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Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance
- Source :
- Communications Biology, Vol 1, Iss 1, Pp 1-9 (2018)
- Publication Year :
- 2018
-
Abstract
- The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide.
- Subjects :
- 0301 basic medicine
medicine.drug_class
Medicine (miscellaneous)
Drug resistance
Protein degradation
urologic and male genital diseases
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Prostate cancer
chemistry.chemical_compound
0302 clinical medicine
Prostate
medicine
Enzalutamide
lcsh:QH301-705.5
business.industry
Proteolysis targeting chimera
fungi
Androgen
medicine.disease
Androgen receptor
030104 developmental biology
medicine.anatomical_structure
chemistry
lcsh:Biology (General)
030220 oncology & carcinogenesis
Cancer research
General Agricultural and Biological Sciences
business
Subjects
Details
- ISSN :
- 23993642
- Volume :
- 1
- Database :
- OpenAIRE
- Journal :
- Communications biology
- Accession number :
- edsair.doi.dedup.....51046816fbe40eda42878432d778b9de