EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model

• Published in: European journal of medicinal chemistry 2024-02, Vol.265, p.116098-116098, Article 116098
• Main Authors: Delabar, Jean M., Gomes, Marco Antônio G.B., Fructuoso, Marta, Sarrazin, Nadège, George, Nicolas, Fleary-Roberts, Nadia, Sun, Hua, Bui, Linh Chi, Rodrigues-Lima, Fernando, Janel, Nathalie, Dairou, Julien, Maria, Edmilson J., Dodd, Robert H., Cariou, Kevin, Potier, Marie-Claude
• Format: Article
• Language: English
• Subjects: Animals; Catechin - analogs & derivatives; catechine derivatives; Cognition; Down Syndrome - drug therapy; Female; Humans; Kinase inhibitors; Mice; Mice, Transgenic; Pregnancy; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Tetrahydroisoquinoline
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.116098

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A. In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity. [Display omitted] •Novel epigallocatechin gallate (EGCG) analogues as a new class of DYRK1A inhibitors.•EGCG derivatives were synthesized.•7cc showed IC50 value of 0.5 μM against DYRK1A and was shown to act as a non competitive inhibitor.•7cc showed inhibited ERK2 phosphorylation in mouse brain.•7cc was more stable in plasma compared to EGCG.•7cc showed no toxicity during embryogenesis and corrected working memory deficit in a Down syndrome model.