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Acute pharmacological degradation of Helios destabilizes regulatory T cells
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Acute pharmacological degradation of Helios destabilizes regulatory T cells
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Journal Article
Acute pharmacological degradation of Helios destabilizes regulatory T cells
2021
Overview
The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T
reg
) 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 T
reg
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.
Two degraders targeting zinc finger transcription factor IKZF2 (Helios) were developed by reprogramming CRL4
CRBN
E3 ligase, and the pharmacologic degradation of Helios results in T
reg
destabilization.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adaptor Proteins, Signal Transducing - genetics
/ Anergy
/ Animals
/ Chemistry and Materials Science
/ DNA-Binding Proteins - drug effects
/ DNA-Binding Proteins - genetics
/ Humans
/ Ikaros Transcription Factor - drug effects
/ Ikaros Transcription Factor - genetics
/ Mice
/ T-Lymphocytes, Regulatory - drug effects
/ Transcription Factors - drug effects
/ Transcription Factors - genetics
/ Ubiquitin-Protein Ligases - metabolism
/ Zinc
