Abstract
The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (Treg) 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 Treg 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Animals
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Cell Line
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DNA-Binding Proteins / drug effects*
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DNA-Binding Proteins / genetics
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Humans
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Ikaros Transcription Factor / drug effects*
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Ikaros Transcription Factor / genetics
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Jurkat Cells
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Mice
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Models, Molecular
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Molecular Structure
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Mutation / genetics
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Small Molecule Libraries
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Substrate Specificity
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T-Lymphocytes, Regulatory / drug effects*
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Transcription Factors / drug effects*
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Transcription Factors / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Crbn protein, mouse
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DNA-Binding Proteins
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IKZF2 protein, human
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Small Molecule Libraries
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Transcription Factors
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Zfpn1a2 protein, mouse
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Ikaros Transcription Factor
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Ubiquitin-Protein Ligases