Discovery of 3-Amino-1<i>H</i>-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family
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 <i>N<...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/23/14834 |
| Summary: | 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 <i>N</i>-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 <i>N</i>-(1<i>H</i>-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor <b>1</b> to target CDK16, by varying different residues. Further optimization steps led to <b>43d</b>, which exhibited high cellular potency for CDK16 (EC<sub>50</sub> = 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, <b>43d</b> 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 <b>43d</b>, caused by inhibition of CDK16. |
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| ISSN: | 1661-6596 1422-0067 |