Targeted delivery of histone deacetylase inhibitors for use in cancer therapy

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Fathi, Shaghayegh
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Cancer is one of the leading causes of death around the world, with lung, breast and prostate cancer being the most common cancers. Most of current cancer treatments are associated with various side effects such as depression, fatigue, hair loss, nausea, infection, fertility problems, anemia, and myelosuppression. Therefore, there is an unmet need to develop new and more potent anticancer therapeutic agents with less off-target toxicities. This thesis documents efforts at the design and synthesis of different classes of HDAC inhibitors (HDACi) as promising therapeutic agents in cancer therapy. These HDACi are anticpated to accumulate at the site of tumor due to selective tissue/cell distribution conferred on them by ligands, known to accumulate in certain tissues or target receptors that are overexpressed on tumor cells, incorporated into their the cap group. FDA approved macrolide, azithromycin, is known to accumulate in macrophage cells. Macrophage cells are known to have a high concentration in lung, hence, azithromycin has the potential to target and acuumulate in lung tissue. An unpublished in vivo data in our lab, showed that azithromycin maintains its lung accumulation after being modified and attached to HDACi moiety. Thus, we hypothesized conjugating the HDACi to azithromycin can lead to their delivery to lung tissues. To this end, in the second chapter, we designed and synthesized three different classes of azithromycin conjugated hydroxamic acid derived HDACi and evaluated their HDAC inhibitory potency and anti-proliferative activity in lung (A549) and breast (MCF-7) cancer cell lines. It is believed that isoform selective HDACi may be endowed with less off-target toxicities and better therapeutic outcome and efficacy compared to pan HDACi which have no selectivity toward different HDAC isoforms. To evaluate this hypothesis, in the third chapter, we designed and synthesized isoform selective azithromycin conjugated HDACi, by replacing the hydroxamic acid zinc binding group with the N-(2-amino-5-(thiophen-2-yl)phenyl)acylamide zinc binding group which is a HDAC1 and HDAC2 selective. Additionally to determine these compounds ability to target lung tissue and protect it from metastasis, we tested the lead compound in a model of lung metastasis of breast cancer using spontaneous mouse mammary tumor model MMTV-PyMT-Tg. The in vivo study results showed that there was a greater tumor regression in mice that were treated with N-(2-amino-5-(thiophen-2-yl)phenyl)acylamide derived HDACi compared to hydroxamic acid derived HDACi. Additionally this class of HDACi was able to protect the lung tissue from metastasis better than its hydroxamic acid analogue. The fourth chapter focuses on continuation of prior SAR study on design multiple ligand compounds with selective estrogen receptor modular (SERM) and HDACi activities. In this study tamoxifen, an estrogen receptor (ER) antagonist, with a high binding affinity for ER, was used as the HDACi cap group. These antiestrogen equipped HDACi are expected to be better uptaken by ER positive breast cancer cells possibly due to tamoxifen affinity for binding to ER. This selective uptake is anticipated to eventually lead to an improved antiproliferative activity. MTT assay results confirmed the hypothesis. Hydroxamic acid derived HDACi showed about 4 fold more cytotoxicity toward ERα positive breast cancer cells compared to ERα negative breast cancer cells. Two of these SERM HDACi conjugates are currently being studied in animal models. The fifth chapter illustrates bifunctional STAT3/HDAC inhibitors for treating STAT3 activated cancers, such as acute myeloid leukemia. In this study, pyrimethamine, a selective STAT3 inhibitor was used as the HDACi cap group. We hypothesized that design multiple ligand compounds comprising STAT3 inhibitor and HADCi will integrate direct STAT3 and HDAC inhibition, and downregulation of Mcl-1 within a single molecular template. These bifunctional compounds can be potential inhibitors of proliferation of CLL, DLBCL and probably other tumors that are dependent on STAT3 signaling pathway.
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