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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.
Affiliation
  • Mohamed AA; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Xavier CP; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Sukumar G; Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland.
  • Tan SH; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Ravindranath L; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Seraj N; Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland.
  • Kumar V; Division of Radiation & Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
  • Sreenath T; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • McLeod DG; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Petrovics G; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Rosner IL; John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Srivastava M; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Strovel J; John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Malhotra SV; Urology Service, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • LaRonde NA; Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland.
  • Dobi A; John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • Dalgard CL; Noble Life Sciences, Gaithersburg, Maryland.
  • Srivastava S; Division of Radiation & Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Cancer Res ; 78(13): 3659-3671, 2018 07 01.
Article in En | MEDLINE | ID: mdl-29712692
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Azo Compounds / Antineoplastic Combined Chemotherapy Protocols / Oncogene Proteins, Fusion Type of study: Diagnostic_studies Limits: Animals / Humans / Male Language: En Journal: Cancer Res Year: 2018 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Azo Compounds / Antineoplastic Combined Chemotherapy Protocols / Oncogene Proteins, Fusion Type of study: Diagnostic_studies Limits: Animals / Humans / Male Language: En Journal: Cancer Res Year: 2018 Document type: Article