期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 11, 页码 4402-4412出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm400080c
关键词
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资金
- Alex's Lemonade Stand Foundation
- NIH/NCI [5R21CA133652]
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 mu M for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 mu M in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.
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