SMI-10B13 is a first-in-class, small molecule inhibitor of Oncostatin M (OSM) with Kd of 6.6 uM, strongly inhibits OSM-mediated STAT3 phosphorylation in T47D and MCF-7 cell lines with IC50 of 136 and 164 nM, respectively.
SMI-10B13 potently inhibits multiple OSM-mediated signaling pathways.
SMI-10B13 is likely on-target and primarily due to the disruption of OSMRβ recruitment at site III, plausibly after the OSM-gp130 complex has already formed.
SMI-10B13 significantly inhibits OSM-mediated tumor growth and increase survival.
SMI-10B13 (50 mg/kg) inhibits tumor growth in ER+ breast cancer xenograft model, inhibits metastasis in vivo.
Oncostatin M (OSM) is a proinflammatory cytokine implicated in inflammatory diseases and multiple cancers, especially breast cancer.
OSM, like all other members of the IL-6 family, is a four α-helical bundle cytokine.
OSM activates its signaling pathways by interacting with two separate receptor complexes: the OSM receptor (OSMR), which consists of glycoprotein 130 (gp130) and OSMRβ, and, to a lesser degree, the LIF receptor complex consisting of gp130/LIFRβ.