Publication: The Nitro Group Reshapes the Effects of Pyrido[3,4-g]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells
Дата
2024
Авторы
Borisevich, S. S.
Aksinina,T. E.
Ilyina, M. G.
Shender,V. O.
Journal Title
Journal ISSN
Volume Title
Издатель
Аннотация
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 structureў??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.
Описание
Ключевые слова
Quinazoline , Alternative Splicing
Цитирование
The Nitro Group Reshapes the Effects of Pyrido[3,4-g]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells / Borisevich, S. S. [et al.] // Cancers. - 2024. - 16. - № 4. - 10.3390/cancers16040834