1. Acute pharmacological degradation of Helios destabilizes regulatory T cells
- Author
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Katherine A. Donovan, Kenneth H. Ngo, Eric S. Wang, Eric S. Fischer, Verano Alyssa, Radosław P. Nowak, Prafulla C. Gokhale, Nathanael S. Gray, Nicholas A. Eleuteri, Patrick H. Lizotte, J Christine Yuan, and Hong Yue
- Subjects
Models, Molecular ,Ubiquitin-Protein Ligases ,HeliOS ,T-Lymphocytes, Regulatory ,Article ,Cell Line ,Substrate Specificity ,Small Molecule Libraries ,Ikaros Transcription Factor ,Jurkat Cells ,Mice ,03 medical and health sciences ,Animals ,Humans ,Receptor ,Molecular Biology ,Transcription factor ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,biology ,Chemistry ,Cereblon ,030302 biochemistry & molecular biology ,Cell Biology ,Phenotype ,Small molecule ,Ubiquitin ligase ,Cell biology ,DNA-Binding Proteins ,Mutation ,biology.protein ,Reprogramming ,Transcription Factors - Abstract
The zinc finger transcription factor Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor Cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of regulatory T cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity., Graphical Abstract
- Published
- 2021
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