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Hybrid Androgen Receptor Inhibitors Outperform Enzalutamide and EPI-001 in in vitro Models of Prostate Cancer Drug Resistance.

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Nicolescu, Radu Costin Bizga  ORCID logo
Pérez-Areales, Francisco Javier  ORCID logo
Pandha, Hardev S 


Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display an 18 to 53 fold improvement in the cell killing potency towards C4-2b prostate cancer (PCa) cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through androgen receptor (AR) mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties - EPI-001 and enzalutamide - into the same molecule.


Funder: Prostate Cancer Foundation; Id:

Funder: UKRI; Id:

Funder: Trinity College Cambridge

Funder: University of Surrey PhD studentship award


androgen receptor, dual inhibitors, enzalutamide, EPI-001., prostate cancer, Male, Humans, Receptors, Androgen, Prostatic Neoplasms, Castration-Resistant, Cell Line, Tumor, Androgen Receptor Antagonists, Drug Resistance, Neoplasm, Nitriles

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Engineering and Physical Sciences Research Council (EP/P020291/1)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (101025271)