DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

• Published in: Scientific reports Vol. 8; no. 1; pp. 2859 - 12
• Main Authors: Neumann, Fernanda, Gourdain, Stéphanie, Albac, Christelle, Dekker, Alain D., Bui, Linh Chi, Dairou, Julien, Schmitz-Afonso, Isabelle, Hue, Nathalie, Rodrigues-Lima, Fernando, Delabar, Jean M., Potier, Marie-Claude, Le Caër, Jean-Pierre, Touboul, David, Delatour, Benoît, Cariou, Kevin, Dodd, Robert H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.02.2018; Nature Publishing Group
• Subjects: 631/154; 631/154/556; 631/378; 64; 64/110; 64/60; 692/308; 692/4017; Animals; Chromosome 21; Cognition - drug effects; Cognitive ability; Disease Models, Animal; Down syndrome; Down Syndrome - enzymology; Down Syndrome - psychology; Down's syndrome; Dyrk Kinases; Humanities and Social Sciences; Humans; Injections, Intraperitoneal; Learning; Learning Disabilities - drug therapy; Life Sciences; Maze Learning - drug effects; Memory; Memory Disorders - drug therapy; Mice; Molecular Structure; multidisciplinary; Neurobiology; Neurons and Cognition; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Science; Science (multidisciplinary); Trisomy
• DOI: 10.1038/s41598-018-20984-z
• ISSN: 2045-2322

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1 H -pyrrolo[2,3- b ]pyridine, 5a ) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.