2025/10/24 by Dong Lu, Xin Qi Yu, Xin Yu +8 · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Protein Degradation and Inhibitors #CAR-T cell therapy research #Ubiquitin and proteasome pathways
paper · doi:10.1021/acs.jmedchem.5c00773
High Resolution Image Download MS PowerPoint Slide Pharmacological degradation of receptor-interacting protein kinase 1 (RIPK1) offers a compelling therapeutic strategy to overcome its scaffolding role in tumor resistance and enhance the efficacy of immune checkpoint blockade (ICB) therapies. In this study, we report the discovery of a novel RIPK1 degrader, LD5097 ( 24b ), developed through systematic optimization of its precursor compound, LD4172 ─specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. LD5097 ( 24b ) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared with LD4172, LD5097 ( 24b ) demonstrates markedly improved metabolic stability and pharmacokinetic properties. In vivo, a single dose of LD5097 ( 24b ) induced over 70% RIPK1 degradation in Jurkat xenograft tumors in mice within 6 h. These results position LD5097 ( 24b ) as a promising therapeutic candidate, combining potent biological activity with favorable drug-like properties, and offering strong potential for application in cancer immunotherapy.