LL1, a novel specific STAT3 inhibitor, displays anti-colorectal cancer activities in vitro and in vivo
School of Basic Medical Sciences and Clinical Pharmacy,China Pharmaceutical UniversityState Key Laboratory of Natural Medicines, China Pharmaceutical UniversityDepartment of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University
摘要：OBJECTIVE The signal transducer and activator of transcription 3（STAT3） is associated with the development and progression of numerous types of human cancer, and STAT3 activation confers metastasis to cancer.However, no STAT3 inhibitor was used clinically. Hence,we discovered a novel potent small-molecule inhibitor of STAT3, LL1, and studied its antitumor effects and the underlying mechanisms in two tumor models. METHODS Using structure-based drug design method, based on the crystal structure of STAT3 protein, we identified a potent STAT3 inhibitor（LL1） targeting STAT3 SH2 domain and characterized its therapeutic properties and potential toxicity in vitro and in vivo using the MTT assay, colony formation assays, histological, immunohistochemical,flow cytometric analysis, tumor xenograft model. RESULTS LL1 is highly selective among STATs family members and specifical y inhibits phosphorylation of STAT3 Tyr-705 site, blocking the whole transmission process of STAT3 signaling. Mechanistical y, LL1 inhibited proliferation, colony formation, migration and invasion of colonic cell lines.STAT3 is orally available to animals and suppresses tumor growth and metastasis in a dosage form compatible to clinical applications. Importantly, it doesn′t cause significant toxicity at several times of an effective dose. CONCLUSION LL1 inhibits tumor growth and metastasis by blocking STAT3 signaling pathway. LL1 could be a promising therapeutic drug candidate for colorectal cancer by inhibiting the STAT3 activation.