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

The pivotal role of receptor-interacting protein kinase 1 (RIPK1) as a scaffold protein in mediating tumor resistance to immune checkpoint inhibitors (ICBs) underscores the significance of pharmacological RIPK1 degradation as a therapeutic strategy to enhance antitumor immunity. In this study, we present the design, synthesis, and evaluation of a novel series of RIPK1 degraders, derived from the optimization of the previously identified compound LD4172. Through systematic refinement of the linker, exit vector of the RIPK1 warhead, and the VHL ligand portion, we identified compound LD5097 (24b), which exhibited potent RIPK1 degradation activity across various cancer cell lines, with DC50 values of single digit nanomolar range and inducing more than 95% maximum degradation. Remarkably, LD5097 (24b) induced rapid and complete degradation of RIPK1 within 2 hours of treatment and enhanced TNF-mediated apoptosis in Jurkat cells. Furthermore, proteomic profiling unveiled the high selectivity of LD5097 (24b) in degrading RIPK1. LD5097 (24b) exhibited excellent metabolic stability and pharmacokinetic properties, characterized by low clearance, an extended half-life, and high plasma drug concentrations. Notably, a single administration of LD5097 (24b) effectively reduced RIPK1 protein levels in Jurkat xenograft tumor tissues in mice at both 6- and 24-hour post-administration. These findings underscore LD5097 (24b) as a promising RIPK1 degrader candidate, offering potent activity, favorable pharmaco-kinetic profiles, and notable pharmacodynamic effects, thereby holding significant promise in cancer immunology therapies.