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Rational optimization of a transcription factor activation domain inhibitor

Shaon Basu1, Paula Martínez-Cristóbal2, Marta Frigolé-Vivas2

  • 1Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Nature Structural & Molecular Biology
|December 4, 2023
PubMed

Insights

Researchers optimized small-molecule inhibitors targeting the androgen receptor's activation domain. This approach shows promise for treating castration-resistant prostate cancer by inhibiting oncogenic transcription factors.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • Transcription factors are critical therapeutic targets but often considered 'undruggable' due to disordered activation domains.
  • The androgen receptor (AR) is a key therapeutic target for castration-resistant prostate cancer (CRPC).

Purpose of the Study:

  • To investigate the role of aromaticity in the AR activation domain's function.
  • To rationally optimize small-molecule inhibitors targeting the AR activation domain for CRPC treatment.

Main Methods:

  • Analyzing the aromatic character and condensation properties of the AR activation domain.
  • Structure-based optimization of a previously identified small-molecule inhibitor.
  • Evaluating inhibitor efficacy in cellular and in vivo models of CRPC.

Main Results:

  • Aromaticity of the AR activation domain is crucial for nuclear translocation and condensate formation.
  • Optimized small molecules demonstrated increased target affinity and inhibited AR-dependent transcription.
  • Inhibitors exhibited significant antitumorigenic effects in preclinical CRPC models.

Conclusions:

  • Targeting the activation domains of oncogenic transcription factors with small molecules is feasible.
  • Rational optimization based on structural understanding can lead to effective CRPC therapeutics.
  • This strategy may be applicable to designing inhibitors for other oncogenic transcription factors.

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