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Ligandability assessment of the C-terminal Rel-homology domain of NFAT1

Jark Böttcher1, Julian E Fuchs1, Moriz Mayer1

  • 1Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.

Archiv Der Pharmazie
|February 24, 2024
PubMed

Insights

Researchers identified small molecule fragments that bind to the nuclear factor of activated T cells 1 (NFAT1) protein domain. This finding opens new therapeutic avenues for diseases involving NFAT1, a challenging transcription factor target.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Transcription factors are crucial disease regulators but often considered undruggable targets.
  • Nuclear factor of activated T cells 1 (NFAT1) plays a key role in T-cell regulation and related diseases.

Purpose of the Study:

  • To assess the ligandability of the C-terminal Rel-homology domain of NFAT1.
  • To identify small molecule binders for NFAT1.

Main Methods:

  • Utilized a combination of experimental and computational approaches.
  • Employed biophysical validation methods.
  • Determined the binding mode using X-ray crystallography.

Main Results:

  • Demonstrated that small molecule fragments can bind to the NFAT1 protein domain.
  • Identified the first validated small molecule binder for NFAT1.
  • Elucidated the binding mode of the identified binder.

Conclusions:

  • The C-terminal Rel-homology domain of NFAT1 is druggable.
  • The identified binder and its eutomer/distomer pair serve as a foundation for developing potent NFAT1-targeting therapeutics.
  • This research paves the way for novel degrader or glue modalities for NFAT1-related diseases.
Keywords:
NFAT1fragment‐based screeningtranscription factor

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