ArticleNature structural & molecular biology2023
Rational optimization of a transcription factor activation domain inhibitor.
Article in Nature structural & molecular biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
What it found
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Who cites it
48 citing papers in PubMed, 62 citations in OpenAlex.
- How do low-complexity domain interactions control transcription?Biochemical Society transactions · 2026Review
- A Spatiotemporal Atlas of the Androgen Receptor Proximal Interactome.bioRxiv : the preprint server for biology · 2026Article
- DNA-Induced Entropic Gain Triggers an Allosteric Switch for Biomolecular Condensation of Heat Shock Transcription Factor 1.Angewandte Chemie (International ed. in English) · 2026Article
- Targeting the intrinsically disordered AR-NTD through a machine learning-based enhanced sampling workflow.Nature communications · 2026Article
- Condensates as Conformation Editors of Disordered Client Proteins.Journal of the American Chemical Society · 2026Article
- Drugging the intrinsically disordered transactivation domain of androgen receptor.Signal transduction and targeted therapy · 2026Article
- Folded domains impose structural heterogeneity and attenuated dynamics in biomolecular condensates.Nature communications · 2026Article
- Targeting phase separation: a new strategy to disrupt the stromal-immune axis in colorectal cancer.Cell communication and signaling : CCS · 2026Review
- Toward a unified framework for determining conformational ensembles of disordered proteins.Nature methods · 2026Review
- Oligomerization enables the selective targeting of an intrinsically disordered region by a small molecule.Science advances · 2026Article
- Biomolecular Condensates Dictate the Folding Landscape of Proteins.bioRxiv : the preprint server for biology · 2026Article
- Liquid liquid phase separation of the intrinsically disordered protein JPT2 compartmentalizes components of NAADP-evoked CabioRxiv : the preprint server for biology · 2026Article
- Molecular grammars of predicted intrinsically disordered regions that span the human proteome.Cell · 2026Article
- How small molecules stabilize oligomers of a phase-separating disordered protein.bioRxiv : the preprint server for biology · 2025Article
- Endocrine Examples of Phase Separation in Biology.Endocrinology · 2025Review
- Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution.Nature communications · 2025Article
- Article
- Targeting protein disorder: the next hurdle in drug discovery.Nature reviews. Drug discovery · 2025Review
- Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation.bioRxiv : the preprint server for biology · 2025Article
- DIRseq: a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
37 authors at 9 institutions in 4 countries.
Funding
Abstract
Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.