PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.
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.
Arvinas, LLC, New Haven, CT 06511;
Kanak
K
Raina
Arvinas, LLC, New Haven, CT 06511;
Jing
J
Lu
Arvinas, LLC, New Haven, CT 06511;
Yimin
Y
Qian
Arvinas, LLC, New Haven, CT 06511;
Martha
M
Altieri
Arvinas, LLC, New Haven, CT 06511;
Deborah
D
Gordon
Arvinas, LLC, New Haven, CT 06511;
Ann Marie K
AM
Rossi
Arvinas, LLC, New Haven, CT 06511;
Jing
J
Wang
Arvinas, LLC, New Haven, CT 06511;
Xin
X
Chen
Arvinas, LLC, New Haven, CT 06511;
Hanqing
H
Dong
Arvinas, LLC, New Haven, CT 06511;
Kam
K
Siu
Arvinas, LLC, New Haven, CT 06511;
James D
JD
Winkler
Arvinas, LLC, New Haven, CT 06511;
Andrew P
AP
Crew
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; Department of Chemistry, Yale University, New Haven, CT 06520; Department of Pharmacology, Yale University, New Haven, CT 06520.
Craig M
CM
Crews
Arvinas, LLC, New Haven, CT 06511; kevin.coleman@arvinas.com.
Kevin G
KG
Coleman
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human
BET; BRD4; PROTAC; prostate; protein degradation