Abstract A071: Non-clinical study of ASP4396, a novel KRAS G12D degrader, shows remarkable anti-tumor activity in KRAS G12D mutant cancer models

Abstract Background: Mutated KRAS is the well-known oncogene with the highest mutation rates and is known to initiate the oncogenic signaling pathways in many types of cancer with a poor prognosis. Among the variety of point mutations of KRAS, KRAS G12D is the most commonly observed KRAS mutation. We have already reported the discovery of ASP3082 as the first clinical KRAS G12D degrader (NCT05382559). In this presentation, we introduce another KRAS G12D degrader, ASP4396, which uses a different E3 ligase than ASP3082, as well as the non-clinical profile of ASP4396 and the differences between the two compounds. Methods: We evaluated degradation of KRAS G12D protein, suppression of downstream signal pathway and inhibition of cell growth by ASP4396 in human cancer cells harboring KRAS G12D mutation using in-cell western blotting and cell viability assay. We also confirmed the difference between the efficacy in KRAS wild-type and KRAS G12D-mutated cell lines by cell growth assay. We evaluated the anti-tumor activity of ASP4396 in mice subcutaneously xenografted with KRAS G12D-mutated pancreatic cancer cells and verified the degradation of KRAS G12D in tumors by western blotting. Results: ASP4396 effectively degraded KRAS G12D-mutated protein, suppressed the phosphorylation of ERK, a key component of the downstream signal pathway, and exhibited the strong growth inhibitory activity in three different KRAS G12D-mutated pancreatic cancer cells. On the other hand, the inhibitory effect on growth was not observed in wild-type KRAS cell lines. In vivo experiment using PK-59 pancreatic cancer xenograft model revealed that once-weekly intravenous administration of ASP4396 induced significant growth inhibition of KRAS G12D pancreatic tumors, resulting in profound tumor regression without body weight loss. ASP4396 demonstrated sustained suppression of KRAS G12D-mutated protein levels in xenograft tumors following a single intravenous administration. Conclusions: A series of our non-clinical studies suggested that ASP4396 could be a promising therapeutic agent for patients with tumors harboring the KRAS G12D mutation. With these results, a Phase I clinical trial is underway (NCT06364696). We are conducting further characterization to understand the differences in the profiles of ASP3082 and ASP4396 due to the differences in E3 ligase and their impact on their respective efficacy and safety profiles. We believe that developing several protein degrader drugs using different types of E3 ligases will maximize patient value and also contribute to future therapeutic research based on targeted protein degradation. References 1. Uprety D, Adjei AA. Cancer Treat Rev. 2020 Sep;89:102070. 2. Li S, Balmain A, Counter CM. Nat Rev Cancer. 2018 Dec;18(12):767-777. 3. Goulding RE et al., Cancer Treat Res Commun. 2020; 24:100200. 4. Tao LY et al., World J Surg Oncol. 2016 May 16:14:146 5. Nagashima T et al., Cancer Res, 2023; 83: 7_Supplement: 5735 Citation Format: Kanako Iguchi, Kohei Inamura, Mamoru Tasaki, Asuka Saito, Chikako Sato, Ayako Nakayama, Yutaro Ono, Masatoshi Yuri, Tomohiro Yoshinari, Takeyuki Nagashima. Non-clinical study of ASP4396, a novel KRAS G12D degrader, shows remarkable anti-tumor activity in KRAS G12D mutant cancer models [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 A071.