D3S-003, an orally bioavailable potent and selective dual-state inhibitor targeting both GDP- and GTP-bound KRAS G12D
Presenter: Jing Zhang, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Jing Zhang 1 , Tienan Wang 1 , Robert A. Mook Jr. 2 , Haibo Xie 1 , Shaonan Wang 1 , Zhiqiang Zheng 1 , Xin Xiong 1 , Hui Wang 1 , Zhi Jian Chen 1 1 D3 Bio, Inc., Shanghai, China, 2 Department of Medicine, Duke University Medical Center, Durham, NC
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 i n 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.
Disclosure
J. Zhang, D3 Bio, Inc. Employment. T. Wang, D3 Bio, Inc. Employment. R. A. Mook Jr., D3 Bio, Inc. Other, Robert A. Mook, Jr. is a consultant for D3 Bio and a professor at Duke University. This work was conducted independently of any of his government-funded research. H. Xie, D3 Bio, Inc. Employment. S. Wang, D3 Bio, Inc. Employment. Z. Zheng, D3 Bio, Inc. Employment. X. Xiong, D3 Bio, Inc. Employment. H. Wang, D3 Bio, Inc. Employment. Z. Chen, D3 Bio, Inc. Employment, g., Board of Directors, non-salaried role).
Cited in
Control: 3397 · Presentation Id: 8827 · Meeting 21436