CXB-7138：一种用于胰腺导管腺癌靶向治疗的新型GSPT1/ZFP91双靶点分子胶降解剂

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by profound intertumoral heterogeneity and a dense tumor microenvironment that limits the effectiveness of current therapies. GSPT1 (eRF3a), a translation termination GTPase historically considered “undruggable,” has recently become targetable through cereblon (CRBN)-mediated protein degradation. ZFP91, an atypical E3 ligase and transcriptional regulator, is also highly expressed in PDAC and correlates with poor clinical outcomes. Here, we present CXB-7138, a CRBN-recruiting molecular glue degrader built on a novel, nontraditional chemical scaffold, designed to induce selective degradation of both GSPT1 and ZFP91. To our knowledge, CXB-7138 represents the first dual-target GSPT1/ZFP91 degrader leveraging CRBN for therapeutic intervention in PDAC. Methods: A panel of PDAC and non-PDAC cancer cell lines was treated with CXB-7138, and viability was assessed across genetically diverse models. Degradation of GSPT1 and ZFP91 was quantified by proteomics, Western blotting, and HiBiT-based assays. Antitumor activity was evaluated in a subcutaneous PDAC xenograft model following oral administration, with tumor volume and body weight monitored longitudinally. Results: CXB-7138 exhibited potent antiproliferative activity across a broad spectrum of cancer cell lines-including but not limited to PDAC-with IC₅₀ values in the sub-nanomolar to double-digit nanomolar range. Within PDAC models, a trend toward increased sensitivity was observed in cell lines harboring SMAD4 alterations, suggesting a potential genomic determinant of CXB-7138 responsiveness. Comparative proteomic profiling confirmed that the compound's pharmacologic effects arise from selective and sustained CRBN-mediated degradation of both GSPT1 and ZFP91. In vivo, oral single-agent CXB-7138 inhibited tumor growth in a PDAC xenograft model, demonstrating potent antitumor efficacy with favorable tolerability. Conclusions: CXB-7138 is a first-in-class CRBN-recruiting dual molecular glue degrader targeting GSPT1 and ZFP91 through a nontraditional scaffold. Its broad antiproliferative activity, molecularly defined sensitivity patterns, and strong in vivo efficacy position CXB-7138 as a highly promising therapeutic strategy for PDAC, a malignancy in urgent need of new treatment options.