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Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer
- Source :
- Oncotarget
- Publication Year :
- 2017
- Publisher :
- Impact Journals, LLC, 2017.
-
Abstract
- // Miriam S. Butler 1, *, # , Mani Roshan-Moniri 1, *, # , Michael Hsing 1, *, # , Desmond Lau 2, *, # , Ari Kim 1 , Paul Yen 1 , Marta Mroczek 1 , Mannan Nouri 1 , Scott Lien 1 , Peter Axerio-Cilies 1 , Kush Dalal 1 , Clement Yau 1 , Fariba Ghaidi 1 , Yubin Guo 1 , Takeshi Yamazaki 1 , Sam Lawn 1 , Martin E. Gleave 1 , Cheryl Y. Gregory-Evans 3 , Lawrence P. McIntosh 2, * , Michael E. Cox 1, * , Paul S. Rennie 1, * and Artem Cherkasov 1, * 1 Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada 2 Department of Biochemistry and Molecular Biology, Department of Chemistry, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada 3 Department 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: mcox@prostatecentre.com Artem Cherkasov, email: acherkasov@prostatecentre.com Keywords: prostate cancer, ERG, rational drug design, small molecule inhibitor, TMPRSS2-ERG Received: July 29, 2016 Accepted: April 04, 2017 Published: April 15, 2017 ABSTRACT 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.
- Subjects :
- Male
Models, Molecular
0301 basic medicine
Gerontology
Magnetic Resonance Spectroscopy
genetic structures
Oncogene Proteins, Fusion
TMPRSS2-ERG
Molecular Conformation
Metastasis
chemistry.chemical_compound
Prostate cancer
Cell Movement
Prostate
Drug Discovery
Zebrafish
small molecule inhibitor
prostate cancer
Small molecule
3. Good health
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Oncology
ERG
rational drug design
Erg
Protein Binding
Research Paper
Cell Survival
Antineoplastic Agents
Eye care
Structure-Activity Relationship
03 medical and health sciences
Transcriptional Regulator ERG
Cell Line, Tumor
medicine
Animals
Humans
Protein Interaction Domains and Motifs
Cell Proliferation
Transcriptional activity
business.industry
Prostatic Neoplasms
medicine.disease
eye diseases
030104 developmental biology
ETS Motif
chemistry
Cancer research
sense organs
business
DNA
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....16c1afad7acff7c115719c3c6e99761b