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Life Sci Alliance. 2019 Aug 20;2(4). pii: e201800213. doi: 10.26508/lsa.201800213. Print 2019 Aug.

A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells.

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Ipsen Innovation, Les Ulis, France.
Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogazici University, Istanbul, Turkey.
Université de Paris, Hôpital St. Louis, Paris, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) unité mixte de recherche (UMR) 944, Equipe labellisée par la Ligue Nationale contre le Cancer, Institut de Recherche St. Louis, Hôpital St. Louis, Paris, France.
Centre National de la Recherche Scientifique (CNRS) UMR 7212, Hôpital St. Louis, Paris, France.
Assistance publique - Hôpitaux de Paris, Service de Biochimie, Hôpital St. Louis, Paris, France.
College de France, PSL Research University, INSERM UMR 1050, CNRS UMR 7241, Paris, France.
Université de Paris, Hôpital St. Louis, Paris, France


Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen-androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects' importance in modulating drug activity in vivo.

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