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Kitel, R.* ; Surmiak, E.* ; Borggräfe, J. ; Kalinowska-Tluscik, J.* ; Golik, P.* ; Czub, M.* ; Uzar, W.* ; Musielak, B.* ; Madej, M.G.* ; Popowicz, G.M. ; Dubin, G.* ; Holak, T.A.*

Discovery of inhibitory fragments that selectively target spire2-FMN2 interaction.

J. Med. Chem. 66, 15715-15727 (2023)
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Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC nuclear magnetic resonance. Extensive structure-activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2-FMN2 interaction.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Actin Nucleation; Protein; Domain; Spire
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Journal Journal of Medicinal Chemistry
Quellenangaben Volume: 66, Issue: 23, Pages: 15715-15727 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants European Union in the framework of the Smart Growth Operational Programme, Measure 4.2
National Science Centre, Poland
PRELUDIUM 14 grant
Narodowe Centrum Nauki
DOI 10.1021/acs.jmedchem.3c00877
WOS ID 001141459700001
Scopus ID 85179600735
PubMed ID 38039505
Erfassungsdatum 2023-12-15
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