A novel small molecule STAT3 inhibitor SLSI-1216 suppresses proliferation and tumor growth of triple-negative breast cancer cells through apoptotic induction.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Owing to the absence of molecular targets, there are limited treatment options, and TNBC patients exhibit high mortality rates. Signal transducer and activator of transcription 3 (STAT3) is overexpressed and aberrantly activated in TNBC cells. Therefore, inhibition of STAT3-mediated signaling provides a potential strategy for the treatment of TNBC. In this study, A series of synthetic derivatives of SLSI-1 (a STAT3 inhibitor) were designed and evaluated for antitumor activity in TNBC cells. A novel derivative (SLSI-1216) exhibited the most potent anti-proliferative activity. SLSI-1216 effectively inhibited STAT3 activity and activation of STAT3, leading to the downregulation of AXL, a downstream target of STAT3 and epithelial-mesenchymal transition (EMT) progression. The inhibition of EMT by SLSI-1216 was associated with modulation of E-cadherin and N-cadherin. Furthermore, SLSI-1216 induced apoptosis by targeting STAT3 and effectively inhibited tumor growth in vivo. These findings suggest that SLSI-1216, as a potential inhibitor of STAT3, may be a promising therapeutic agent for TNBC.