Abstract 1648: LT-010366, a first-in-class orally bioavailable KRAS G12D degrader in the treatment of multiple KRAS G12D-mutated cancer models <i>in vitro</i> and <i>in vivo</i>

Abstract Recent successes in targeting KRASG12C have provided both insight and inspiration for targeting alternative KRAS mutants. Among KRAS mutations, KRAS G12D is the most frequent driver mutated isoform and is found in approximately 34% of patients with pancreatic ductal adenocarcinoma (PDAC), 12% of patients with colorectal cancer (CRC), 4% of patients with lung adenocarcinoma, and in a subset of patients with other solid tumors. We have developed LT-010366 as a first-in-class orally bioavailable KRAS G12D degrader with high potency and selectivity. In In vitro degradation assays, LT-010366 demonstrated extraordinary degradation activities with DC50 of 0.96-2.55 nM and efficiency (Dmax) over 95% against KRAS protein in multiple cancer cell lines harboring KRAS G12D mutation, as well as remarkable inhibition of p-ERK with IC50 of 0.52-26.06 nM in those cell lines. In cell proliferation assays, LT-010366 showed a strong antiproliferative potency with IC50s of 0.12-15.77 nM and max inhibition of 74.42-98.4% in tested KRAS G12D mutant cancer cell lines. Moreover, LT-010366 selectively degrades KRAS, sparing HRAS and NRAS. In CDX tumor, daily oral administration of LT-010366 exhibited potent antitumor activities in both PDAC (PK-59) and CRC (GP2D) models with KRAS G12D mutation, resulting in profound tumor regression without body weight loss. In GP2D xenograft model, LT-010366 demonstrated dose-dependent tumor inhibition at the dose of 10 mg/kg, 30 mg/kg and 100 mg/kg PO, QD with TGI of 95.7%, 114.4% and 116.5% after 14-day treatment, respectively. In PK-59 model, LT-010366 demonstrated dose-dependent tumor inhibition at the dose of 3 mg/kg, 10 mg/kg and 30 mg/kg PO, QD with TGI of 69.3%, 116% and 126.8% after 15-day treatment, respectively. In GP2D model, LT-010366 also exhibited dose-dependent degradation of KRAS protein and demonstrated marked inhibition of downstream p-ERK and p-S6. In addition, LT-010366 also displays a high-quality drug-like profile. In summary, our results demonstrated that LT-010366 induced degradation of KRAS G12D protein, inhibition of KRAS downstream signaling mediators and exhibited antitumor activity in multiple KRAS G12D-mutated cancer cells in vitro and in vivo. LT-010366 is a promising therapeutic agent to be advanced to clinical development for patients with tumors harboring KRAS G12D mutation. Citation Format: Shuang Yan, Zhengqing Ye, Haiji Chen, Chenli Ding, Juan Xu, Yan Feng. LT-010366, a first-in-class orally bioavailable KRAS G12D degrader in the treatment of multiple KRAS G12D-mutated cancer models in vitro and in vivo [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 1648.