Advances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Abstract
Transcription factors (TFs) represent key biological players in diseases including cancer, autoimmunity, diabetes and cardiovascular disease. However, outside nuclear receptors, TFs have traditionally been considered 'undruggable' by small-molecule ligands due to significant structural disorder and lack of defined small-molecule binding pockets. Renewed interest in the field has been ignited by significant progress in chemical biology approaches to ligand discovery and optimization, especially the advent of targeted protein degradation approaches, along with increasing appreciation of the critical role a limited number of collaborators play in the regulation of key TF effector genes. Here, we review current understanding of TF-mediated gene regulation, discuss successful targeting strategies and highlight ongoing challenges and emerging approaches to address them.
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The inherent complexity of protein-protein interactions is a challenge for targeting transcription factors therapeutically.
“These include the inherent complexity of their protein‒protein interactions [15] and the lack of readily druggable pockets for most transcription factors [16].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [15]
Recent advancements in drug discovery, such as novel chemical libraries and protein engineering techniques, are paving the way for overcoming obstacles to targeting transcription factors.
“However, recent advancements in drug discovery, such as the development of novel chemical libraries and protein engineering techniques, are paving the way for overcoming these obstacles [15, 17, 18].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [15]
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“…(Filippa-kopoulos et al, 2010), ER-PROTAC (Clinical trials NCT04072952), and AR-PROTAC (Clinical Trials NCT03888612), demonstrate the attention of the drug development community to the advantages of harnessing the E3-ubiquitin-proteosome pathway as a therapeutic target (Henley and Koehler, 2021).”
Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease
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- Authors
- Henley, M. J., & Koehler, A. N.
- Affiliations
- Broad Institute (US)
- Venue
- Nature Reviews Drug Discovery
- Published
- 2021-05-18
- Volume
- 20
- Issue
- 9
- Pages
- 669-688
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W3161432498
- Cited by
- 409
- References
- 44
- Citations by year
- 2026: 73 · 2025: 117 · 2024: 88 · 2023: 66 · 2022: 56 · 2021: 8
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- transcription factors, undruggable targets, small-molecule ligands, targeted protein degradation, chemical biology, ligand discovery, transcription factor inhibitors
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Ligands, Transcription Factors, Small Molecule Libraries, Drug Discovery, Molecular Targeted Therapy, Proteolysis
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