Novel VHL ligand-based PROTACs targeting JNK1: design, synthesis, and biological evaluation with potent anti-EMT activity.
TL;DR
This work describes the design, synthesis, and biological evaluation of a series of JNK1-targeting PROTACs that recruit either CRBN or VHL E3 ligases that demonstrates excellent degradation potency and selectivity for JNK1, highlighting its potential as a valuable chemical probe for EMT-associated pathologies.
Abstract
Epithelial-mesenchymal transition (EMT) is essential for embryogenesis and tissue regeneration, yet its aberrant activation is closely associated with organ fibrosis and tumor metastasis. c-Jun N-terminal kinase 1 (JNK1) has been identified as a key mediator of transforming growth factor-β (TGF-β)-driven EMT, making it a promising therapeutic target. Herein, we describe the design, synthesis, and biological evaluation of a series of JNK1-targeting PROTACs that recruit either CRBN or VHL E3 ligases. Systematic structure-activity relationship optimization led to the discovery of compound YC2, which incorporates a newly developed VHL ligand modified with a 2,4-dimethyloxazole moiety, as a potent and selective degrader. YC2 induced efficient, concentration- and time-dependent degradation of JNK1 (DC₅₀ of 4.90 nM) via VHL-mediated ubiquitin-proteasome pathway engagement, while displaying strong selectivity over related kinases including JNK2, p38α, and ERK. Moreover, YC2 markedly attenuated TGF-β1-induced EMT, as evidenced by reduced fibronectin levels and restoration of E-cadherin expression, with efficacy comparable to nintedanib. Collectively, YC2 featuring a novel VHL ligand demonstrates excellent degradation potency and selectivity for JNK1, highlighting its potential as a valuable chemical probe for EMT-associated pathologies.