2. Academic Validation
  3. Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth

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

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. ssrivastava@cpdr.org clifton.dalgard@usuhs.edu.
  • 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. ssrivastava@cpdr.org clifton.dalgard@usuhs.edu.
  • # 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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