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Nat Rev Drug Discov DOI:10.1038/s41573-021-00199-0

Advances in targeting 'undruggable' transcription factors with small molecules.

Publication TypeJournal Article
Year of Publication2021
AuthorsHenley, MJ, Koehler, AN
JournalNat Rev Drug Discov
Date Published2021 May 18

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.


Alternate JournalNat Rev Drug Discov
PubMed ID34006959