Abstract A059: Discovery of PSTA-2413, an oral pan-RAS inhibitor with wild type selectivity and potent in vitro and in vivo efficacy

Abstract Introduction The RAS pathway is one of the most frequently dysregulated oncogenic drivers, implicated in approximately 20–30% of all human cancers. KRAS mutations are highly prevalent in pancreatic (∼90%), colorectal (∼40%), and NSCLC cancers (∼30%). Multiple therapeutic strategies are under exploration to target the KRAS pathway—including mutation-specific inhibitors (e.g., G12C, G12D), pan-KRAS inhibitors, and broader multi-RAS approaches. While each modality offers distinct advantages and limitations, a consensus on the optimal strategy has yet to emerge. These efforts are paving the way towards personalized treatment of RAS-driven cancers. Here, we present the discovery of PSTA-2413, a novel oral pan-RAS inhibitor that demonstrates selectivity over wild-type KRAS and robust in vitro potency and in vivo efficacy. Methods and Results PSTA-2413 demonstrates potent and selective inhibition of KRAS-mutant cancer cells. In a panel of cell lines harboring KRAS G12C, G12D, and G12V mutations, PSTA-2413 exhibited IC50 values of 0.1 to 2 nM, representing a 3- to 7-fold increase in potency compared to RMC-6236 in head-to-head assays. PSTA-2413 retained nanomolar activity in AMG510-resistant cells, suggesting potential to overcome G12C inhibitor resistance. In contrast, PSTA-2413 showed relatively reduced activity in KRAS wild-type cells compared to RMC-6236 and ERAS-0015. Selectivity analysis using PK-59 (KRAS G12D) as a reference revealed a WT/G12D IC50 ratio of 13 for PSTA-2413, 3-fold higher than RMC-6236 (ratio: 3.8) and 10-fold higher than ERAS-0015 (reported ratio: 1.3), indicating a significantly improved therapeutic window. Pharmacokinetic (PK) profiling showed that PSTA-2413 has a clearance (CL) of 4.3 mL/min/kg, a Vdss of 2.1 L/kg, and a t1/2 of 7.9 hours, compared to 10.2 mL/min/kg, 1.4 L/kg, and 2.4 hours for RMC-6236. These attributes support its superior in vivo efficacy. Preliminary PK modeling predicts that PSTA-2413 will be suitable for once-daily (QD) administration in humans. In a PK-59 xenograft model (KRAS G12D), PSTA-2413 achieved tumor growth inhibition (TGI) of 109%, 110% and 111% at doses of 0.3, 1 and 3 mg/kg, respectively, compared to 105% TGI for RMC-6236 at 3 mg/kg. The ED50 for PSTA-2413 was around 0.1 mg/kg. Similarly, in the NCI-H727 xenograft model (KRAS G12V), PSTA-2413 achieved TGIs of 104% and 107% at 1 and 3 mg/kg, respectively, versus 100% for RMC-6236 at 3 mg/kg further highlighting the enhanced antitumor activity of PSTA-2413 across KRAS mutation subtypes. Mice tolerated PSTA-2413 well through efficacy studies. PSTA-2413 was negative in mini-Ames, micronuclear test with no hERG issue. A preliminary rat toxicity study indicated a 10-fold safety margin. Conclusions PSTA-2413 shows distinct advantages over existing pan-RAS inhibitors, including enhanced in vitro potency, selectivity over wild-type KRAS, robust in vivo antitumor activity with tumor regression, favorable pharmacokinetics, and a promising safety profile—supporting its potential for clinical advancement. Citation Format: Lihong Hu, Wenxi Li, Zhenzhen Zhu, Zhouchong Wang, Tao Yu, Zhichao Wang, Chi-Chung Chan, Jian Li, Shuhui Chen. Discovery of PSTA-2413, an oral pan-RAS inhibitor with wild type selectivity and 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 A059.