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Correction of aberrant splicing of ELP1 pre-mRNA by kinetin derivatives A structure activity relationship study
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SYSNO ASEP 0616886 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Correction of aberrant splicing of ELP1 pre-mRNA by kinetin derivatives A structure activity relationship study Author(s) Maková, B. (CZ)
Mik, V. (CZ)
Lišková, B. (CZ)
Drašarová, Lenka (UEB-Q) ORCID
Medvedíková, M. (CZ)
Hořínková, A. (CZ)
Vojta, P. (CZ)
Zatloukal, M. (CZ)
Plíhalová, L. (CZ)
Hönig, M. (CZ)
Doležal, Karel (UEB-Q) RID, ORCID
Forejt, K. (CZ)
Oždian, T. (CZ)
Hajdúch, M. (CZ)
Strnad, Miroslav (UEB-Q) RID, ORCID
Voller, J. (CZ)Number of authors 16 Article number 117176 Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 284, FEB 15 (2025)Number of pages 14 s. Language eng - English Country FR - France Keywords familial dysautonomia ; cell-line ; ikbkap ; gene ; protein ; inhibition ; expression ; model ; brain ; quantification ; Kinetin ; Cytokinin ; elp1 ; Alternative splicing ; mRNA metabolism ; ADME in vitro OECD category Medicinal chemistry Method of publishing Open access Institutional support UEB-Q - RVO:61389030 UT WOS 001401577100001 EID SCOPUS 85214011763 DOI https://doi.org/10.1016/j.ejmech.2024.117176 Annotation Familial dysautonomia is a debilitating congenital neurodegenerative disorder with no causative therapy. It is caused by a homozygous mutation in ELP1 gene, resulting in the production of the transcript lacking exon 20. The compounds studied as potential treatments include the clinical candidate kinetin, a plant hormone from the cytokinin family. We explored the relationship between the structure of a set of kinetin derivatives (N = 72) and their ability to correct aberrant splicing of the ELP1 gene. Active compounds can be obtained by the substitution of the purine ring with chlorine and fluorine at the C2 atom, with a small alkyl group at the N7 atom, or with diverse groups at the C8 atom. On the other hand, a substitution at the N3 or N9 atoms resulted in a loss of activity. We successfully tested a hypothesis inspired by the remarkable tolerance of the position C8 to substitution, postulating that the imidazole of the purine moiety is not required for the activity. We also evaluated the activity of phytohormones from other families, but none of them corrected ELP1 mRNA aberrant splicing. A panel of in vitro ADME assays, including evaluation of transport across model barriers, stability in plasma and in the presence of liver microsomal fraction as well as plasma protein binding, was used for an initial estimation of the potential bioavailability of the active compounds. Finally, a RNA-seq data suggest that 8-aminokinetin modulates expression spliceosome components. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2025 Electronic address https://doi.org/10.1016/j.ejmech.2024.117176
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