PPI-101

PPI-101 is a novel arylsulfonamide molecular glue degrader designed to target the splicing factor RBM39 for the treatment of neuroblastoma. Developed by Peak Perform Innova, it functions by recruiting RBM39 to the CRL4-DCAF15 E3 ligase complex, leading to its ubiquitination and subsequent proteasomal degradation. PPI-101 was optimized to address the limitations of earlier RBM39 degraders like E7820, such as dose-limiting hematotoxicity and poor tumor penetration. In preclinical studies, PPI-101 demonstrated superior pharmacokinetic and pharmacodynamic properties, including lower human plasma protein binding, a higher volume of distribution, and enhanced tumor penetration, resulting in a significantly improved therapeutic index in neuroblastoma xenograft models.