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
  • 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.
Products