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

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, <b>LD5097</b> (<b>24b</b>), developed through systematic optimization of its precursor compound, <b>LD4172</b>─specifically refining the linker, RIPK1 warhead exit vector, and VHL ligand components. <b>LD5097</b> (<b>24b</b>) exhibits potent and selective RIPK1 degradation, triggering rapid and efficient downregulation of RIPK1 and significantly enhancing TNFα-mediated apoptosis in Jurkat cells. Compared with <b>LD4172</b>, <b>LD5097</b> (<b>24b</b>) demonstrates markedly improved metabolic stability and pharmacokinetic properties. <i>In vivo</i>, a single dose of <b>LD5097</b> (<b>24b</b>) induced over 70% RIPK1 degradation in Jurkat xenograft tumors in mice within 6 h. These results position <b>LD5097</b> (<b>24b</b>) as a promising therapeutic candidate, combining potent biological activity with favorable drug-like properties, and offering strong potential for application in cancer immunotherapy.