Abstract 391: Pharmacological suppression of neuroblastoma growth via RBM39 degradation by the molecular glue PPI-011

Abstract High-risk neuroblastoma, often driven by the amplification or overexpression of MYC family oncogenes (MYCN and MYC), remains a significant cause of pediatric cancer mortality, contributing to 15% of tumor-related deaths in children. Despite multimodal treatment approaches, prognosis remains poor, underscoring an urgent need for new therapies. The current study targets the degradation of RBM39, an RNA splicing factor linked to splicing irregularities in MYC-driven tumors. We identified PPI-011, a proprietary molecular glue, using an AI-assisted integrated drug design platform. Demonstrated by the Time-Resolved Förster’s Resonance Energy Transfer recruitment assay, PPI-011 promotes the formation of the ternary complex involving RBM39 and DDB1-DCAF15, a substrate adaptor in the RBX-CUL4-DDA1-DDB1-DCAF15 E3 ligase. PPI-011 induced dose-dependent degradation of RBM39 across multiple neuroblastoma cell lines, a mechanism confirmed by the inhibitory effects of a neddylation blocker and DCAF15 knockout, validating CUL4-DCAF15-mediated proteasomal degradation as the underlying pathway. RBM39 degradation resulted in splicing changes in multiple genes, including CDK4 and PEX3, and led to cancer cell death. Preliminary pharmacokinetic studies indicated that PPI-011 possessed good PK profiles, with oral bioavailability of ∼100% and high exposure. In vivo, daily oral administration of PPI-011 (15 mg/kg) suppressed tumor growth by 90% (P < 0.001 vs. vehicle) in IMR-32 neuroblastoma xenografts in balb/c nude mice, with almost complete tumor elimination at 30 and 50 mg/kg within 28 days, and no associated weight loss at any dose. The suppressed tumor growth was associated with decreased RBM39 protein in the xenografts. Notably, tumor suppression at 50 mg/kg was sustained for 72 days even after treatment discontinued. Similarly, PPI-011 significantly (P < 0.001 vs. vehicle) inhibited the growth of LAN-5 xenografts, another neuroblastoma model, at doses of 3, 10, and 30 mg/kg in a dose-dependent manner. In a patient-derived xenograft model, using cells from a chemotherapy-relapsed neuroblastoma, PPI-011 achieved 88% tumor suppression (P < 0.001 vs. vehicle) at 30 mg/kg, and complete tumor clearance at 90 mg/kg within 21 days. Furthermore, PPI-011 has no apparent safety liabilities, supported by in vitro genetic toxicology and hERG assays, warranting further in vivo toxicological analysis. Our findings demonstrate that PPI-011, developed through an innovative drug design platform targeting previously undruggable targets, effectively inhibits neuroblastoma growth by inducing RBM39 degradation. This suggests PPI-011 as a promising new therapeutic strategy for MYC-driven malignancies, including neuroblastoma. Citation Format: Yu Cao, Qilei Han, Penxuan Ren, Bin Zhang, Lin Wang, Xianglei Zhang, Lei Zhou, Song Feng, James X. Rong, Lianghe Mei, Kai Li, Fang Bai. Pharmacological suppression of neuroblastoma growth via RBM39 degradation by the molecular glue PPI-011 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 391.