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
Summary
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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