Browsing by Subject "survivin"

Now showing 1 - 4 of 4
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    Effective targeting of the survivin dimerization interface with small molecule inhibitors
    (AACR, 2016-01) Qi, Jing; Dong, Zizheng; Liu, Jianguo; Peery, Robert C.; Zhang, Shaobo; Liu, Jingyuan; Zhang, Jian-Ting; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable.
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    Optimization of Survivin Dimerization Inhibitors for the Treatment of Docetaxel-Resistant Prostate Cancer
    (2020-01) Peery, Robert Craig; Jerde, Travis; Zhang, Jian-Ting; Pili, Roberto; Safa, Ahmad; Sullivan, William J., Jr.
    Despite therapeutic advancements, prostate cancer remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with metastatic prostate cancer. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. Survivin has a classical biological role in cancer, in fact survivin has been shown to be overexpressed in almost every solid tumor and is associated with drug resistance and clinically aggressive disease. In these studies I demonstrate that docetaxel resistant cells have overexpression of survivin compared to sensitive parental cells, knockdown of survivin decreases docetaxel resistance, and stable overexpression of survivin increases resistance to docetaxel. The data in these studies suggest that survivin is likely implicated in docetaxel resistance and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. To this end the evaluation and optimization of two different backbones of survivin inhibitors was performed. One such inhibitor identified is LQZ-7-3 which decreases survivin level via proteasome degradation, leads to apoptosis of cells, and showed efficacy in a prostate cancer xenograft model in vivo when given in an oral formulation. LQZ- 7-3 showed strong specificity to survivin versus other IAP family members at the protein level. Another inhibitor, LQZ-7F-1, demonstrated nanomolar inhibition of cancer cell growth and similar effects on survivin. Both compounds synergized with docetaxel in vitro warranting future in vivo efficacy studies as a combinatorial therapy. Overall, our findings indicate survivin is a significant contributor to docetaxel resistance in metastatic prostate cancer at the molecular level and survivin inhibitors may prove efficacious as a new therapy to sensitize cancer cells to chemotherapies.
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    Synthesis and Identification of a Novel Lead Targeting Survivin Dimerization for Proteasome-Dependent Degradation
    (ACS, 2020-05) Peery, Robert; Kyei-Baffour, Kwaku; Dong, Zizheng; de Andrade Horn, Pedro; Dai, Mingji; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine
    Survivin, a homodimeric member of the Inhibitor of Apoptosis Protein (IAP) family, is required for cancer cell survival and overexpressed in almost all solid tumors. However, targeting survivin has been challenging due to its “undruggable” nature. Recently, we used a novel approach to target the dimerization interface and identified inhibitors of two scaffolds that can directly bind to and inhibit survivin dimerization. One of the scaffolds, represented by the compound LQZ-7, contains an undesirable labile hydrazone linker and a potentially nonfunctional furazanopyrazine ring that we attempted to eliminate in this study. We found one compound, 7I, that is more active than the parent compound, LQZ-7, and when given orally effectively inhibits xenograft tumor growth and induces survivin loss in tumors. These findings indicate that 7I with a stable linker and a quinoxaline ring can be used as a lead for further optimization of this novel class of survivin inhibitors.
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    Targeting survivin for therapeutic discovery: past, present, and future promises
    (Elsevier, 2017-10) Peery, Robert C.; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine
    Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery.