Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth

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

doi:10.1158/0008-5472.CAN-17-2949

Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth

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

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of themost 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.

Original language	English (US)
Pages (from-to)	3659-3671
Number of pages	13
Journal	Cancer Research
Volume	78
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-2949
State	Published - Jul 1 2018
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-17-2949

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Mohamed, A. A., Xavier, C. P., Sukumar, G., Tan, S. H., Ravindranath, L., Seraj, N., Kumar, V., Sreenath, T., McLeod, D. G., Petrovics, G., Rosner, I. L., Srivastava, M., Strovel, J., Malhotra, S. V., LaRonde, N. A., Dobi, A., Dalgard, C. L., & Srivastava, S. (2018). Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth. Cancer Research, 78(13), 3659-3671. https://doi.org/10.1158/0008-5472.CAN-17-2949

Mohamed, AA, Xavier, CP, Sukumar, G, Tan, SH, Ravindranath, L, Seraj, N, Kumar, V, Sreenath, T, McLeod, DG, Petrovics, G, Rosner, IL, Srivastava, M, Strovel, J, Malhotra, SV, LaRonde, NA, Dobi, A, Dalgard, CL & Srivastava, S 2018, 'Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth', Cancer Research, vol. 78, no. 13, pp. 3659-3671. https://doi.org/10.1158/0008-5472.CAN-17-2949

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title = "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 themost 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.",

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

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doi = "10.1158/0008-5472.CAN-17-2949",

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T1 - Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth

AU - Mohamed, Ahmed A.

AU - Xavier, Charles P.

AU - Sukumar, Gauthaman

AU - Tan, Shyh Han

AU - Ravindranath, Lakshmi

AU - Seraj, Nishat

AU - Kumar, Vineet

AU - Sreenath, Taduru

AU - McLeod, David G.

AU - Petrovics, Gyorgy

AU - Rosner, Inger L.

AU - Srivastava, Meera

AU - Strovel, Jeffrey

AU - Malhotra, Sanjay V.

AU - LaRonde, Nicole A.

AU - Dobi, Albert

AU - Dalgard, Clifton L.

AU - Srivastava, Shiv

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of themost 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.

AB - Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of themost 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.

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Identification of a small molecule that selectively inhibits ERG-positive cancer cell growth

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