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Computational Design, Synthesis and Evaluation of Novel Specific IL-6/gp130 Inhibitors as Potential Anticancer Agents

Mao, Liguang
http://rave.ohiolink.edu/etdc/view?acc_num=osu1512060214967449

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
The objective of this dissertation is to design and discover novel small molecule IL-6/gp130 inhibitors targeting gp130 D1 domain for anticancer therapy. The IL-6/gp130/STAT3 signaling pathway has been found to be protumorigenic in many cancers. IL-6 first binds to IL-6Ra, which recruits gp130 on the cell membrane; then dimerization of two of the IL-6/IL-6Ra/gp130 trimers allows signal transduction via gp130 cytoplasmic domains, which activates JAKs then STAT3 (Tyr705 phosphorylation), leading to STAT3 nuclear translocation, DNA binding, and transcription of multiple oncogenes. The D1 domain of gp130 is a unique binding site for IL-6/gp130 signaling compared to the other IL-6 family cytokines. Various computational tools were applied to design potent and specific IL-6/gp130 inhibitors by targeting the gp130 D1 domain, and these inhibitors were synthesized and tested. Chapter 1 and 2 mainly cover the background of IL-6 signaling, its important role in cancer, the structure of the signaling complex assembly and some potential small IL-6/gp130 inhibitors that are related to this research. Chapter 2 describes our effort in finding novel IL-6/gp130 inhibitors via computational fragment-based drug design (FDBB) and multiple ligand simultaneous docking (MLSD). Five novel compounds were selected for synthesis and LLM4 was identified as the best compound, with an IC50 value of 17.0 µM against breast cancer cell line SUM159 and high specificity in inhibiting the IL-6 signaling pathway. Chapter 4 describes our further efforts in finding more potent IL-6/gp130 inhibitors by using molecular hybridization strategy. Ten novel inhibitors were selected for synthesis and three of them showed good cancer cell inhibition. As an example, LLM418 showed nearly ten fold increase in potency compared to its parent compound LLM4. LLM418 was also found to show high specificity in inhibiting IL-6 signaling while having little effect on other cytokines. Overall, the computational drug design strategies used in this research such as computational FDBB together with MLSD and molecular hybridization can be applied to other drug targets in general, especially in targeting protein-protein interactions. The novel small molecule IL-6/gp130 inhibitors discovered in this research can be used either as probes to study the IL-6 signaling pathway or can serve as drug candidates for further testing and modification.
Karl Werbovetz (Advisor)
Chenglong Li (Committee Member)
James Fuchs (Committee Member)
159 p.
Pharmacy Sciences

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Citations

  • Mao, L. (2017). Computational Design, Synthesis and Evaluation of Novel Specific IL-6/gp130 Inhibitors as Potential Anticancer Agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1512060214967449

    APA Style (7th edition)

  • Mao, Liguang. Computational Design, Synthesis and Evaluation of Novel Specific IL-6/gp130 Inhibitors as Potential Anticancer Agents. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1512060214967449.

    MLA Style (8th edition)

  • Mao, Liguang. "Computational Design, Synthesis and Evaluation of Novel Specific IL-6/gp130 Inhibitors as Potential Anticancer Agents." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1512060214967449

    Chicago Manual of Style (17th edition)

osu1512060214967449
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.