ASP3082, a First-in-class novel KRAS G12D degrader, exhibits remarkable anti-tumor activity in KRAS G12D mutated cancer models

Background: KRAS is one of the most frequently mutated oncogenes in various cancers. Among KRAS mutations, KRAS G12D is the most frequent driver mutation and is found in approximately 34% of pancreatic ductal adenocarcinoma (PDAC), 10% to 12% of colorectal cancer, 4% of lung adenocarcinoma and also in a subset of other solid tumors. However, there is no direct KRAS G12D-targeted inhibitors used in the clinical setting. Here, we identified ASP3082, a novel KRAS G12D degrader with high potency and selectivity. Methods: We investigated (1) binding affinity of ASP3082 to KRAS G12D protein and an E3 ligase in the conditions of binary complex and ternary complex formation using surface plasmon resonance assay, (2) degradation activity of ASP3082 on KRAS G12D protein using western blotting or in-cell western method, (3) inhibitory effect of ASP3082 on the growth of human cancer cells harboring KRAS G12D mutation and KRAS wild-type, (4) specificity for ASP3082-mediated degradation using proteomics approach, (5) antitumor activity of ASP3082 in mice subcutaneously xenografted with KRAS G12D-mutated pancreatic cancer cells, (6) PK-PD profile of ASP3082 after a single intravenous administration in the xenograft model. Results: ASP3082 directly bound to KRAS G12D-mutated protein and the E3 protein to form a ternary complex. Also, ASP3082 potently degraded KRAS G12D-mutated protein and inhibited phosphorylation of ERK in KRAS G12D-mutated pancreatic cancer cells. In addition, ASP3082 showed the growth inhibitory activity of KRAS G12D-mutated pancreatic cancer cells, but not of KRAS wildtype cancer cells. Furthermore, the quantitative proteomics analysis suggested that ASP3082 selectively degraded the KRAS G12D-mutated protein over other (>9000) proteins. in vivo experiment revealed that once-weekly intravenous administration of ASP3082 induced dose-dependent and significant growth inhibition of KRAS G12D PDAC tumors, resulting in profound tumor regression without body weight loss. ASP3082 showed sustained concentrations in the xenograft tumors after a single intravenous administration and decreased KRAS G12D-mutated protein levels according to the duration of the ASP3082 concentrations. Conclusions: ASP3082 is a potential therapeutic agent for patients with tumors harboring the KRAS G12D mutation. Currently, Phase I clinical trial is underway (NCT05382559). Conflict of interest: Corporate-sponsored Research: All authors are employees of Astellas Pharma Inc.