Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction

  • J Med Chem. 2023 Dec 14;66(23):15715-15727. doi: 10.1021/acs.jmedchem.3c00877.
Radoslaw Kitel  1 ,  Ewa Surmiak  1 ,  Jan Borggräfe  2  3 ,  Justyna Kalinowska-Tluscik  1 ,  Przemyslaw Golik  1 ,  Miroslawa Czub  1 ,  Wiktor Uzar  1  4 ,  Bogdan Musielak  1 ,  Mariusz Madej  5 ,  Grzegorz M Popowicz  2  3 ,  Grzegorz Dubin  6 ,  Tad A Holak  1
Affiliations
  • 1. Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kracow, Poland.
  • 2. Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, 85764 München, Germany.
  • 3. Bavarian NMR Center, School of Natural Sciences, Technical University of Munich Garching, 85748 München, Germany.
  • 4. Doctoral School of Exact and Natural Sciences, Jagiellonian University, Prof. S. Lojasiewicza 11, 30-348 Krakow, Poland.
  • 5. Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Cracow, Poland.
  • 6. Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland.
PMID: 38039505 DOI: 10.1021/acs.jmedchem.3c00877
Abstract

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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