Abstract 4569: D3S-003, an orally bioavailable potent and selective dual-state inhibitor targeting both GDP- and GTP-bound KRAS G12D

Abstract KRAS G12D is the most prevalent KRAS mutation in human cancers and represents a highly attractive yet challenging oncogenic target. Compared with KRAS G12C, the intrinsic hydrolysis rate of KRAS G12D is significantly slower, resulting in a more persistent active (GTP-bound) state that limits the efficacy of GDP-state inhibitors. To address this challenge, we identified D3S-003, a potent and selective small-molecule inhibitor that targets both the GDP-bound (OFF) and GTP-bound (ON) forms of KRAS G12D through intensive optimization guided by molecular dynamics and co-crystal-based SAR interrogation. In SPR binding assays, D3S-003 sub-nanomolar affinity for both GDP-bound and GTP-bound KRAS G12D, with a target residence half-life exceeding 13 hours on the GDP-bound form, a key feature enabling a covalent-like inhibition. In biochemical assays, D3S-003 inhibited GDP-bound KRAS G12D nucleotide exchange and disrupted GTP-bound KRAS G12D-cRAF interaction with single-digit nanomolar IC50 values, validating its dual-state molecular mechanism of action. In cellular assays, D3S-003 demonstrated nanomolar IC50 inhibition in both p-ERK inhibition and proliferation across a panel of KRAS G12D-mutant cell lines, while maintaining high selectivity over KRAS non-G12D lines. Notably, D3S-003 showed improved potency and selectivity compared with RMC-9805, an investigational KRAS G12D (ON) inhibitor currently in clinical trials. D3S-003 exhibits desirable drug-like properties, oral bioavailability across multiple preclinical species, and a robust GLP safety profile. In in vivo studies, it demonstrated robust antitumor activity in KRAS G12D-driven HPAC pancreatic cancer xenografts, requiring only 17.5 nM·h and 56 nM·h free drug AUC to achieve 30% tumor regression (PR) and 100% complete remission (CR), respectively. Across a broad panel of PDX and CDX models of NSCLC and pancreatic cancer with KRAS G12D mutations and diverse genetic backgrounds, D3S-003 achieved a 70% overall response rate (ORR), indicating broad efficacy across these tumor types. Together, these findings highlight D3S-003 as a potent and selective KRAS G12D dual-state inhibitor with strong translational potential. A Phase 1 first-in-human (FIH) study is currently being planned. Citation Format: Jing Zhang, Tienan Wang, Robert A. Mook Jr., Haibo Xie, Shaonan Wang, Zhiqiang Zheng, Xin Xiong, Hui Wang, Zhi Jian Chen. D3S-003, an orally bioavailable potent and selective dual-state inhibitor targeting both GDP- and GTP-bound KRAS G12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4569.