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

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.