Combinatorial use of VHL and KEAP1 PROTACs reveals unexpected synergy and hook effect relief
Year: 2025
Type: preprint
Abstract: Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. However, PROTACs are not without limitations, including suboptimal target degradation and the "hook effect," a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation. In this study, we introduce a novel dual-PROTAC strategy utilizing two distinct E3 ligases, such as KEAP1 and VHL, to synergistically degrade KRAS(G12D) and androgen receptor (AR) by promoting ubiquitin chain elongation and also mitigating the hook effect. In conclusion, a dual-E3 ligase approach represents a promising avenue for optimizing PROTAC-based therapeutics.
Source: Genes & Development
Authors: Sehbanul Islam, Haihong Jin, Dong Liu, Dan Lu, Yunkai Zhang, Eric Christenson, Renxu Chang, Joel Austin, Anneliese Faustino, Thomas Beer, Hsin-Yao Tang, Lan Huang, James R. Tonra, Luca Busino
Institutions: University of Pennsylvania, The Wistar Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G120344028, G1732014367, Regulation of emergency hematopoiesis by the ubiquitin-proteasome system, Assessing the Therapeutic Potential of PARPi and PROTACs in BRCA-Mutated Cancers, Advancing Cancer Research through Comprehensive Proteomics and Metabolomics Analyses, Role of KLHL6 inactivation in mature B-cell malignancies, Consolidated Basic Cancer Research Program, G915722980
OpenAlex ID: W4417128205