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

  • Cancer Res. 2018 Jul 1;78(13):3659-3671. doi: 10.1158/0008-5472.CAN-17-2949.
Ahmed A Mohamed   #  1 ,  Charles P Xavier   #  1 ,  Gauthaman Sukumar  2 ,  Shyh-Han Tan  1 ,  Lakshmi Ravindranath  1 ,  Nishat Seraj  3 ,  Vineet Kumar  4 ,  Taduru Sreenath  1 ,  David G McLeod  1 ,  Gyorgy Petrovics  1  5 ,  Inger L Rosner  1  5  6 ,  Meera Srivastava  2  5 ,  Jeffrey Strovel  7 ,  Sanjay V Malhotra  4 ,  Nicole A LaRonde  3 ,  Albert Dobi  1  5 ,  Clifton L Dalgard  8  5 ,  Shiv Srivastava  9  5
Affiliations
  • 1. 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.
  • 2. Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland.
  • 3. Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland.
  • 4. Division of Radiation & Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
  • 5. John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • 6. Urology Service, Walter Reed National Military Medical Center, Bethesda, Maryland.
  • 7. Noble Life Sciences, Gaithersburg, Maryland.
  • 8. Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland. [email protected] [email protected].
  • 9. 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. [email protected] [email protected].
  • # Contributed equally.
PMID: 29712692 DOI: 10.1158/0008-5472.CAN-17-2949
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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