Exploring the target scope of KEAP1 E3 ligase-based PROTACs. Issue 10 (20th October 2022)

• Record Type: Journal Article
• Authors: Du, Guangyan; Jiang, Jie; Henning, Nathaniel J.; Safaee, Nozhat; Koide, Eriko; Nowak, Radosław P.; Donovan, Katherine A.; Yoon, Hojong; You, Inchul; Yue, Hong; Eleuteri, Nicholas A.; He, Zhixiang; Li, Zhengnian; Huang, Hubert T.; Che, Jianwei; Nabet, Behnam; Zhang, Tinghu; Fischer, Eric S.; Gray, Nathanael S.
• Is Part Of: Cell chemical biology. Volume 29:Issue 10(2022)
• Page Start: 1470
• Page End: 1481.e31
• Publication Date: 2022-10-20
• Subjects: targeted protein degradation -- degrader -- KEAP1 -- BRD4 -- FAK -- PROTACs; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.08.003
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: DGY-06-177-pk2 induced KEAP1-dependent BRD4 degradation NJH-04-098 results in FAK degradation in mice but not human cells KEAP1-recruiting PROTACs are less versatile than VHL or CRBN CRBN-based KEAP1 PROTAC effectively degrades KEAP1 Abstract : Du et al. explores a variety of bivalent KEAP1-recruiting degraders to assess the generality of KEAP as an E3 ligase for targeted protein degradation They found the targets easily degraded using a cereblon (CRBN)- or VHL-recruiting degrader were refractory to KEAP1-mediated degradation.