A Targeted Bivalent Androgen Receptor Binding Compound for Prostate Cancer Therapy


The androgen-directed treatment of prostate cancer (PCa) is fraught with the recurrent profile of failed treatment due to drug resistance and must be addressed if we are to provide an effective therapeutic option. The most singular difficulty in the treatment of PCa is the failure to respond to classical androgen withdrawal or androgen blockade therapy, which often develops as the malignancy incurs genetic alterations and gain-of-function somatic mutations in the androgen receptor (AR). Physical cellular damaging therapeutic agents, such as radiation or activatable heat-generating transducers would circumvent classical “anti-functional” biological resistance, but to become ultimately effective would require directed application modalities. To this end, we have developed a novel AR-directed therapeutic agent by creating bivalent androgen hormone-AF-2 compounds that bind with high affinity to AR within cells. Here, we used molecular modeling and synthetic chemistry to create a number of compounds by conjugating 5α-dihydrotestosterone (DHT) to various AF-2 motif sequence peptides, through the use of a glycine and other spacer linkers. Our data indicates these compounds will bind to the AR in vitro and that altering the AF-2 peptide composition of the compound does indeed improve affinity for the AR. We also show that many of these bivalent compounds can readily pass through the plasma membrane and effectively compete against androgens alone.

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The work was supported by a grant from Prostate Cancer Canada/Movember Foundation—Pilot Grant (#2012-905). Salary support for S.C. was provided by The Department of Urology—Jewish General Hospital (Montreal, Canada).

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Correspondence to Miltiadis Paliouras.

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Dr. Miltiadis Paliouras and Dr. Mark Trifiro share senior authorship.

Electronic supplementary material

. SPEP-24 trajectory of the 50 ns MD simulation in explicit water. (MP4 29559 kb)

Supplemental Data 1

Kinetic binding assays of selected SPEP compounds. (PDF 182 kb)

Supplemental Video 1

. SPEP-24 trajectory of the 50 ns MD simulation in explicit water. (MP4 29559 kb)

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Chowdhury, S., Beitel, L.K., Lumbroso, R. et al. A Targeted Bivalent Androgen Receptor Binding Compound for Prostate Cancer Therapy. HORM CANC 10, 24–35 (2019). https://doi.org/10.1007/s12672-018-0353-6

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  • Androgen receptor
  • Prostate cancer
  • Androgen
  • Bivalent compound
  • AF-2 domain
  • Therapeutics
  • Molecular dynamics simulation