良好的 DMPK 特性使新型芳基磺酰胺 RBM39 分子胶降解剂 PPI-101 的开发成为可能，用于治疗神经母细胞瘤

Background: E7820 and related arylsulfonamides have recently been recognized as molecular glues that recruit the splicing factor RBM39 to the CRL4-DCAF15 E3 ligase complex, triggering RBM39 ubiquitination and degradation. Despite clinical evaluation, these degraders have shown limited efficacy and dose-limiting hematotoxicity. The underlying in vivo pharmacology of RBM39 degraders remains poorly defined, hindering optimization. Methods: We characterized the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy relationships of E7820 and analogs (PPI-101, R134, R111, R011) in an IMR32 neuroblastoma xenograft model. Compounds were administered orally once daily for 28 days. Tumor growth inhibition (TGI), plasma/tumor exposures, and RBM39 protein levels were quantified to establish PK/PD relationships and identify next-generation RBM39 degraders with improved therapeutic index (TI). Results: E7820, PPI-101, R134, and R011 achieved complete tumor growth inhibition at 30 mg/kg. TGI correlated with unbound exposure normalized by cellular DC50 values, exhibiting a sigmoidal relationship between efficacy and exposure multiples. Following 3-day dosing, tumor RBM39 remained ≥75% depleted for up to 30 hours after the last dose, even when unbound plasma and tumor concentrations had fallen >300-fold below DC50, indicating slow RBM39 recovery kinetics and sustained pharmacodynamic effect. PPI-101 showed the most favorable DMPK profile, with the lowest human plasma protein binding, the highest volume of distribution (Vss = 0.77 L/kg)-an indicator of drug distribution between plasma and peripheral tissues-and superior tumor penetration (tumor/plasma ratio = 1.0, ~50% higher than E7820). Consequently, lower plasma exposure was required for equivalent tumor coverage, reducing systemic exposure and the risk of hematologic toxicity. Preliminary toxicology studies revealed a markedly improved TI (14 for PPI-101 vs <2.7 for E7820), consistent with reduced reticulocyte and lymphocyte suppression. Conclusions: This study defines, for the first time, the in vivo PK/PD relationships governing RBM39 degradation and demonstrates that favorable distribution properties can markedly enhance therapeutic index. PPI-101 emerges as a potent and safer RBM39 degrader candidate for neuroblastoma therapy, warranting GLP toxicology and IND-enabling development.