Author: Fernandez-Blanco, Álvaro ; Verhofstad, Eva ; Aret, Edwin ; Dairou, Julien ; Sadownik, Jan ; George, Pascal ; Roche, Didier ; Krämer, Andreas ; Miege, Frédéric ; Dierssen, Mara ; Greverie, Marie ; Deau, Emmanuel ; Brugman, Sander J T ; Santangelo, Sara ; Tinnemans, Paul ; Knapp, Stefan ; Sleegers, Dennis ; George, Nicolas ; Lindberg, Mattias F ; Gavard, Julie ; Merlet, Laura ; de Gelder, René ; Meijer, Laurent

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21's selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug's biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.

Journal of Medicinal Chemistry

Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate

Author: Sadownik, Jan ; George, Pascal ; Tinnemans, Paul ; George, Nicolas ; Merlet, Laura ; Miege, Frederic ; Dairou, Julien ; Lindberg, Mattias F. ; Roche, Didier ; Greverie, Marie ; Deau, Emmanuel ; Fernandez-Blanco, Alvaro ; Kramer, Andreas ; Gavard, Julie ; de Gelder, Rene ; Brugman, Sander J. T. ; Santangelo, Sara ; Verhofstad, Eva ; Knapp, Stefan ; Dierssen, Mara ; Sleegers, Dennis ; Aret, Edwin ; Meijer, Laurent

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacol. inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-activated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer disease.Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations.We here report its physicochem. properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile.Leucettinib-21 selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug biol. effects.Leucettinib-21 was cocrystd. with CLK1 and modeled in the DYRK1A structure.Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau).Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn.Leucettinib-21 is now entering safety/tolerance phase 1 clin. trials.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	France	Perha Pharmaceuticals	05 Dec 2023
Down Syndrome	Preclinical	France	Perha Pharmaceuticals	05 Dec 2023

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