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Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy

Yu, Wenying
http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Pharmacy.
The objective of this dissertation is to design and discover promising homo-dimerization inhibitors on Signal Transducer and Activator of Transcription 3 (STAT3) protein for anticancer therapy. Constitutive activation of STAT3 has been found in nearly every major cancer, including solid tumors, blood tumors and lymphoma, specific cancer types including breast cancers, pancreatic cancers, sarcoma cancers, etc1. It has been validated as an attractive therapeutic target for cancer therapy. To block both STAT3 activation and dimerization, a viable strategy is to design inhibitors competing with the native phosphotyrosine peptide that binds to the STAT3 SH2 domain. The work can be divided into four stages including computational, synthetic, biochemical and biological studies. For the computational study, an improved fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study to discover novel series of STAT3 inhibitors. Multiple Ligand Simultaneous Docking (MLSD) as an alternative method was also used to search for inhibitors which can tightly bind to STAT3 SH2 domain. For the synthetic study, we found the first copper-catalyzed one-pot highly regioselective C-N coupling of substituted naphthoquinones and chemoselective intramolecular ring fusion of sulfonamide synthetic approaches. Facile chemoselective synthetic routes were discovered to obtain diverse ring-opening and reversible ring-fused compounds with great functional group tolerance. Stereochemistry was confirmed by NMRs. For the biochemical study, the binding between 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5) and STAT3 SH2 domain was confirmed by fluorescence polarization assay. The binding between 5,8-dioxo-6-(3-(piperazin-1-yl)phenylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY17) and STAT3 SH2 domain was confirmed by microscale thermophoresis (MST) tests. For the biological assays, four out of the five selected and synthesized compounds from in silico site-directed FBDD method have IC50 values lower than 5 µM for the U2OS cancer cells. LY5 has an IC50 range in 0.5-1.4 µM in various cancer cell lines. Using the MLSD method, LY17 has an IC50 about 1.15 µM and LY13 has an IC50 about 1.49 µM in UW426 cancer cell line. For the in vivo study, LY5 was also found significantly suppressed tumor growth in mice. The results have demonstrated the feasibility of both in silico site-directed FBDD and MLSD approaches for STAT3 drug discovery, which can be applied in other drug targets in general too. LY5 and LY17 were found to be very promising drug candidates and their druggability will be confirmed by further studies.
Chenglong Li (Advisor)
172 p.
Pharmacy Sciences
STAT3; Anti-cancer therapy; In silico site-directed FBDD; MLSD

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Citations

  • Yu, W. (2013). Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058

    APA Style (7th edition)

  • Yu, Wenying. Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058.

    MLA Style (8th edition)

  • Yu, Wenying. "Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058

    Chicago Manual of Style (17th edition)

osu1373328058
1,147
© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.