LL1, a novel and highly selective STAT3 inhibitor, displays anti‐colorectal cancer activities in v itro and in vivo
| Autor: | Wenying Yu, Lingnan Guan, Zhe Liu, Maode Lai, Chong Lai, Huan Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
STAT3 Transcription Factor 0301 basic medicine Protein Conformation Mice Nude Antineoplastic Agents Metastasis Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Cell Movement In vivo medicine Animals Humans Neoplasm Invasiveness MTT assay Neoplasm Metastasis Phosphorylation STAT3 Cell Proliferation Pharmacology Mice Inbred ICR Binding Sites biology Chemistry HCT116 Cells medicine.disease Xenograft Model Antitumor Assays Research Papers In vitro Tumor Burden Molecular Docking Simulation 030104 developmental biology Mechanism of action Cell culture Drug Design STAT protein Cancer research biology.protein Caco-2 Cells medicine.symptom Colorectal Neoplasms HT29 Cells 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 0007-1188 |
| Popis: | Background and purpose Signal transducer and activator of transcription 3 (STAT3) factor is associated with the development and progression of numerous types of human cancer. STAT3 activation is involved in metastasis. However, no STAT3 inhibitor has been used therapeutically. Hence, we syntheised a novel, potent and small-molecule inhibitor of STAT3, LL1, and studied its antitumour effects and investigated its mechanism of action in two tumour models. Experimental approach 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 assay, histological, immunohistochemical, flow cytometric analysis, and tumour xenograft model. Key results LL1 is highly selective among STATs family members and specifically inhibits phosphorylation of STAT3 Tyr-705 site, blocking the whole transmission process of STAT3 signalling. LL1 inhibited proliferation, colony formation, migration, and invasion of colonic cell lines. STAT3 is orally available to animals and suppresses tumour growth and metastasis in a dosage level compatible to clinical applications. Importantly, it does not cause significant toxicity at several times the effective dose. Conclusions and implications LL1 inhibits tumour growth and metastasis by blocking STAT3 signalling pathway. LL1 could be a promising therapeutic drug candidate for colorectal cancer by inhibiting the STAT3 activation. |
| Databáze: | OpenAIRE |
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