Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Amrhein JA

PROVIDER: S-EPMC9736855 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Amrhein Jennifer Alisa JA Berger Lena Marie LM Tjaden Amelie A Krämer Andreas A Elson Lewis L Tolvanen Tuomas T Martinez-Molina Daniel D Kaiser Astrid A Schubert-Zsilavecz Manfred M Müller Susanne S Knapp Stefan S Hanke Thomas T

International journal of molecular sciences 20221127 23

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. Her ...[more]

PMID: 36499165

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Project description:The discovery of novel CDK2 inhibitors is crucial for developing targeted anticancer therapies. Thus, in this study, we aimed to design, synthesize, and evaluate a series of novel pyrazole derivatives (2a-g, 7a-d, 8a and b, 9, and 10) for their potential as CDK2/cyclin A2 enzyme inhibitors. The newly synthesized compounds were screened in vitro at 50 μM for CDK2 inhibition, followed by IC50 profiling of the most promising candidates. Compounds 4, 7a, 7d, and 9 exhibited the strongest inhibition, with IC50 values of 3.82, 2.0, 1.47, and 0.96 μM, respectively. To assess their anti-proliferative effects, all target compounds were further screened against a panel of 60 National Cancer Institute (NCI) cell lines representing various carcinoma types. Among them, compound 4 demonstrated exceptional anti-proliferative activity with a mean growth inhibition (GI) of 96.47% across the panel, while compound 9 showed a mean GI of 65.90%. Additionally, compounds 2b and 7c exhibited notable inhibition against MCF7 breast cancer cells, with GI rates of 86.1% and 79.41%, respectively. Compound 4 was selected for further five-dose concentration evaluations, displaying a full-panel GI50 value of 3.81 μM, with a subpanel range of 2.36-9.17 μM. Western blot analysis of compounds 4 and 9 in HCT-116 cell lines confirmed their inhibitory effects on CDK2. Furthermore, compound 4 induced significant cell cycle arrest at the G1 phase and promoted apoptosis. In silico molecular docking studies revealed that compounds 4, 7a, 7d, and 9 adopt a similar binding mode as AT7519 (I) within the CDK2 binding site. Molecular dynamics simulations further validated the stability of these compounds within the catalytic domain of CDK2. ADME/TOPKAT analyses indicated their favorable pharmacokinetic profiles, which were confirmed by their low toxicity in normal cell lines. Based on these findings, it was concluded that the synthesized pyrazole derivatives, particularly compound 4, show potent CDK2 inhibition and significant anticancer activity, with promising drug-like properties and minimal toxicity. This positions them as strong candidates for further development as CDK2-targeting anticancer agents.

Dataset Information

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

Publications

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

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