PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
| Autor: | Kam W. Siu, Kanak Raina, Craig M. Crews, Ann Marie Rossi, James D. Winkler, Kevin Coleman, Martha Altieri, Hanqing Dong, Andrew P. Crew, Xin Chen, Deborah M. Gordon, Jing Wang, Jing Lu, Yimin Qian |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine BRD4 medicine.drug_class Antineoplastic Agents Cell Cycle Proteins Protein Serine-Threonine Kinases Protein degradation urologic and male genital diseases Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine Prostate Cell Line Tumor medicine Animals Humans Multidisciplinary business.industry Proteolysis targeting chimera Nuclear Proteins RNA-Binding Proteins Biological Sciences medicine.disease Androgen Bromodomain Androgen receptor Prostatic Neoplasms Castration-Resistant 030104 developmental biology medicine.anatomical_structure Receptors Androgen 030220 oncology & carcinogenesis Proteolysis Immunology Cancer research business Signal Transduction Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:7124-7129 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1521738113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|