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

Mohamed, Ahmed A ; Xavier, Charles P ; Sukumar, Gauthaman ; Tan, Shyh-Han ; Ravindranath, Lakshmi ; Seraj, Nishat ; Kumar, Vineet ; Sreenath, Taduru ; McLeod, David G ; Petrovics, Gyorgy ; Rosner, Inger L ; Srivastava, Meera ; Strovel, Jeffrey ; Malhotra, Sanjay V ; LaRonde, Nicole A ; Dobi, Albert ; Dalgard, Clifton L ; Srivastava, Shiv

Cancer research (Chicago, Ill.), 2018-07, Vol.78 (13), p.3659-3671 [Periódico revisado por pares]

United States: American Association for Cancer Research, Inc

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Título:
Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth
Autor: Mohamed, Ahmed A ; Xavier, Charles P ; Sukumar, Gauthaman ; Tan, Shyh-Han ; Ravindranath, Lakshmi ; Seraj, Nishat ; Kumar, Vineet ; Sreenath, Taduru ; McLeod, David G ; Petrovics, Gyorgy ; Rosner, Inger L ; Srivastava, Meera ; Strovel, Jeffrey ; Malhotra, Sanjay V ; LaRonde, Nicole A ; Dobi, Albert ; Dalgard, Clifton L ; Srivastava, Shiv
Assuntos: Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Azo Compounds - pharmacology ; Azo Compounds - therapeutic use ; Biotechnology ; Cancer therapies ; Cell Line, Tumor ; Endothelial cells ; ERG protein ; Humans ; Kinases ; Male ; Mice ; Mice, Nude ; Molecular chains ; Monoclonal antibodies ; Naphthol ; Oncogene Proteins, Fusion - antagonists & inhibitors ; Oncogene Proteins, Fusion - genetics ; Phenylthiohydantoin - analogs & derivatives ; Phenylthiohydantoin - pharmacology ; Phenylthiohydantoin - therapeutic use ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; RNA, Small Interfering - metabolism ; Small Molecule Libraries ; Toxicity ; Transcriptional Regulator ERG - antagonists & inhibitors ; Transcriptional Regulator ERG - genetics ; Tumor cell lines ; Xenograft Model Antitumor Assays ; Xenografts
É parte de: Cancer research (Chicago, Ill.), 2018-07, Vol.78 (13), p.3659-3671
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SourceType-Scholarly Journals-1
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Descrição: Oncogenic activation of the ETS-related gene ( ) 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 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. , 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. A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. .
Editor: United States: American Association for Cancer Research, Inc
Idioma: Inglês

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

United States: American Association for Cancer Research, Inc

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