Abstract 2797: Synthesis and evaluation of derivatives of selective inhibitor ERGi USU, for ERG-positive prostate cancer cells

作者：Charles P. Xavier, Ahmed A. Mohamed, Nishat Seraj, Vineet Kumar, Taduru Sreenath, Inger L. Rosner, György Petrovics, Meera Srivastava, Clifton L. Dalgard, Sanjay V. Malhotra, Nicole A. LaRonde, Albert Dobi, Shiv Srivastava · 发表于：Cancer Research · 年份：2018 · DOI：10.1158/1538-7445.am2018-2797 · 被引用次数：2 · 研究领域：Glutathione Transferases and Polymorphisms、Prostate Cancer Treatment and Research、Cancer, Hypoxia, and Metabolism

Abstract Introduction and objectives: Prostate cancer is the most frequently diagnosed non-skin malignancy and third leading cause of cancer related deaths among men in the United States. Currently, early detected organ confined prostate cancer (CaP) is managed by active surveillance, surgery or radiation therapy. A significant subset of patients (20% to 40%) experience biochemical recurrence after definitive treatment. New AR axis inhibitors (abiraterone and enzalutamide) are leading to significant improvements in treatment of late stages of CaP. However, sustained therapeutic response remains a challenge due to high mutation load at late stages of the disease. Thus, there is an urgent need for evaluating new therapeutic targets for early stages of CaP. ERG oncoprotein and ERG dependent pathways are promising targets for early stage cancer therapy. Previously identified ERGi-USU from our laboratory, demonstrated remarkable exclusivity for inhibiting ERG protein and cell growth of ERG positive tumor cells in both in vitro and in vivo. With comprehensive structure activity relationship (SAR) studies, we generated new derivatives with substituents around the core structure to further enhance efficacy. Methods: Cell growth inhibition of small molecules was validated with established prostate cancer cell lines and normal prostate/endothelial derived cell panel. Preferential species-specific binding of ERGi-USU to human RIOK2 was confirmed by tryptophan fluorescence quenching assa...