The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma 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. Inv...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/4/834 |
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| author | Sophia S. Borisevich Tatiana E. Aksinina Margarita G. Ilyina Victoria O. Shender Ksenia S. Anufrieva Georgij P. Arapidi Nadezhda V. Antipova Fabrice Anizon Yannick J. Esvan Francis Giraud Victor V. Tatarskiy Pascale Moreau Mikhail I. Shakhparonov Marat S. Pavlyukov Alexander A. Shtil |
| author_facet | Sophia S. Borisevich Tatiana E. Aksinina Margarita G. Ilyina Victoria O. Shender Ksenia S. Anufrieva Georgij P. Arapidi Nadezhda V. Antipova Fabrice Anizon Yannick J. Esvan Francis Giraud Victor V. Tatarskiy Pascale Moreau Mikhail I. Shakhparonov Marat S. Pavlyukov Alexander A. Shtil |
| author_sort | Sophia S. Borisevich |
| collection | DOAJ |
| description | 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-<i>g</i>]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-<i>g</i>]quinazoline-2,10-diamine <b>1</b> and 10-nitro pyrido[3,4-<i>g</i>]quinazoline-2-amine <b>2</b>, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound <b>1</b>, compound <b>2</b> efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of <b>1</b> and <b>2</b> with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of <b>2</b> with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with <b>2</b> revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, <b>2</b> 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 <b>2</b> previously demonstrated in in vivo GBM models. |
| first_indexed | 2024-03-07T22:39:13Z |
| format | Article |
| id | doaj.art-f4b3e28217c945669ca9e886717f9bb2 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-07T22:39:13Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f4b3e28217c945669ca9e886717f9bb22024-02-23T15:11:23ZengMDPI AGCancers2072-66942024-02-0116483410.3390/cancers16040834The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma CellsSophia S. Borisevich0Tatiana E. Aksinina1Margarita G. Ilyina2Victoria O. Shender3Ksenia S. Anufrieva4Georgij P. Arapidi5Nadezhda V. Antipova6Fabrice Anizon7Yannick J. Esvan8Francis Giraud9Victor V. Tatarskiy10Pascale Moreau11Mikhail I. Shakhparonov12Marat S. Pavlyukov13Alexander A. Shtil14Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Ufa 450054, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaUfa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Ufa 450054, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaLopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, Moscow 119435, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaUniversité Clermont Auvergne, Centre National de la Recherche Scientifique, Clermont Auvergne Institut National Polytechnique, Institute of Chemistry of Clermont-Ferrand, F-63000 Clermont-Ferrand, FranceUniversité Clermont Auvergne, Centre National de la Recherche Scientifique, Clermont Auvergne Institut National Polytechnique, Institute of Chemistry of Clermont-Ferrand, F-63000 Clermont-Ferrand, FranceUniversité Clermont Auvergne, Centre National de la Recherche Scientifique, Clermont Auvergne Institut National Polytechnique, Institute of Chemistry of Clermont-Ferrand, F-63000 Clermont-Ferrand, FranceInstitute of Gene Biology, Russian Academy of Sciences, Moscow 119334, RussiaUniversité Clermont Auvergne, Centre National de la Recherche Scientifique, Clermont Auvergne Institut National Polytechnique, Institute of Chemistry of Clermont-Ferrand, F-63000 Clermont-Ferrand, FranceShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaShemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, RussiaBlokhin National Medical Research Center of Oncology, Moscow 115522, RussiaSerine-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-<i>g</i>]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-<i>g</i>]quinazoline-2,10-diamine <b>1</b> and 10-nitro pyrido[3,4-<i>g</i>]quinazoline-2-amine <b>2</b>, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound <b>1</b>, compound <b>2</b> efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of <b>1</b> and <b>2</b> with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of <b>2</b> with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with <b>2</b> revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, <b>2</b> 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 <b>2</b> previously demonstrated in in vivo GBM models.https://www.mdpi.com/2072-6694/16/4/834pyridoquinazolinesDYRK protein kinasesCLK protein kinasesquantum chemical calculationsgene transcriptionRNA splicing |
| spellingShingle | Sophia S. Borisevich Tatiana E. Aksinina Margarita G. Ilyina Victoria O. Shender Ksenia S. Anufrieva Georgij P. Arapidi Nadezhda V. Antipova Fabrice Anizon Yannick J. Esvan Francis Giraud Victor V. Tatarskiy Pascale Moreau Mikhail I. Shakhparonov Marat S. Pavlyukov Alexander A. Shtil The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells Cancers pyridoquinazolines DYRK protein kinases CLK protein kinases quantum chemical calculations gene transcription RNA splicing |
| title | The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells |
| title_full | The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells |
| title_fullStr | The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells |
| title_full_unstemmed | The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells |
| title_short | The Nitro Group Reshapes the Effects of Pyrido[3,4-<i>g</i>]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells |
| title_sort | nitro group reshapes the effects of pyrido 3 4 i g i quinazoline derivatives on dyrk clk activity and rna splicing in glioblastoma cells |
| topic | pyridoquinazolines DYRK protein kinases CLK protein kinases quantum chemical calculations gene transcription RNA splicing |
| url | https://www.mdpi.com/2072-6694/16/4/834 |
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