Abstract A070: Optimal efficacious dose prediction of a novel protein degrader ASP3082 selectively targeting KRAS G12D using quantitative systems pharmacology

Abstract Background: KRAS is a membrane-bound protein and a member of the RAS family of GTPases. It acts as a molecular switch to turn on or off receptor tyrosine kinase signal transduction by binding to GTP or GDP, respectively. Among KRAS mutations, KRAS G12D is one of the most frequent driver mutations associated with multiple cancers, including pancreatic cancer, colorectal cancer, and lung adenocarcinoma. ASP3082 is currently being investigated as a potential drug candidate for the treatment of cancer in which the KRAS G12D mutation is a driver. ASP3082 binds to the protein of interest and E3 ubiquitin ligase resulting in ubiquitination of KRAS G12D protein and subsequent degradation by the proteosome. In this study, a QSP model targeting KRAS G12D was developed using the SimBiology🄬 toolbox within MATLAB🄬. The final model was validated using the observed xenograft mice data from different cell lines, and then the human model was scaled using available physiological properties. Methods: The QSP schematic consisted of three compartments: central, peripheral, and tumor. The drug binds to the E3 ligase and KRAS G12D and creates a ternary complex. After the formation of the complex and the ubiquitination of KRAS G12D, the complex dissociates causing KRAS G12D degradation through the ubiquitin-proteasome system. During this time, the drug recycles back in the tumor compartment and finds the next available KRAS G12D. The proposed QSP model was able to model the dynamics of KRAS G12D over time and its effect on tumor cell growth. Results: In nonclinical studies, ASP3082 a protein degrader under investigation showed sustained decreases in KRAS G12D mutated protein level and induced significant growth inhibition of the tumors in the mouse model. The proposed QSP model predicted the nonclinical data and was used to determine the optimal first-in-human (FIH) efficacious dose. The efficacious dose was defined as dose resulting in 100% tumor growth inhibition relative to baseline tumor size. Conclusions: The designed degradation QSP model was used to estimate the optimal efficacious dose in the ongoing first in human study (NCT05382559). Citation Format: Pouye Sedighian, Stanley C. Gill, Junko Toyoshima, Yoshihiro Nishizono, Mamoru Tasaki, Kanako Iguchi, Yosuke Yamanaka, Peter Bonate. Optimal efficacious dose prediction of a novel protein degrader ASP3082 selectively targeting KRAS G12D using quantitative systems pharmacology [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A070.