Development of the First Small-Molecule Inhibitor Targeting Oncostatin M for Treatment of Breast Cancer

  • J Med Chem. 2025 Aug 14;68(15):15422-15445. doi: 10.1021/acs.jmedchem.4c03233.
Cody L Wolf  1  2 ,  Andrea Feci  3 ,  Joseph P Tuccinardi  3 ,  Grace H Coughlin  3 ,  Kelsey A Holdaway  3 ,  Thaaer Muhammed  3 ,  Clyde Pruett  2 ,  Darren Lighter  2 ,  Cooper McGrath  2 ,  Terrell Engmann  1  2 ,  Maria Pou-Torres  1  2 ,  Brittany Rushing  3 ,  Luke Woodbury  4 ,  Sierra E Haile  2 ,  Hannah Scott  2 ,  Ken Tawara  1  2 ,  Simion Dinca  1  2 ,  Dong Xu  5 ,  Matthew D King  3 ,  Lisa Rose Warner  3 ,  Cheryl L Jorcyk  2 ,  Don L Warner  3
Affiliations
  • 1. Department of Biomolecular Sciences, Boise State University, Boise, Idaho 83725, United States.
  • 2. Department of Biological Sciences, Boise State University, Boise, Idaho 83725, United States.
  • 3. Department of Chemistry and Biochemistry, Boise State University, Boise, Idaho 83725, United States.
  • 4. Biomedical Research Institute, Boise State University, Boise, Idaho 83725, United States.
  • 5. Biomedical and Pharmaceutical Sciences, Idaho State University, Meridian, Idaho 83642, United States.
PMID: 40747931 DOI: 10.1021/acs.jmedchem.4c03233
Abstract

Oncostatin M (OSM) is a proinflammatory cytokine implicated in inflammatory diseases and multiple cancers, especially breast Cancer. To date, no federally approved anti-OSM therapeutics exist. We computationally screened ∼1.65 million compounds to identify small-molecule inhibitors (SMIs) of the OSM, and candidates were validated in human breast Cancer models. We identified a tetrasubstituted furan (SMI-10) that inhibited OSM signaling, and optimization generated SMI-10B (KD = 12.9 μM) and SMI-10B13 (KD = 6.6 μM). SMI-10B13 strongly inhibited OSM-mediated STAT3 phosphorylation in T47D and MCF-7 cell lines (IC50= 136 and 164 nM, respectively). Fluorescence quenching, NMR, and surface plasmon resonance assays were used to characterize SMI/OSM interactions and identify a number of analogs with low-micromolar affinity for OSM. In a human breast Cancer mouse model, SMI-10B13 reduced tumor growth (p < 0.001). Kaplan-Meier analysis showed improved survival in SMI-10B13-treated mice (p = 0.04), highlighting its potential as the first anti-OSM therapeutic to inhibit breast Cancer progression and extend survival.

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