Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth.

Abstract

Oncogenic 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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 13 Pg. 3659-3671 (07 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29712692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Azo Compounds
• Benzamides
• ERG protein, human
• Nitriles
• Oncogene Proteins, Fusion
• RNA, Small Interfering
• Small Molecule Libraries
• TMPRSS2-ERG fusion protein, human
• Transcriptional Regulator ERG
• 1-(2-thiazolylazo)-2-naphthol
• Phenylthiohydantoin
• enzalutamide
• Protein Serine-Threonine Kinases
• RIOK2 protein, human

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Azo Compounds (pharmacology, therapeutic use)
• Benzamides
• Cell Line, Tumor
• Humans
• Male
• Mice
• Mice, Nude
• Nitriles
• Oncogene Proteins, Fusion (antagonists & inhibitors, genetics)
• Phenylthiohydantoin (analogs & derivatives, pharmacology, therapeutic use)
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Small Molecule Libraries
• Transcriptional Regulator ERG (antagonists & inhibitors, genetics)
• Xenograft Model Antitumor Assays