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Commun Biol. 2018 Aug 2;1:100. doi: 10.1038/s42003-018-0105-8. eCollection 2018.

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

Author information

1
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, 06511 CT USA.
2
2Department of Pharmacology, Yale School of Medicine, New Haven, 06510 CT USA.
3
Arvinas, LLC, 5 Science Park, New Haven, 06511 CT USA.
4
4Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, 27710 NC USA.
5
5Department of Chemistry, Yale University, New Haven, 06511 CT USA.

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.

Conflict of interest statement

C.M.C. is the founder, consultant, and shareholder in Arvinas, LLC, which also supports research in his lab. D.P.M. is a consultant for Arvinas, which provided research support for his lab. R.R.W., N.J.V., J.W., H.D., M.J., A.P.C. and T.K.N. are shareholders in Arvinas, LLC.

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