Anti-tumor Activity of Novel STAT3 Inhibitors on Retinoblastoma.

Signal transducer and activator of transcription 3 (STAT3) is a therapeutic target in the treatment of retinoblastoma, the most common intraocular malignant tumor in children. STAT3, a transcription factor for several genes related to tumorigenesis, is activated in retinoblastoma tumors as well as other cancers. In this study, we investigated the structure-activity relationship of a library of STAT3 inhibitors including a novel series of derivatives of the previously reported compound with a Michael acceptor (compound 1). We chose two novel STAT3 inhibitors, compounds 11 and 15, from the library based on their inhibitory effects on the phosphorylation and transcription activity of STAT3. These STAT3 inhibitors effectively suppressed the phosphorylation of STAT3 and inhibited the expression of STAT3-related genes, CCND1, CDKN1A, BCL2, BCL2L1, BIRC5, MYC, MMP1, MMP9, and VEGFA Intraocularly administered STAT3 inhibitors decreased the degree of tumor formation in the vitreous cavity of Balb/c nude mice of an orthotopic transplantation model. It is noteworthy that compounds 11 and 15 did not induce in vitro and in vivo toxicity on retinal constituent cells and retinal tissues, respectively, despite their potent anti-tumor effects. We suggest that these novel STAT3 inhibitors be utilized in the treatment of retinoblastoma. Significance Statement In the current study, we suggest the novel STAT3 inhibitors with Michael acceptors possess anti-tumor activity on retinoblastoma, the most common intraocular cancer in children. Based on a detailed structure-activity relationship studies, we found a 4-fluoro and 3-trifluoro analog (compound 11) and a mono-chloro analog (compound 15) of the parental compound (compound 1) inhibited STAT3 phosphorylation, leading to suppress retinoblastoma in vitro and in vivo.