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Cited by 189Protein Degradation and InhibitorsComputational Drug Discovery MethodsChemical Synthesis and Analysis

A complex task? Direct modulation of transcription factors with small molecules

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Koehler, Angela N·2010·Current Opinion in Chemical Biology
DOI 10.1016/j.cbpa.2010.03.022PMC PMC3248789
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Abstract

Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein-protein or protein-DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be 'undruggable.' This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.

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  • Hypoxia-inducible factors were considered undruggable transcription factors because they lack an obvious ligand-binding domain analogous to steroid hormone receptors.

    “For many years, hypoxia-inducible factors were considered “undruggable” transcription factors, largely because they lack an obvious ligand-binding domain analogous to those found in steroid hormone receptors [272].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [272]

    The Introduction describes transcription factors generally as historically challenging to target and often perceived as ‘undruggable.’ The Nuclear Receptors section describes ligand binding in that class, and the Latent Cytoplasmic Factors section discusses HIF inhibitors. Neither section says HIFs were considered undruggable specifically because they lack an obvious ligand-binding domain analogous to steroid hormone receptors. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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References 82 · Cited by 189

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Authors
Koehler, A. N.
Affiliations
Broad Institute (US)
Corresponding author
Koehler, Angela N
ORCID
Koehler, Angela N
Venue
Current Opinion in Chemical Biology
Publisher
Elsevier BV
Published
2010-06
Volume
14
Issue
3
Pages
331-340
ISSN
1367-5931 (ISSN-L)
DOI
10.1016/j.cbpa.2010.03.022
PMC
PMC3248789
OpenAlex
W2027704988
Cited by
189
References
82
Citations by year
2026: 3 · 2025: 6 · 2024: 10 · 2023: 9 · 2022: 12 · 2021: 12 · 2020: 11 · 2019: 13 · 2018: 17 · 2017: 11 · 2016: 12 · 2015: 16 · 2014: 12 · 2013: 18 · 2012: 11
FWCI
1.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Opinion in Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
  • National Institutes of Health (n01co12400-79-0-22)
  • U.S. Public Health Service (-C0-012400)
  • National Cancer Institute (N01CO12400, N01-CO-012400)
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, chemical probes, protein-protein interaction, protein-DNA interactions, undruggable targets, oncology therapeutics, small-molecule drug design
MeSH terms
Pharmaceutical Preparations, Humans, Transcription Factors, Oncogene Proteins, Fusion, Drug Delivery Systems, Receptors, Cytoplasmic and Nuclear, Drug Discovery

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