On 7 February 2022, a review entitled Current strategies and progress for targeting the ‘undruggable’ transcription factors was published in Acta Pharmacologica Sinica (English edition of the Journal of Pharmacology) by Wulab in collaboration with Lu Tie’s team at the School of Basic Medical Sciences Peking University. Dr. Jingjing Zhuang was the first author of the article, and Profs. Dalei Wu and Lu Tie were the co-corresponding authors.

Transcription factors (TFs) specifically bind to DNA, recruit cofactor proteins and regulate target gene expression, which play important roles in regulating a wide range of biological processes. TFs’ mutations and dysregulation have been associated with a variety of human diseases. Many signalling pathways ultimately converge on TFs, so direct targeting of these TFs may be more specific and have fewer side effects than targeting upstream molecules in these pathways.TFs have great potential and high selectivity as therapeutic drug targets, but TFs have long been regarded as ‘non-druggable’, mainly due to the lack of structural information, especially about ligand binding sites and protein-protein interactions, leading to relatively limited options for drug design targeting TFs.

In this review, we summarised the recent advances in targeting TF drugs and highlight strategies for targeting TFs, using some representative drugs that have been approved or are in clinical trials. A variety of strategies have been developed to directly or indirectly target TFs. Common direct strategies include targeting identified binding pockets, protein hydrolysis-targeted chimeras (PROTAC) and mutant protein reactivation. However, common indirect strategies include inhibiting TF interactions with other proteins, blocking TF expression, targeting post-translational modifications, and targeting TF-DNA interactions.

Full text link: https://www.nature.com/articles/s41401-021-00852-9

Figure source: Jingjing Zhuang

Editor: Yating Yang