Open AccessAcute pharmacological degradation of Helios destabilizes regulatory T cells
Author(s) -
Eric S. Wang,
Alyssa Verano,
Radosław P. Nowak,
Jingting Yuan,
Katherine A. Donovan,
Nicholas A. Eleuteri,
Hong Yue,
Kenneth Ngo,
Patrick H. Lizotte,
Prafulla C. Gokhale,
Nathanael S. Gray,
Eric S. Fischer
Publication year - 2021
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-021-00802-w
Subject(s) - ubiquitin ligase , reprogramming , transcription factor , zinc finger , microbiology and biotechnology , ubiquitin , cereblon , ubiquitin protein ligases , chemistry , biology , cell , biochemistry , gene
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.