| Autor: |
Borisevich, Sophia S., Aksinina, Tatiana E., Ilyina, Margarita G., Shender, Victoria O., Anufrieva, Ksenia S., Arapidi, Georgij P., Antipova, Nadezhda V., Anizon, Fabrice, Esvan, Yannick J., Giraud, Francis, Tatarskiy, Victor V., Moreau, Pascale, Shakhparonov, Mikhail I., Pavlyukov, Marat S., Shtil, Alexander A. |
| Předmět: |
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| Zdroj: |
Cancers; Feb2024, Vol. 16 Issue 4, p834, 22p |
| Abstrakt: |
Simple Summary: The complex mode of gene expression regulation is a key reason underlying the biological heterogeneity and clinical diversity of malignant gliomas. In particular, high variabilities of gene expression are associated with alternative RNA splicing, a mechanism that generates the transcripts of different structures and functions from the same gene. Protein kinases of the DYRK and CLK families are part of the splicing regulation machinery; therefore, pharmacological targeting of these enzymes in gliomas is therapeutically relevant. We demonstrate that the pyrido[3,4-g]quinazoline scaffold is a source of compounds with differential inhibitory efficacy against individual DYRK and CLK enzymes. Our in silico calculations and omics experiments showed that a single chemical substitution in the scaffold can change the kinase inhibitory profile. This modification yielded the splicing antagonist with a high cytotoxic potency against patient-derived glioma cells. Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4-g]quinazoline scaffold led to the discovery of DYRK/CLK binders with differential potency against individual enzyme isoforms. Exploring the structure–activity relationship within this chemotype, we demonstrated that two structurally close compounds, pyrido[3,4-g]quinazoline-2,10-diamine 1 and 10-nitro pyrido[3,4-g]quinazoline-2-amine 2, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound 1, compound 2 efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of 1 and 2 with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of 2 with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with 2 revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, 2 affected the genes that perform critical functions for cancer cells including DNA damage response, p53 signaling and transcription. Altogether, these results provide a mechanistic basis for the therapeutic efficacy of 2 previously demonstrated in in vivo GBM models. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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