8P08

Crystal structure of human CLK1 in complex with Leucettinib-21

Summary for 8P08

• Entry DOI: 10.2210/pdb8p08/pdb
• Descriptor: Dual specificity protein kinase CLK1, (4~{Z})-4-(1,3-benzothiazol-6-ylmethylidene)-2-[[(2~{R})-1-methoxy-4-methyl-pentan-2-yl]amino]-1~{H}-imidazol-5-one (3 entities in total)
• Functional Keywords: kinase, typ1 inhibitor, clk1, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39939.97

Authors

Kraemer, A.,Schroeder, M.,Meijer, L.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-05-09, release date: 2023-05-17, Last modification date: 2024-07-31)

Primary citation

Lindberg, M.F.,Deau, E.,Miege, F.,Greverie, M.,Roche, D.,George, N.,George, P.,Merlet, L.,Gavard, J.,Brugman, S.J.T.,Aret, E.,Tinnemans, P.,de Gelder, R.,Sadownik, J.,Verhofstad, E.,Sleegers, D.,Santangelo, S.,Dairou, J.,Fernandez-Blanco, A.,Dierssen, M.,Kramer, A.,Knapp, S.,Meijer, L.
Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate.
J.Med.Chem., 66:15648-15670, 2023

PubMed 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.

PubMed: 38051674
DOI: 10.1021/acs.jmedchem.3c01888

Experimental method

X-RAY DIFFRACTION (2.4 Å)