posted on 2023-12-05, 18:20authored byMattias
F. Lindberg, Emmanuel Deau, Frédéric Miege, Marie Greverie, Didier Roche, Nicolas George, Pascal George, Laura Merlet, Julie Gavard, Sander J. T. Brugman, Edwin Aret, Paul Tinnemans, René de Gelder, Jan Sadownik, Eva Verhofstad, Dennis Sleegers, Sara Santangelo, Julien Dairou, Álvaro Fernandez-Blanco, Mara Dierssen, Andreas Krämer, Stefan Knapp, Laurent Meijer
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.