PUBLICATION
Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer
- Authors
- Butler, M.S., Roshan-Moniri, M., Hsing, M., Lau, D., Kim, A., Yen, P., Mroczek, M., Nouri, M., Lien, S., Axerio-Cilies, P., Dalal, K., Yau, C., Ghaidi, F., Guo, Y., Yamazaki, T., Lawn, S., Gleave, M.E., Gregory-Evans, C.Y., McIntosh, L.P., Cox, M.E., Rennie, P.S., Cherkasov, A.
- ID
- ZDB-PUB-170504-8
- Date
- 2017
- Source
- Oncotarget 8(26): 42438-42454 (Journal)
- Registered Authors
- Keywords
- ERG, TMPRSS2-ERG, prostate cancer, rational drug design, small molecule inhibitor
- MeSH Terms
-
- Molecular Conformation
- Antineoplastic Agents/chemistry*
- Antineoplastic Agents/pharmacology*
- Animals
- Cell Proliferation/drug effects
- Zebrafish
- ETS Motif*
- Protein Binding
- Humans
- Cell Survival/drug effects
- Cell Survival/genetics
- Models, Molecular
- Oncogene Proteins, Fusion/chemistry
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Transcriptional Regulator ERG/chemistry*
- Transcriptional Regulator ERG/genetics
- Transcriptional Regulator ERG/metabolism*
- Cell Movement/drug effects
- Cell Movement/genetics
- Cell Line, Tumor
- Drug Discovery*/methods
- Protein Interaction Domains and Motifs*
- Structure-Activity Relationship
- Gene Expression Regulation, Neoplastic
- Male
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/metabolism*
- Magnetic Resonance Spectroscopy
- PubMed
- 28465491 Full text @ Oncotarget
Citation
Butler, M.S., Roshan-Moniri, M., Hsing, M., Lau, D., Kim, A., Yen, P., Mroczek, M., Nouri, M., Lien, S., Axerio-Cilies, P., Dalal, K., Yau, C., Ghaidi, F., Guo, Y., Yamazaki, T., Lawn, S., Gleave, M.E., Gregory-Evans, C.Y., McIntosh, L.P., Cox, M.E., Rennie, P.S., Cherkasov, A. (2017) Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer. Oncotarget. 8(26):42438-42454.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping