PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Abstract

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 extraterminal (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.BET | BRD4 | protein degradation | prostate | PROTAC

Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

“…One promising strategy undergoing clinical evaluation in CRPC is targeting BET family proteins (ClinicalTrials.gov identifier: NCT02711956, NCT03150056). Several BETi, and PROTAC induced BET protein degraders, have shown promising efficacy in preclinical models of CRPC, regulating AR signaling and AR-V7 expression (29,30,(33)(34)(35)(36). Although the mechanism by which BET inhibition regulates AR signaling is well described, the ability to regulate expression of AR-V7…”

“…Furthermore, increased BRD4 protein stability in substrate-binding adaptor speckle-type POZ protein (SPOP) mutant prostate cancers is associated with AR signaling (31,32). BET inhibitors (BETi) and proteolysis targeting chimera (PROTAC) induced BET protein degraders have anti-tumor activity in CRPC models (29,30,(33)(34)(35)(36), attenuating AR signaling and potently reducing C-MYC expression (29,30,33,34,36). More recently, BETi have been shown to decrease AR-V7 expression by regulating splicing factors required for its generation (30).…”

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

“…Cofactor inhibitors would have the hypothesized advantage that as they are "downstream" of AR, resistance cannot easily be brought about by upregulation of AR or its ligand, making the case for cofactor inhibitor use up-front in combination with traditional antiandrogens to enhance efficacy and block potential resistance mechanisms. Advances in technologies to interrogate chromatin have resulted in the identification of a number of essential AR coactivators and their proposal as potential drug targets (30,(42)(43)(44)(45). Historically, such cofactors and epigenetic regulators have proved notoriously difficult targets for the design of small-molecule inhibitors, hindering progress in this area.…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…Disruption of this interaction with a small-molecule inhibitor of BRD4, JQ1, blocked AR chromatin association, transcriptional activity and AR-mediated PCa growth (Asangani et al 2014). More recently, a pan-BET degrader (based on PROTAC technology) was shown to have potent anti-CRPC activity (Raina et al 2016). Importantly, we and others have shown that BET inhibition has a dual mechanism of action, suppressing not only AR transcriptional activity but also AR gene transcription (Chan et al 2015, Raina et al 2016.…”

“…More recently, a pan-BET degrader (based on PROTAC technology) was shown to have potent anti-CRPC activity (Raina et al 2016). Importantly, we and others have shown that BET inhibition has a dual mechanism of action, suppressing not only AR transcriptional activity but also AR gene transcription (Chan et al 2015, Raina et al 2016. This finding, combined with the mapping of the BRD4 interaction surface to the AR-NTD, suggests that BET inhibitors would have activity in CRPC driven by AR-LBD mutants and/or AR-Vs, a prediction that has been experimentally substantiated (Chan et al 2015, Asangani et al 2016, Raina et al 2016.…”