Abstract 4382: Discovery and characterization of potent and orally bioavailable KRAS G12D inhibitors with therapeutic potential for KRAS G12D-mutated solid tumors

Abstract Background: KRAS G12D is the most prevalent KRAS mutation commonly found in pancreatic ductal adenocarcinoma (PDAC) and colorectal adenocarcinoma (CRC). This mutation drives tumorigenesis through aberrant downstream signaling, making it a critical therapeutic target. Tens of KRAS G12D inhibitors are currently under development, however many encounter challenges related to drug-likeness. Here, we present orally bioavailable KRAS G12D inhibitors designed to overcome these barriers. Methods: Binding affinity to KRAS-mutant proteins was evaluated using thermal shift assays (TSA). The inhibitory effects on cancer cells were assessed by measuring ERK phosphorylation levels via ELISA. Cell proliferation assays were performed across various KRAS wild-type (WT) and mutant cell lines to determine compound selectivity and potency. In vivo efficacy was assessed using PDAC and CRC models harboring KRAS G12D mutation. Combination studies were evaluated using in vitro cell proliferation assays, and synergistic effects were confirmed with Combenefit software. Results: A series of KRAS G12D inhibitors with novel and differentiated structures were identified through optimization of physicochemical properties to maintain inhibitory potency while achieving high plasma exposure following oral administration. These compounds exhibited strong binding affinity to KRAS G12D with remarkable selectivity over other KRAS mutant proteins. In KRAS G12D-driven cancer cell lines, our compounds demonstrated potent inhibition of pERK and cell proliferation at low nanomolar concentrations. In contrast, proliferation inhibition in cell lines expressing WT or other KRAS mutations was 50- to 1000-fold lower, highlighting exceptional KRAS G12D selectivity and minimal impact on normal cells. Additionally, our compounds exhibited favorable metabolic stability. Following oral administration at 30 mg/kg in mice, selected compounds achieved a Cmax exceeding 1 µg/mL, surpassing plasma exposure levels reported for other KRAS G12D inhibitors. High plasma and tumor exposure led to robust inhibition of pERK in tumor tissues. In KRAS G12D-driven pancreatic (PDAC) and colorectal (CRC) cancer xenograft models, oral administration of the lead compound resulted in potent, dose-dependent tumor growth inhibition without notable body weight loss. Conclusion: Our potent and selective KRAS G12D inhibitors demonstrate favorable ADME properties and significant antitumor activity in KRAS G12D-mutant xenograft models, addressing a critical unmet need for patients with KRAS G12D-driven cancers. Citation Format: Mijin Moon, Jiyoung Song, Soyoung Ki, Beomjin Hong, Ilkyoo Koh, Hyunho Cho, Seona Lim, Chuneung Park, Eunsung Jang, Gyeong Hi Cho, Hoiyun Jung, Minchang Cho, Sook-Kyung Park. Discovery and characterization of potent and orally bioavailable KRAS G12D inhibitors with therapeutic potential for KRAS G12D-mutated solid tumors [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 4382.