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Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.

Publication ,  Journal Article
Gustafson, JL; Neklesa, TK; Cox, CS; Roth, AG; Buckley, DL; Tae, HS; Sundberg, TB; Stagg, DB; Hines, J; McDonnell, DP; Norris, JD; Crews, CM
Published in: Angew Chem Int Ed Engl
August 10, 2015

Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of selective androgen receptor degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small-molecule AR ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to second-generation AR antagonists.

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Published In

Angew Chem Int Ed Engl

DOI

EISSN

1521-3773

Publication Date

August 10, 2015

Volume

54

Issue

33

Start / End Page

9659 / 9662

Location

Germany

Related Subject Headings

  • Small Molecule Libraries
  • Receptors, Androgen
  • Proteolysis
  • Prostatic Neoplasms
  • Prostate
  • Point Mutation
  • Phenylthiohydantoin
  • Organic Chemistry
  • Nitriles
  • Male
 

Citation

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Gustafson, J. L., Neklesa, T. K., Cox, C. S., Roth, A. G., Buckley, D. L., Tae, H. S., … Crews, C. M. (2015). Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angew Chem Int Ed Engl, 54(33), 9659–9662. https://doi.org/10.1002/anie.201503720
Gustafson, Jeffrey L., Taavi K. Neklesa, Carly S. Cox, Anke G. Roth, Dennis L. Buckley, Hyun Seop Tae, Thomas B. Sundberg, et al. “Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.Angew Chem Int Ed Engl 54, no. 33 (August 10, 2015): 9659–62. https://doi.org/10.1002/anie.201503720.
Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae HS, et al. Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angew Chem Int Ed Engl. 2015 Aug 10;54(33):9659–62.
Gustafson, Jeffrey L., et al. “Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.Angew Chem Int Ed Engl, vol. 54, no. 33, Aug. 2015, pp. 9659–62. Pubmed, doi:10.1002/anie.201503720.
Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae HS, Sundberg TB, Stagg DB, Hines J, McDonnell DP, Norris JD, Crews CM. Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angew Chem Int Ed Engl. 2015 Aug 10;54(33):9659–9662.
Journal cover image

Published In

Angew Chem Int Ed Engl

DOI

EISSN

1521-3773

Publication Date

August 10, 2015

Volume

54

Issue

33

Start / End Page

9659 / 9662

Location

Germany

Related Subject Headings

  • Small Molecule Libraries
  • Receptors, Androgen
  • Proteolysis
  • Prostatic Neoplasms
  • Prostate
  • Point Mutation
  • Phenylthiohydantoin
  • Organic Chemistry
  • Nitriles
  • Male