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

Exploring the target scope of KEAP1 E3 ligase-based PROTACs

  • Cell Chem Biol. 2022 Aug 29;S2451-9456(22)00311-7. doi: 10.1016/j.chembiol.2022.08.003.
Guangyan Du 1,  Jie Jiang 1,  Nathaniel J Henning 1,  Nozhat Safaee 1,  Eriko Koide 1,  Radosław P Nowak 1,  Katherine A Donovan 1,  Hojong Yoon 1,  Inchul You 2,  Hong Yue 1,  Nicholas A Eleuteri 1,  Zhixiang He 1,  Zhengnian Li 3,  Hubert T Huang 1,  Jianwei Che 1,  Behnam Nabet 4,  Tinghu Zhang 3,  Eric S Fischer 5,  Nathanael S Gray 6
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 3 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 4 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
  • 6 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA. Electronic address: [email protected].
PMID: 36070758 DOI: 10.1016/j.chembiol.2022.08.003
Abstract

Targeted protein degradation (TPD) uses small molecules to recruit E3 ubiquitin ligases into the proximity of proteins of interest, inducing ubiquitination-dependent degradation. A major bottleneck in the TPD field is the lack of accessible E3 ligase ligands for developing degraders. To expand the E3 ligase toolbox, we sought to convert the Kelch-like ECH-associated protein 1 (KEAP1) inhibitor KI696 into a recruitment handle for several targets. While we were able to generate KEAP1-recruiting degraders of BET family and murine focal adhesion kinase (FAK), we discovered that the target scope of KEAP1 was narrow, as targets easily degraded using a Cereblon (CRBN)-recruiting degrader were refractory to KEAP1-mediated degradation. Linking the KEAP1-binding ligand to a CRBN-binding ligand resulted in a molecule that induced degradation of KEAP1 but not CRBN. In sum, we characterize tool compounds to explore KEAP1-mediated ubiquitination and delineate the challenges of exploiting new E3 Ligases for generating bivalent degraders.

Keywords

BRD4; FAK; KEAP1; PROTACs; degrader; targeted protein degradation.

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