Design, Optimization, and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties

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Abstract 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.

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