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PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Kanak Raina1, Jing Lu1, Yimin Qian1
1Arvinas, LLC, New Haven, CT 06511;
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 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.
Insights
A novel PROTAC therapy, ARV-771, effectively degrades androgen receptor (AR) signaling and levels in castration-resistant prostate cancer (CRPC). This approach shows significant promise for treating CRPC, a challenging solid-tumor malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Prostate cancer is a leading cause of cancer death in men.
- Castration-resistant prostate cancer (CRPC) progresses despite androgen deprivation therapy.
- Current therapies targeting androgen receptor (AR) signaling face resistance, necessitating new treatments.
Purpose of the Study:
- To evaluate the efficacy of ARV-771, a proteolysis-targeting chimera (PROTAC) small-molecule pan-BET degrader.
- To compare ARV-771's activity against CRPC models with existing BET inhibitors.
- To investigate ARV-771's impact on AR signaling and levels in CRPC.
Main Methods:
- Utilized cellular models of CRPC.
- Employed proteolysis-targeting chimera (PROTAC) technology to develop ARV-771, a pan-BET degrader.
- Tested ARV-771 in a CRPC mouse xenograft model.
Main Results:
- ARV-771 demonstrated superior efficacy in CRPC cellular models compared to BET inhibitors.
- ARV-771 effectively suppressed both AR signaling and AR protein levels.
- ARV-771 induced tumor regression in a CRPC mouse xenograft model.
Conclusions:
- Small-molecule BET degraders, like ARV-771, offer a promising therapeutic strategy for CRPC.
- ARV-771's mechanism involves simultaneous suppression of AR signaling and reduction of AR levels.
- This study highlights the potential of BET degraders as a novel treatment for solid-tumor malignancies, particularly CRPC.
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