Applicability of KEAP1 E3 Ligase to the PROTAC Platform

• 발행기관: 대한약학회
• 저자명: Raju Gurung Jae Rim Lee Min Ju Cho Jin Ah Jeong Sung Jean Park Kwang Won Jeong Dongyun Shin
• 간행물 정보: 『약학회지』제68권 제4호(2024년), 276~286쪽, 전체 11쪽
• 주제분류: 의약학 > 기타의약학
• 파일형태: PDF
• 발행일자: 2024.08.31

국문 초록

Proteolysis-targeting chimeras (PROTACs) represent an innovative approach for drug design involving the creation of a heterobifunctional molecule. This molecule uses an E3 ligase to target and degrade specific proteins via the ubiquitin-proteasome system (UPS). The three essential components of PROTAC are a ligand for the protein of interest (POI), a binder to recruit an E3 ligase, and a linker connecting these two elements. Given the relatively large number of E3 ligases in the human body (>600), only a few such as VHL, CRBN, MDM2, cIAP1, DCAF15, RNF4, and RNF114 have been used in existing PROTACs. PROTACs facilitate degradation of pathological proteins through the UPS pathway. Consequently, the identification of a broad range of E3 ligase recruiters is crucial for advancing targeted protein degradation (TPD) strategies. In this study, we focused on designing KEAP1 binder PROTACs, using a selective, potent small-molecule inhibitor of KEAP1 as an E3 ligase recruiter. It was linked to JQ1 (a POI ligand) via a flexible aliphatic linker. Our compound SD-2406, with KEAP1 E3 ligase recruiter, effectively degraded BRD4 target proteins in LNCaP cells. This demonstrates the potential of expanding the E3 ligase toolbox for the development of PROTAC technology.

목차

Introduction

Methods

Results

Discussion

Conclusion

Acknowledgment

Conflict of Interest

References

키워드

Proteolysis-targeting chimera (PROTAC) KEAP1 BRD4 JQ1 E3 ligase