Discovery of 2‑Amino-3-cyanothiophene Derivatives as Potent STAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis

Osteosarcoma
is one of the most common malignant bone tumors. However,
the treatment and clinical outcomes of osteosarcoma have hardly changed
over the past three decades due to the comprehensive heterogeneity
and higher rate of mutation of osteosarcoma. Recent studies have shown
that STAT3 has the potential to suppress the proliferation and metastasis
of osteosarcoma. In this study, a novel class of 2-amino-3-cyanothiophene
derivatives were designed and synthesized to inhibit osteosarcoma
by targeting STAT3. Representative compound 6f showed
potent antiproliferative effects against osteosarcoma cells, directly
bound to the STAT3 SH2 domain with a KD of 0.46 μM, and inhibited the phosphorylation of STAT3 Y705
in a dose-dependent manner. Furthermore, compound 6f promoted
osteosarcoma cell apoptosis in vitro and significantly
suppressed the growth and metastasis of osteosarcoma in vivo. These findings demonstrate that targeting STAT3 may be a feasible
therapeutic strategy for the treatment of metastatic osteosarcoma.