journal contribution posted on 2023-03-31, 02:00 authored by Ahmed A. Mohamed, Charles P. Xavier, Gauthaman Sukumar, Shyh-Han Tan, Lakshmi Ravindranath, Nishat Seraj, Vineet Kumar, Taduru Sreenath, David G. McLeod, Gyorgy Petrovics, Inger L. Rosner, Meera Srivastava, Jeffrey Strovel, Sanjay V. Malhotra, Nicole A. LaRonde, Albert Dobi, Clifton L. Dalgard, Shiv Srivastava
S1. Comparison and confirmation of ERGi-USU effect on ERG protein, cell growth and gene expression, S2. Antibody based Screening and identification of small molecule inhibitors of the ERG oncoprotein expression, S3. Evaluation of dose-dependent effect of ERGi-USU on ERG transcript with ERG cell panel, S4. Evaluation of the effect of ERGi-USU on cell growth of ERG negative prostate cancer cell lines, S5. ERGi-USU selectively decreases AR protein levels, only in TMPRSS2-ERG harboring VCaP cells.
USU and HJF Office of Technology
P. Murtha Cancer Center
ARTICLE ABSTRACTOncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2–ERG) is one of the most validated and prevalent genomic alterations present in early stages of prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in TMPRSS2–ERG harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-[2-Thiazolylazo]-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature. In vivo, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity–based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.Significance: A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. Cancer Res; 78(13); 3659–71. ©2018 AACR.