Home Products Cited in Publications Worldwide Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction
Kitel, Radoslaw; Surmiak, Ewa; Borggrafe, Jan; Kalinowska-Tluscik, Justyna; Golik, Przemyslaw; Czub, Miroslawa; Uzar, Wiktor; Musielak, Bogdan; Madej, Mariusz; Popowicz, Grzegorz M.; Dubin, Grzegorz; Holak, Tad A.
DOI:10.1021/acs.jmedchem.3c00877 PMID:38039505
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 inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. 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 chem. probes targeting the Spire2-FMN2 interaction.