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|Ref Type||Journal Article|
|Authors||Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, Wang J, Chen X, Dong H, Siu K, Winkler JD, Crew AP, Crews CM, Coleman KG|
|Title||PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date||2016 06 28|
|Abstract Text||Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ARV-771||ARV 771|ARV771||ARV-771 is a bifunctional molecule that targets BET proteins for proteolytic degradation, resulting in reduced target gene expression and potentially leading to increased apoptosis and reduced tumor growth (PMID: 31217338, PMID: 27274052).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||prostate cancer||not applicable||ARV-771||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ARV-771 treatment induced apoptosis and inhibited proliferation of prostate cancer cell lines in culture, and inhibited tumor growth and induced regression in a cell line xenograft model (PMID: 27274052).||27274052|
|Unknown unknown||prostate cancer||not applicable||Birabresib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Birabresib (OTX015) treatment inhibited tumor growth in a cell line xenograft model of prostate cancer (PMID: 27274052).||27274052|