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Exploring the target scope of KEAP1 E3 ligase-based PROTACs.

Guangyan Du1, Jie Jiang1, Nathaniel J Henning1

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.

Cell Chemical Biology
|September 7, 2022
PubMed
Summary
This summary is machine-generated.

Researchers explored using KEAP1 as an E3 ligase for targeted protein degradation (TPD). They found KEAP1 has a limited target scope compared to CRBN, highlighting challenges in developing new TPD degraders.

Keywords:
BRD4FAKKEAP1PROTACsdegradertargeted protein degradation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) is a therapeutic strategy that hijacks cellular machinery to eliminate disease-causing proteins.
  • Developing novel degraders is hindered by a limited number of E3 ubiquitin ligase ligands.
  • KEAP1 is an E3 ligase whose ligands could expand the TPD toolbox.

Purpose of the Study:

  • To investigate the potential of KEAP1 as an E3 ligase for TPD by repurposing the KEAP1 inhibitor KI696.
  • To assess the target scope and efficacy of KEAP1-recruiting degraders.
  • To explore the development of bivalent degraders utilizing KEAP1.

Main Methods:

  • Chemical synthesis of KEAP1-recruiting molecules.
  • Generation of degraders for BET family proteins and focal adhesion kinase (FAK).
  • Comparative degradation assays using KEAP1 and CRBN E3 ligases.

Main Results:

  • KEAP1-recruiting degraders for BET proteins and FAK were successfully generated.
  • KEAP1 demonstrated a narrower target scope than CRBN, with some targets refractory to KEAP1-mediated degradation.
  • Bivalent molecules designed to recruit both KEAP1 and CRBN preferentially degraded KEAP1, not the intended co-target.

Conclusions:

  • KEAP1 is a viable E3 ligase for TPD, but its target scope is limited.
  • Exploiting new E3 ligases like KEAP1 presents challenges for degrader development.
  • Further research is needed to overcome limitations in developing novel TPD strategies and bivalent degraders.