CXB-7138, A novel GSPT1/ZFP91 dual molecular glue degrader, for targeted treatment of pancreatic ductal adenocarcinoma
Presenter: Heung Sik Hahm, Dr Rer Nat Session: Proximity-Induced Drug Discovery 2 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Jin-Hee Park , Jae-Seon Lee , Shin-Hae Lee , NamKyoung Kim , Sumin Kim , Chaeseon Kim , Yong Chan Kim , Eunbin Park , Jiah Kim , Heung Sik Hahm , Jung Beom Son , Nam Doo Kim , Hwan Geun Choi CoBX Bio Co., Ltd, Seoul, Korea, Republic of
Abstract
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.
Disclosure
J. Park, CoBX Bio Co., Ltd, Employment. J. Lee, CoBX Bio Co., Ltd, Employment. S. Lee, CoBX Bio Co., Ltd, Employment. N. Kim, CoBX Bio Co., Ltd, Employment. S. Kim, CoBX Bio Co., Ltd, Employment. C. Kim, CoBX Bio Co., Ltd, Employment. Y. Kim, CoBX Bio Co., Ltd, Employment. E. Park, CoBX Bio Co., Ltd, Employment. J. Kim, CoBX Bio Co., Ltd, Employment. H. Hahm, CoBX Bio Co., Ltd, Employment. J. Son, CoBX Bio Co., Ltd, g., Board of Directors, non-salaried role). N. Kim, CoBX Bio Co., Ltd, g., Board of Directors, non-salaried role). H. Choi, CoBX Bio Co., Ltd, g., Board of Directors, non-salaried role).
Cited in
Control: 5939 · Presentation Id: 8734 · Meeting 21436