Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Salami, J; Alabi, S; Willard, RR; Vitale, NJ; Wang, J; Dong, H; Jin, M; McDonnell, DP; Crew, AP; Neklesa, TK; Crews, CM

Published Date

  • 2018

Published In

Volume / Issue

  • 1 /

Start / End Page

  • 100 -

PubMed ID

  • 30271980

Pubmed Central ID

  • 30271980

Electronic International Standard Serial Number (EISSN)

  • 2399-3642

Digital Object Identifier (DOI)

  • 10.1038/s42003-018-0105-8


  • eng

Conference Location

  • England