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

Autor:	Czestkowski W; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Krzemiński Ł; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Piotrowicz MC; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Mazur M; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Pluta E; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Andryianau G; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Koralewski R; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Matyszewski K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Olejniczak S; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Kowalski M; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Lisiecka K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Kozieł R; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Piwowar K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Papiernik D; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Nowotny M; Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, Warsaw 02-109, Poland., Napiórkowska-Gromadzka A; Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, Warsaw 02-109, Poland., Nowak E; Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, Warsaw 02-109, Poland., Niedziałek D; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Wieczorek G; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Siwińska A; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Rejczak T; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Jędrzejczak K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Mulewski K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Olczak J; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Zasłona Z; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Gołębiowski A; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Drzewicka K; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland., Bartoszewicz A; Molecure S.A., Żwirki I Wigury 101, Warsaw 02-089, Poland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Mar 14; Vol. 67 (5), pp. 3959-3985. Date of Electronic Publication: 2024 Mar 01.
DOI:	10.1021/acs.jmedchem.3c02255
Abstrakt:	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.
Databáze:	MEDLINE
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