2. Academic Validation
  3. Acute pharmacological degradation of Helios destabilizes regulatory T cells

Acute pharmacological degradation of Helios destabilizes regulatory T cells

  • Nat Chem Biol. 2021 Jun;17(6):711-717. doi: 10.1038/s41589-021-00802-w.
Eric S Wang  # 1 2,  Alyssa L Verano  # 1 2,  Radosław P Nowak  # 1 2,  J Christine Yuan  # 1 2,  Katherine A Donovan 1 2,  Nicholas A Eleuteri 1,  Hong Yue 1 2,  Kenneth H Ngo 3,  Patrick H Lizotte 3,  Prafulla C Gokhale 3,  Nathanael S Gray 4 5,  Eric S Fischer 6 7
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 7 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 34035522 DOI: 10.1038/s41589-021-00802-w
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.

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