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Jonathan Etter Dissertation.pdf (14.5 MB)

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Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents

Etter, Jonathan Parker
http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Pharmacy.
STAT3 is hyperactive in a wide variety of cancers, including leukemias, lymphomas and numerous solid tumors. JAK2 is a critical upstream activator of STAT3, and has itself been implicated in cancer, as well as a number of myeloproliferative disorders. The JAK/STAT signaling pathway is activated in response to numerous hormones and cytokines. IL-6 is one of these cytokines, as it is a primary activator of STAT3 signaling. IL-6 signals through the transmembrane protein, GP130. After activation of the receptor complex, JAKs become phosphorylated and activate several signaling cascades, including the STAT pathway. Once STATs are phosphorylated by JAKs, they dimerize and translocate to the nucleus, where they regulate the transcription of target genes. STAT3 is anti-apoptotic in nature, and its target genes include those corresponding to the proteins Bcl-2 and Bcl-xL, which mediate cell survival, among others. However, other STATs, such as STAT1 and STAT2, are pro-apoptotic in nature. This makes the selective targeting of STAT3 desirable. Unfortunately, there are not currently any selective JAK2 or STAT3 inhibitors on the market, as the structural similarities between JAKs and STATs have made the development of such inhibitors difficult. There are several JAK2-specific inhibitors that are currently in clinical trials, which is promising. However, there has only been one phase 0 clinical trial involving the direct targeting of STAT3. In this document, the development of small molecule inhibitors of JAK2 and STAT3 is reported. Some of the compounds that have been synthesized and evaluated were based on the structures of WP1066 and AG490, which are known to inhibit JAK2. However, the majority of the compounds were directed at STAT3. There are several current strategies for the direct inhibition of STAT3. These involve targeting the N-terminal, DNA binding, or SH2 domains. The STAT3 inhibitors reported herein target the SH2 domain. The majority of them are derivatives of the natural product, curcumin, which has previously been shown to act as an inhibitor of STAT3. Computational modeling has suggested that it is able to bind to JAK2 as well, making it a dual inhibitor. However, it has limited potency and bioavailability, and also has numerous biological targets. These features have limited its therapeutic usefulness. Herein the development of curcumin analogues with drastically improved potency and selectivity for STAT3 is reported. The development of 1,4-naphthoquinones and improved analogues of LLL12 is also reported in this document. LLL12 is a potent STAT3 inhibitor. Its structure was derived from the first reported STAT3 SH2 domain inhibitor, STA-21, which was identified through virtual screening. The structural similarities to LLL12 of known 1,4-naphthoquinones, such as plumbagin and juglone, led to the development of additional 1,4-naphthoquinones as well, which were evaluated for their abilities to inhibit STAT3.
James Fuchs (Advisor)
Karl Werbovetz (Committee Member)
Chenglong Li (Committee Member)
470 p.
Biochemistry; Biology; Organic Chemistry; Pharmacy Sciences
STAT3; curcumin; LLL12; FLLL32; JAK2; medicinal chemistry

Recommended Citations

Citations

  • Etter, J. P. (2013). Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461

    APA Style (7th edition)

  • Etter, Jonathan. Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461.

    MLA Style (8th edition)

  • Etter, Jonathan. "Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.