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

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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.

 

Autors :

Mattias F Lindberg 1Emmanuel Deau 1Frédéric Miege 2Marie Greverie 1Didier Roche 2Nicolas George 3Pascal George 1Laura Merlet 4 5Julie Gavard 4 5 6Sander J T Brugman 7Edwin Aret 7Paul Tinnemans 8René de Gelder 8Jan Sadownik 7Eva Verhofstad 7Dennis Sleegers 7Sara Santangelo 7Julien Dairou 9Álvaro Fernandez-Blanco 10Mara Dierssen 10Andreas Krämer 11 12Stefan Knapp 11 12Laurent Meijer 1

 

References :

J. Med. Chem. 2023, 66, 23, 15648–15670
Publication Date:December 5, 2023

https://doi.org/10.1021/acs.jmedchem.3c01888
Copyright © 2023 American Chemical Society

 

1Perharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, France.

2Edelris, Bâtiment Bioserra 1, 60 Avenue Rockefeller, 69008 Lyon, France.

3Oncodesign, 25-27 Avenue du Québec, 91140 Villebon-sur-Yvette, France.

4Team SOAP, CRCI2NA, Nantes Université, Inserm, CNRS, Université d’Angers, 8 Quai Moncousu, 44007 Nantes Cedex 1, France.

5Equipe Labellisée Ligue Contre le Cancer, 75013 Paris, France.

6Institut de Cancérologie de l’Ouest (ICO), Boulevard Professeur Jacques Monod, 44800 Saint-Herblain, France.

7Symeres, Peelterbaan 2, 6002 NK Weert, The Netherlands.

8Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.

9Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS, 45 rue des Saints Pères, 75006 Paris, France.

10Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08036, Spain.

11Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von Laue Strasse 15, 60438 Frankfurt am Main, Germany.

12Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von Laue Strasse 9, 60438 Frankfurt am Main, Germany.