...
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Muller, S
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Knapp, S
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Hanke, T
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show less...
- Articles in the publication
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International jo ...
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Karolinska Institutet