AI Article Synopsis
- About half of prostate cancer cases involve genomic alterations with the ERG gene, leading to the production of abnormal ERG proteins that promote cancer progression.
- Researchers identified a new class of small molecule antagonists that block the ETSD domain of ERG, disrupting its DNA binding and transcriptional activity.
- One compound, VPC-18005, was shown to reduce aggressive cancer cell behaviors and metastasis in models, suggesting its potential as a new treatment for advanced prostate cancer linked to ERG.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522078 | PMC |
| http://dx.doi.org/10.18632/oncotarget.17124 | DOI Listing |
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