Discovery of Inhibitory Fragments That Selectively Target Spire2–FMN2 Interaction

• Published in: Journal of medicinal chemistry 2023-12, Vol.66 (23), p.15715-15727
• Main Authors: Kitel, Radoslaw, Surmiak, Ewa, Borggräfe, Jan, Kalinowska-Tluscik, Justyna, Golik, Przemyslaw, Czub, Miroslawa, Uzar, Wiktor, Musielak, Bogdan, Madej, Mariusz, Popowicz, Grzegorz M., Dubin, Grzegorz, Holak, Tad A.
• Format: Article
• Language: English
• Subjects: Drug Discovery; Ligands; Molecular Docking Simulation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00877

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.