Advances in KEAP1-based PROTACs as emerging therapeutic modalities: Structural basis and progress.

Area of Science:

• Biochemistry and Molecular Biology
• Drug Discovery and Development
• Cellular Biology

Background:

• Kelch-like ECH-associated protein 1 (KEAP1) acts as a substrate adaptor for the Cullin 3-RING E3 ligase, targeting nuclear factor erythroid 2-related factor 2 (NRF2) for proteasomal degradation.
• This regulation is crucial for maintaining cellular redox homeostasis by preventing NRF2 overactivation.

Purpose of the Study:

• To provide a comprehensive review of KEAP1's structure, function, and interactions with NRF2 and Cullin 3.
• To discuss the development and potential of KEAP1-recruiting Proteolysis-Targeting Chimeras (PROTACs) for targeted protein degradation.
• To highlight recent progress and challenges in KEAP1-based targeted protein degradation strategies.

Main Methods:

• Review of existing literature on KEAP1 structure, function, and interactions.
• Analysis of KEAP1-based PROTAC development, including various ligand classes (peptides, covalent, non-covalent inhibitors).
• Examination of specific KEAP1-based PROTACs targeting proteins like BRD4, CDK9, FAK, Tau, and KEAP1 itself.

Main Results:

• KEAP1 is a versatile E3 ligase recruiter for PROTACs, with diverse inhibitor-derived ligands enhancing its utility.
• KEAP1-based PROTACs have shown promise in degrading various target proteins, with ongoing efforts in ligand optimization for efficacy and specificity.
• Structural insights into KEAP1 interactions are vital for advancing PROTAC design.

Conclusions:

• KEAP1 represents a promising E3 ligase for PROTAC development, offering diverse recruitment strategies.
• Further research is needed to overcome current challenges in KEAP1-based targeted protein degradation and optimize ligand properties.
• Exploring novel protein targets for KEAP1-mediated degradation could significantly advance this therapeutic modality.