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.
Subject(s)
Antineoplastic Agents/administration & dosage , Nuclear Proteins/metabolism , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Protein Serine-Threonine Kinases/metabolism , RNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Animals , Cell Cycle Proteins , Cell Line, Tumor , Humans , Male , Mice , Nuclear Proteins/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Protein Serine-Threonine Kinases/genetics , Proteolysis , RNA-Binding Proteins/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Signal Transduction/drug effects , Transcription Factors/geneticsABSTRACT
BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors.
Subject(s)
Azepines/pharmacology , Nuclear Proteins/metabolism , Peptide Hydrolases/metabolism , Signal Transduction/drug effects , Thalidomide/analogs & derivatives , Transcription Factors/metabolism , Acetanilides/toxicity , Adaptor Proteins, Signal Transducing , Apoptosis/drug effects , Azepines/chemistry , Azepines/toxicity , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Heterocyclic Compounds, 3-Ring/toxicity , Humans , Nuclear Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-myc/metabolism , Thalidomide/chemistry , Thalidomide/pharmacology , Transcription Factors/antagonists & inhibitors , Triazoles/toxicity , Ubiquitin-Protein LigasesABSTRACT
A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.
