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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)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Actin Nucleation; Protein; Domain; Spire
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Zeitschrift Journal of Medicinal Chemistry
Quellenangaben Band: 66, Heft: 23, Seiten: 15715-15727 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen European Union in the framework of the Smart Growth Operational Programme, Measure 4.2
National Science Centre, Poland
PRELUDIUM 14 grant
Narodowe Centrum Nauki