2. Academic Validation
  3. Identification of novel CLK1 inhibitors by computational fragment-based ligand design, co-crystallization, chemical synthesis and structure activity relationships

Identification of novel CLK1 inhibitors by computational fragment-based ligand design, co-crystallization, chemical synthesis and structure activity relationships

  • Eur J Med Chem. 2026 Oct 5:315:118977. doi: 10.1016/j.ejmech.2026.118977.
Stéphane Bourg 1,  Matthieu Place 1,  Chloé Copin 1,  Apirat Chaikuad 2,  Thomas Robert 3,  Hanna Holzmann 2,  Susanne Müller 2,  Stéphane Bach 3,  Sandrine Ruchaud 4,  Stefan Knapp 2,  Frédéric Buron 5,  Sylvain Routier 6,  Pascal Bonnet 7
Affiliations

Affiliations

  • 1 Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans, France.
  • 2 Institut für Pharmazeutische Chemie and Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main, 60438, Germany.
  • 3 Sorbonne Université, CNRS, FR 2424, Plateforme de Criblage KISSf, Station Biologique de Roscoff, Roscoff, 29680, France; Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Roscoff, 29680, France.
  • 4 Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Roscoff, 29680, France.
  • 5 Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans, France. Electronic address: [email protected].
  • 6 Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans, France. Electronic address: [email protected].
  • 7 Université d'Orléans, CNRS, ICOA, UMR 7311, Orléans, France. Electronic address: [email protected].
PMID: 42176653 DOI: 10.1016/j.ejmech.2026.118977
Abstract

CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer's disease and Other Diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.

Keywords

CLK1; FBDD; Imidazothiadiazole; Molecular modeling; SAR.

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