Resumen
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.