期刊
ONCOTARGET
卷 8, 期 26, 页码 42438-42454出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17124
关键词
prostate cancer; ERG; rational drug design; small molecule inhibitor; TMPRSS2-ERG
资金
- Terry Fox New Frontiers Program Project Grant [TFF116129]
- Centres of Excellence for Commercialization and Research (CECR)
- NIH Pacific Northwest Prostate Cancer SPORE [P50 CA097186]
- Prostate Cancer Foundation of British Columbia Grant-in-Aid Award
- Canadian Institute of Health Research (CIHR) [MOP-136834]
- Prostate Cancer Canada Postdoctoral Fellowship [PDF2015-01]
- CIHR Banting and Best Doctoral Fellowship [347940]
- Roman M Babicki Doctoral Award
- US Department of Defense CDMRP Postdoctoral Training Award [W81XWH-14-1-0153]
- CIHR
- Canada Foundation for Innovation (CFI)
- British Columbia Knowledge Development Fund (BCKDF)
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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