Abstract A060: Characterization of PSTA-5204, an oral KRAS G12D (ON) inhibitor with potent in vitro and in vivo efficacy

Abstract Introduction The KRAS G12D mutation is one of the most prevalent oncogenic RAS alterations, particularly in pancreatic (∼40%), colorectal (∼15%), and non-small cell lung cancers (∼5%). Therapeutic strategies targeting this mutation include KRAS G12D inhibitors designed to bind either the GDP-bound (inactive), GTP-bound (active), or both conformations of the protein—referred to as OFF, ON, and ON/OFF inhibitors, respectively. At ASCO, KRAS G12D (ON) inhibitor RMC-9805 and (ON/OFF) inhibitor VS-7375 showed promising clinical antitumor activity in NSCLC and PDAC. RMC-9805 demonstrated an impressive safety profile, with low rates of dose modification and grade ≥3 adverse events. Building on this momentum, we describe the discovery of PSTA-5204, a novel oral KRAS G12D (ON) inhibitor with potent in vitro activity and strong in vivo efficacy. Parallel efforts to develop selective KRAS G12V inhibitors are also underway and will be reported. Methods and Results PSTA-5204 is a covalent KRAS G12D inhibitor that demonstrates strong target engagement and potent anticancer activity in KRAS-G12D mutant cancer cells, with >50-fold selectivity over wild type cells. Across a panel of KRAS G12D-mutant cell lines, PSTA-5204 exhibited nanomolar antiproliferative activity, while showing minimal activity in KRAS wild-type cells (IC50>1uM). In addition, PSTA-5204 inhibited p-ERK in KRAS G12D mutant ASPC1 cell with an IC50 of 6 nM, displaying 4-fold greater potency than RMC-9805. PSTA-5204 demonstrated favorable pharmacokinetic (PK) properties. In mouse, it exhibited very low systemic clearance and a relatively long half-life (∼4 hours). In rat, it showed moderate-to-low clearance and a large volume of distribution (Vd) of ∼ 4.3 L/kg, resulting in a half-life of 4∼5 hours. These PK characteristics, particularly the large Vd and prolonged half-life are expected to enhance in vivo efficacy. In a PK-59 PDAC xenograft model (KRAS G12D), PSTA-5204 achieved tumor growth inhibition (TGI) of 97% and 111% at doses of 7.5 and 15 mg/kg, respectively, compared to 113% TGI for RMC-9805 at 30 mg/kg. Notably, tumors in the PSTA-5204 15 mg/kg group showed near-complete regression by day 21 post-treatment. PSTA-5024 was well tolerated throughout the study and showed no evidence of hERG inhibition, supporting its safety profile. Conclusions PSTA-5204, an oral KRAS G12D (ON) inhibitor, demonstrates enhanced in vitro potency, near-complete tumor growth inhibition at a low dose of 7.5 mg/kg, along with a favorable pharmacokinetic and safety profile—highlighting its potential as a preclinical candidate. Citation Format: Lihong Hu, Wenxi Li, Zhenzhen Zhu, Zhouchong Wang, Tao Yu, Zhichao Wang, Chi-Chung Chan, Jian Li, Shuhui Chen. Characterization of PSTA-5204, an oral KRAS G12D (ON) inhibitor with potent in vitro and in vivo efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A060.