2. Academic Validation
  3. Development of the First Small-Molecule Inhibitor Targeting Oncostatin M for Treatment of Breast Cancer

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

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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