1. Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer’s Disease Drug Candidate
- Author
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Lindberg, Mattias F., Deau, Emmanuel, Miege, Frédéric, Greverie, Marie, Roche, Didier, George, Nicolas, George, Pascal, Merlet, Laura, Gavard, Julie, Brugman, Sander J. T., Aret, Edwin, Tinnemans, Paul, de Gelder, René, Sadownik, Jan, Verhofstad, Eva, Sleegers, Dennis, Santangelo, Sara, Dairou, Julien, Fernandez-Blanco, Álvaro, Dierssen, Mara, Krämer, Andreas, Knapp, Stefan, and Meijer, Laurent
- Abstract
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.
- Published
- 2023
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