Protein?protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. Biologics based therapeutics, such as antibodies, exemplify success in PPI regulation. However, antibodies can only be applied to protein targets on cell surface due to their impermeability to plasma membranes. Although small molecule drugs can readily cross membranes, applying small molecule inhibitors (SMIs) to disrupt PPIs is a challenging task because approximately 750?1,500 2 of protein surface area is involved at the interface of PPIs, which is too large for SMIs to cover. In addition, these interacting protein surfaces do not have pocket-like small molecule binding sites. Therefore, these PPI sites are deemed as ?undruggable? targets for SMIs. The Holy Grail of drug development is to render small molecules the power of biologics to regulate PPIs. We recently developed a cell-based functional assay for high throughput screening (HTS) to identify SMIs for steroid receptor coactivator-3 (SRC-3), a large and mostly non- structured nuclear protein. Without any SRC-3 structural information, we identified and improved a series of SMIs that can target SRC-3?the 1st generation SMI gossypol, the 2nd generation SMI bufalin, and the 3rd generation SMI SI-2, a highly promising drug candidate. In our recent report (PNAS 2016), we demonstrated that SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nM range (3-20 nM) while not affecting normal cell viability. Furthermore, the in vivo study demonstrated that SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. Despite of the encouraging antitumor activities of SI-2, it has a relatively short plasma half-life (1 h). In the preliminary study, we have identified SI-12 that has similar biological activities to SI-2 but a much improved plasma half-life (6 h).
In Aim 1, we will further optimize SI-2 SRC-3 SMI `unique' derivatives with improved drug- like properties.
In Aims 2 and 3, we will take advantage of the novel SRC-3 SMI to address the two major challenges for current breast cancer treatment?resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer and tumor metastasis in triple negative breast cancer (TNBC). Successful completion of this project will not only significantly improve breast cancer treatment through the development of a `first-in-class' drug that targets oncogenic coactivators, but also encourage other researchers to develop strategies to target protein-protein interactions that are designated as `important but undruggable' targets in the future.

Public Health Relevance

Breast cancer is the most frequently diagnosed and second most lethal cancer among women in the United States. Drug resistance and tumor metastasis are the major challenges to current breast cancer treatment. In this proposal, we will develop a targeted therapy to reverse drug resistance and reduce metastasis in breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fu, Yali
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Baylor College of Medicine
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Spiciarich, David R; Oh, Stephen T; Foley, Amy et al. (2018) A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia. Cancer Res 78:6762-6770
Li, Yujing; Liu, Yunhua; Xu, Hanchen et al. (2018) Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nat Commun 9:4394
Jiang, Xiqian; Wang, Lingfei; Carroll, Shaina L et al. (2018) Challenges and Opportunities for Small-Molecule Fluorescent Probes in Redox Biology Applications. Antioxid Redox Signal 29:518-540
Rothmiller, Simone; Schröder, Sarah; Strobelt, Romano et al. (2018) Sulfur mustard resistant keratinocytes obtained elevated glutathione levels and other changes in the antioxidative defense mechanism. Toxicol Lett 293:51-61
Gates, Leah A; Gu, Guowei; Chen, Yue et al. (2018) Proteomic profiling identifies key coactivators utilized by mutant ER? proteins as potential new therapeutic targets. Oncogene 37:4581-4598
Jiang, Xiqian; Zhang, Chengwei; Chen, Jianwei et al. (2018) Quantitative Real-Time Imaging of Glutathione with Sub-Cellular Resolution. Antioxid Redox Signal :
Rohira, Aarti D; Yan, Fei; Wang, Lei et al. (2017) Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells. Cancer Res 77:4293-4304
Han, Bing; Sivaramakrishnan, Priya; Lin, Chih-Chun J et al. (2017) Microbial Genetic Composition Tunes Host Longevity. Cell 169:1249-1262.e13
Chen, Jianwei; Jiang, Xiqian; Zhang, Chengwei et al. (2017) Reversible Reaction-Based Fluorescent Probe for Real-Time Imaging of Glutathione Dynamics in Mitochondria. ACS Sens 2:1257-1261
Jiang, Xiqian; Chen, Jianwei; Baji?, Aleksandar et al. (2017) Quantitative real-time imaging of glutathione. Nat Commun 8:16087

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