Реферат: 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. Abstract 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.

Библиографическая ссылка: Borisevich S.S. , Aksinina T.E. , Ilyina M.G. , Shender V.O. , Anufrieva K.S. , Arapidi G.P. , Antipova N.V. , Anizon F. , Esvan Y.J. , Giraud F. , Tatarskiy V.V. , Moreau P. , Shakhparonov M.I. , Pavlyukov M.S. , Shtil A.A.
The Nitro Group Reshapes the Effects of Pyrido[3,4-g]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells
Cancers. 2024. V.16. N4. 834 :1-22. DOI: 10.3390/cancers16040834 WOS Scopus OpenAlex

Даты:

Поступила в редакцию:	30 дек. 2023 г.
Принята к публикации:	15 февр. 2024 г.
Опубликована в печати:	19 февр. 2024 г.
Опубликована online:	19 февр. 2024 г.

Идентификаторы БД:

Web of science:	WOS:001175204800001
Scopus:	2-s2.0-85185930035
OpenAlex:	W4391971049

Цитирование в БД: Пока нет цитирований

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