Research Papers:

Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

Miriam S. Butler, Mani Roshan-Moniri, Michael Hsing, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin E. Gleave, Cheryl Y. Gregory-Evans, Lawrence P. McIntosh, Michael E. Cox, Paul S. Rennie and Artem Cherkasov _

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Oncotarget. 2017; 8:42438-42454. https://doi.org/10.18632/oncotarget.17124

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Miriam S. Butler1,*,#, Mani Roshan-Moniri1,*,#, Michael Hsing1,*,#, Desmond Lau2,*,#, Ari Kim1, Paul Yen1, Marta Mroczek1, Mannan Nouri1, Scott Lien1, Peter Axerio-Cilies1, Kush Dalal1, Clement Yau1, Fariba Ghaidi1, Yubin Guo1, Takeshi Yamazaki1, Sam Lawn1, Martin E. Gleave1, Cheryl Y. Gregory-Evans3, Lawrence P. McIntosh2,*, Michael E. Cox1,*, Paul S. Rennie1,* and Artem Cherkasov1,*

1Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada

2Department of Biochemistry and Molecular Biology, Department of Chemistry, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada

3Department of Ophthalmology and Visual Sciences, Eye Care Centre, University of British Columbia, Vancouver, BC V5Z 3N9, Canada

*These authors contributed equally to this work

#Co-first authors

Correspondence to:

Michael E. Cox, email: [email protected]

Artem Cherkasov, email: [email protected]

Keywords: prostate cancer, ERG, rational drug design, small molecule inhibitor, TMPRSS2-ERG

Received: July 29, 2016     Accepted: April 04, 2017     Published: April 15, 2017


Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG-ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer.

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