Abstract 2797: Synthesis and evaluation of derivatives of selective inhibitor ERGi USU, for ERG-positive prostate cancer cells
Authors: Xavier Charles Peter , Mohamed Ahmed A. , Seraj Nishat , Kumar Vineet , Sreenath Taduru , Rosner Inger L. , Petrovics Gyorgy , Srivastava Meera , Dalgard Clifton L. , Malhotra Sanjay V. , LaRonde Nicole A. , Dobi Albert , Srivastava Shiv 
Published: August 2018

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 assay.
Result: Based on SAR of the parental ERGi-USU, 90 new ERGi-USU derivatives were designed using structure based predictions. Of these, 37 compounds were prioritized for chemical synthesis and biological evaluations using assays that were developed earlier in our laboratory. We completed primary screen of these compounds in cell culture models. Among these one compound (ERGi-USU-6) inhibited the growth of ERG positive prostate cancer cells with remarkable improvement IC50=70 nM. This value is in the range of current FDA approved drugs. The result also confirmed the high selectivity of ERGi-USU-6 for the inhibition of ERG positive cancer cell growth. Further, mechanistic studies revealed ERGi-USU binding and disruption of the atypical RIOK2 kinase basic function of ribosome biogenesis, due to initiation of ribosomal stress, cell cycle arrest and apoptosis in ERG positive VCaP cells. We also demonstarte preferential binding of ERGi-USU to human RIOK2 by tryptophan fluorescence quenching assay.
Conclusion: The ERGi-USU-6, derivative of ERGi-USU showed improved efficacy in selectively inhibiting the growth of ERG positive cancer cells. Since ERG is a prostate cancer causing oncogene that affects approximately one third of CaP patients world-wide, early therapeutic intervention with ERGi-USU derivatives may prevent the development of late stage disease in prostate cancer patients.
Citation Format: Charles Peter Xavier, Ahmed A. Mohamed, Nishat Seraj, Vineet Kumar, Taduru Sreenath, Inger L. Rosner, Gyorgy Petrovics, Meera Srivastava, Clifton L. Dalgard, Sanjay V. Malhotra, Nicole A. LaRonde, Albert Dobi, Shiv Srivastava. Synthesis and evaluation of derivatives of selective inhibitor ERGi USU, for ERG-positive prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2797.