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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator

Eric Biron1, François Bédard1

  • 1Faculty of Pharmacy and Centre de recherche en endocrinologie moléculaire et oncologique et génomique humaine, Université Laval, Canada; Laboratory of Medicinal Chemistry, CHU de Québec Research Centre, G1 V 4G2, Québec, QC, Canada.

The Journal of Steroid Biochemistry and Molecular Biology
|July 22, 2015
PubMed

Insights

Targeting androgen receptor (AR) coactivator interactions offers a new strategy for treating castration-resistant prostate cancer (CRPC). Small-molecule inhibitors are being developed to block these interactions, overcoming resistance to current therapies.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • The androgen receptor (AR) is crucial for prostate cancer cell growth and survival.
  • Current androgen-deprivation therapies are effective but often lead to treatment resistance, resulting in castration-resistant prostate cancer (CRPC).
  • AR signaling is reactivated in CRPC through various mechanisms, including mutations and splice variants.

Purpose of the Study:

  • To review the design and development of small-molecule inhibitors targeting AR-coactivator interactions.
  • To explore therapeutic strategies effective against AR signaling in treatment-resistant prostate cancer.

Main Methods:

  • Review of structural analyses of the AR to identify protein-protein interaction surfaces.
  • Discussion of the design principles for small-molecule inhibitors targeting AR-coactivator binding.
  • Analysis of therapeutic potential for AR-coactivator binding inhibitors in prostate cancer treatment.

Main Results:

  • Structural insights have enabled the development of promising inhibitors that block AR-coactivator interactions.
  • Targeting coactivator recruitment presents a viable strategy to overcome resistance to conventional endocrine therapies.

Conclusions:

  • Small-molecule inhibitors targeting AR-coactivator interactions represent a promising therapeutic avenue for advanced prostate cancer.
  • This approach offers a potential solution for patients with castration-resistant prostate cancer who have exhausted current treatment options.
Keywords:
Androgen receptorCoactivator binding inhibitionCoregulator recruitmentPeptidomimeticsProstate cancerProtein–protein interactions

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