Abstract 385: Discovery of OST08267, an orally available PDE3A-SLFN12 molecular glue for the treatment of gastrointestinal stromal tumors with tyrosine kinase inhibitors (TKIs) resistance

Abstract Gastrointestinal stromal tumor (GIST) is the critically mesenchymal malignancy inhabiting the GI tract, which crucially induced by receptor tyrosine kinase (KIT) gene mutation. Although the tyrosine kinase inhibitors (TKIs), such as imatinib has prolonged survival significantly, the intrinsic and acquired resistance still disturbed more than 20% patients. Therefore, significant unmet medical remains needed. phosphodiesterase 3A (PDE3A)- Schlafen family member 12 (SLFN12) molecular glue is a novel anti-tumor targeted drug, mainly by mediating the formation of a complex between PDE3A and SLFN12, ultimately leading to the tumor apoptosis. In this study, we present OST08267, an orally available PDE3A-SLFN12 molecular glue tailored from the FDA-approved PDE3A inhibitor. Our transcriptional profiling of over 2, 000 patient samples revealed high expression levels of PDE3A and SLFN12 in GIST tumors, suggesting that GIST is a promising indication for this treatment with a high responsive rate of up to 60%. In vitro, OST08267 demonstrated significant anti-tumor activity, irrespective of KIT mutation status by testing against multiple GIST patient-derived organoids. In vivo, OST08267 causes dose-dependent regression of tumor volume in the GIST patient-derived xenograft (PDX) model with imatinib resistance, with 4 mg/kg/day dose resulting in deeper and durable tumor regressions that were maintained for at least a month even after the dosing had discontinued.Moreover, OST08267 exhibited favorable pharmacokinetic and toxicity properties. These promising preclinical results strongly support the potential of OST08267 to address unmet needs in GIST treatment, justifying its further clinical development. Citation Format: Fangrui Wu, Lisheng Deng, Zhixiong Ma, Zhenyao Lu, Gabriel Deng. Discovery of OST08267, an orally available PDE3A-SLFN12 molecular glue for the treatment of gastrointestinal stromal tumors with tyrosine kinase inhibitors (TKIs) resistance [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 385.