Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer’s Disease Drug CandidateClick to copy article linkArticle link copied!
- Mattias F. LindbergMattias F. LindbergPerharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, FranceMore by Mattias F. Lindberg
- Emmanuel DeauEmmanuel DeauPerharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, FranceMore by Emmanuel Deau
- Frédéric MiegeFrédéric MiegeEdelris, Bâtiment Bioserra 1, 60 Avenue Rockefeller, 69008 Lyon, FranceMore by Frédéric Miege
- Marie GreverieMarie GreveriePerharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, FranceMore by Marie Greverie
- Didier RocheDidier RocheEdelris, Bâtiment Bioserra 1, 60 Avenue Rockefeller, 69008 Lyon, FranceMore by Didier Roche
- Nicolas GeorgeNicolas GeorgeOncodesign, 25−27 Avenue du Québec, 91140 Villebon-sur-Yvette, FranceMore by Nicolas George
- Pascal GeorgePascal GeorgePerharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, FranceMore by Pascal George
- Laura MerletLaura MerletTeam SOAP, CRCI2NA, Nantes Université, Inserm, CNRS, Université d’Angers, 8 Quai Moncousu, 44007 Nantes Cedex 1, FranceEquipe Labellisée Ligue Contre le Cancer, 75013 Paris, FranceMore by Laura Merlet
- Julie GavardJulie GavardTeam SOAP, CRCI2NA, Nantes Université, Inserm, CNRS, Université d’Angers, 8 Quai Moncousu, 44007 Nantes Cedex 1, FranceEquipe Labellisée Ligue Contre le Cancer, 75013 Paris, FranceInstitut de Cancérologie de l’Ouest (ICO), Boulevard Professeur Jacques Monod, 44800 Saint-Herblain, FranceMore by Julie Gavard
- Sander J. T. BrugmanSander J. T. BrugmanSymeres, Peelterbaan 2, 6002 NK Weert, The NetherlandsMore by Sander J. T. Brugman
- Edwin Aret
- Paul TinnemansPaul TinnemansInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by Paul Tinnemans
- René de GelderRené de GelderInstitute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The NetherlandsMore by René de Gelder
- Jan Sadownik
- Eva Verhofstad
- Dennis Sleegers
- Sara Santangelo
- Julien DairouJulien DairouLaboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris Cité, CNRS, 45 rue des Saints Pères, 75006 Paris, FranceMore by Julien Dairou
- Álvaro Fernandez-BlancoÁlvaro Fernandez-BlancoCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08036, SpainMore by Álvaro Fernandez-Blanco
- Mara DierssenMara DierssenCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08036, SpainMore by Mara Dierssen
- Andreas KrämerAndreas KrämerStructural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von Laue Strasse 15, 60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von Laue Strasse 9, 60438 Frankfurt am Main, GermanyMore by Andreas Krämer
- Stefan KnappStefan KnappStructural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von Laue Strasse 15, 60438 Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von Laue Strasse 9, 60438 Frankfurt am Main, GermanyMore by Stefan Knapp
- Laurent Meijer*Laurent Meijer*Email: [email protected]Perharidy Research Center, Perha Pharmaceuticals, 29680 Roscoff, Bretagne, FranceMore by Laurent Meijer
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.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 10 publications.
- Gerrit Wilms, Kevin Schofield, Shayna Maddern, Christopher Foley, Yeng Shaw, Breland Smith, L. Emilia Basantes, Katharina Schwandt, Aaron Babendreyer, Timothy Chavez, Nicholas McKee, Vijay Gokhale, Sebastian Kallabis, Felix Meissner, Samantha N. Rokey, Travis Dunckley, William R. Montfort, Walter Becker, Christopher Hulme. Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B. Journal of Medicinal Chemistry 2024, 67
(19)
, 17259-17289. https://doi.org/10.1021/acs.jmedchem.4c01130
- Huanhua Chen, Xudong Gao, Xinzhu Li, Chong Yu, Wenwu Liu, Jingsong Qiu, Wenjie Liu, Hefeng Geng, Fangyuan Zheng, Hao Gong, Zihua Xu, Jingming Jia, Qingchun Zhao. Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer’s Disease. Journal of Medicinal Chemistry 2024, 67
(15)
, 12571-12600. https://doi.org/10.1021/acs.jmedchem.4c00483
- Arturo Bujarrabal-Dueso, George A. Garinis, Paul D. Robbins, Jan Vijg, Björn Schumacher. Targeting DNA damage in ageing: towards supercharging DNA repair. Nature Reviews Drug Discovery 2025, 592 https://doi.org/10.1038/s41573-025-01212-6
- Huanjun Kong, Antonio Valverde‐González, Régina Maruchenko, Laurent Bouteiller, Matthieu Raynal. Enhanced Stability and Properties of Benzene‐1,3,5‐Tricarboxamide Supramolecular Copolymers through Engineered Coupled Equilibria**. Angewandte Chemie International Edition 2025, 64
(12)
https://doi.org/10.1002/anie.202421991
- Huanjun Kong, Antonio Valverde‐González, Régina Maruchenko, Laurent Bouteiller, Matthieu Raynal. Enhanced Stability and Properties of Benzene‐1,3,5‐Tricarboxamide Supramolecular Copolymers through Engineered Coupled Equilibria**. Angewandte Chemie 2025, 137
(12)
https://doi.org/10.1002/ange.202421991
- Zhi-Hong Wen, Ya-Jen Chiu, San‑Nan Yang, Tzu-Yi Huang, Chien-Wei Feng, Nan-Fu Chen, Chun-Sung Sung, Wu-Fu Chen. Soft Corals-derived Dihydrosinularin Attenuates Neuronal Apoptosis in 6-hydroxydopamine-induced Cell Model of Parkinson's Disease by Regulating the PI3K Pathway. Current Medicinal Chemistry 2025, 32
(8)
, 1606-1620. https://doi.org/10.2174/0109298673323198240823070219
- Miriam Ems, Anna Brichkina, Matthias Lauth. A safe haven for cancer cells: tumor plus stroma control by DYRK1B. Oncogene 2025, 44
(6)
, 341-347. https://doi.org/10.1038/s41388-025-03275-6
- Matthew Malueg, Keagan G Moo, Azlann Arnett, Thomas H Edwards, Susan L Ruskin, Katharina Lambert, Aditi Subramanyam, Matthew J Dufort, Vivian H Gersuk, Rebecca Partridge, Jane H Buckner, Bernard Khor. Defining a novel DYRK1A-gp130/IL-6R-pSTAT axis that regulates Th17 differentiation. ImmunoHorizons 2025, 9
(1)
https://doi.org/10.1093/immhor/vlae005
- Chao-Hsiang Peng, Tsong-Long Hwang, Shao-Chi Hung, Huang-Ju Tu, Yen-Tzu Tseng, Tony Eight Lin, Cheng-Chung Lee, Yi-Chi Tseng, Chiung-Yuan Ko, Shih-Chung Yen, Kai-Cheng Hsu, Shiow-Lin Pan, Wei-Chun HuangFu. Identification, biological evaluation, and crystallographic analysis of coumestrol as a novel dual-specificity tyrosine-phosphorylation-regulated kinase 1A inhibitor. International Journal of Biological Macromolecules 2024, 282 , 136860. https://doi.org/10.1016/j.ijbiomac.2024.136860
- Laurent Meijer, Emilie Chrétien, Denis Ravel, , , , , , , , . Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer’s Disease and Down Syndrome. Journal of Alzheimer's Disease 2024, 101
(s1)
, S95-S113. https://doi.org/10.3233/JAD-240078
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.