2. Academic Validation
  3. A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation

A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation

  • Eur J Med Chem. 2023 Jul 5;255:115344. doi: 10.1016/j.ejmech.2023.115344.
Thomas Ihle Aarhus 1,  Jan Eickhoff 2,  Bert Klebl 2,  Anke Unger 2,  Joanna Boros 2,  Axel Choidas 2,  Mia-Lisa Zischinsky 2,  Camilla Wolowczyk 3,  Geir Bjørkøy 3,  Eirik Sundby 4,  Bård Helge Hoff 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway; Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
  • 2 Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
  • 3 Department of Biomedical Laboratory Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway.
  • 4 Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway.
  • 5 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.
PMID: 37141705 DOI: 10.1016/j.ejmech.2023.115344
Abstract

The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory processes, and overexpression of the kinase is implicated in several disease states. Identifying selective, small-molecule inhibitors of CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, and a systematic structure-activity relationship study, we have identified a number of potent and highly selective purine-based inhibitors of CSF1R. The optimized 6,8-disubstituted antagonist, compound 9, has enzymatic IC50 of 0.2 nM, and displays a strong affinity toward the autoinhibited form of CSF1R, contrasting that of Other previously reported inhibitors. As a result of its binding mode, the inhibitor shows excellent selectivity (Selectivity score: 0.06), evidenced by profiling towards a panel of 468 kinases. In cell-based assays, this inhibitor shows dose-dependent blockade of CSF1-mediated downstream signalling in murine bone marrow-derived macrophages (IC50 = 106 nM) as well as disruption of osteoclast differentiation at nanomolar levels. In vivo experiments, however, indicate that improve metabolic stability is needed in order to further progress this compound class.

Keywords

Autoinhibited form; CSF1R; Osteoclast differentiation; PLX3397; Purines.

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