2. Academic Validation
  3. Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1

Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1

  • J Med Chem. 2024 Mar 14;67(5):3959-3985. doi: 10.1021/acs.jmedchem.3c02255.
Wojciech Czestkowski 1,  Łukasz Krzemiński 1,  Michał C Piotrowicz 1,  Marzena Mazur 1,  Elżbieta Pluta 1,  Gleb Andryianau 1,  Robert Koralewski 1,  Krzysztof Matyszewski 1,  Sylwia Olejniczak 1,  Michał Kowalski 1,  Katarzyna Lisiecka 1,  Rafał Kozieł 1,  Katarzyna Piwowar 1,  Diana Papiernik 1,  Marcin Nowotny 2,  Agnieszka Napiórkowska-Gromadzka 2,  Elżbieta Nowak 2,  Dorota Niedziałek 1,  Grzegorz Wieczorek 1,  Anna Siwińska 1,  Tomasz Rejczak 1,  Karol Jędrzejczak 1,  Krzysztof Mulewski 1,  Jacek Olczak 1,  Zbigniew Zasłona 1,  Adam Gołębiowski 1,  Katarzyna Drzewicka 1,  Agnieszka Bartoszewicz 1
Affiliations

Affiliations

  • 1 Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland.
  • 2 Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, Warsaw 02-109, Poland.
PMID: 38427954 DOI: 10.1021/acs.jmedchem.3c02255
Abstract

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and Cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

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