Abstract A068: Preclinical investigation of orally bioavailable, potent pan-KRAS (ON/OFF) inhibitor JAB-23E73

Abstract Background: Mutant KRAS is commonly found as an oncogenic driver and has remained an undruggable target for decades. Despite the recent success of mutant-specific KRASG12C inhibitors, there are limited therapeutic options for patients carrying other KRAS driver mutations. Development of pan-KRAS inhibitors targeting a broad range of KRAS-driven cancers represents a promising strategy to address the unmet patient needs. Methods: The Induced Allosteric Drug Discovery Platform (IADDP) integrating medicinal chemistry, biophysical studies and computational techniques was applied for the design of JAB-23E73. Surface Plasmon Resonance (SPR) was applied to determine JAB-23E73 binding affinity for KRAS. Guanine nucleotide exchange assay and effector interaction assay were applied to measure the functional inhibition of GDP- and GTP-bound KRAS at the biochemical level. ERK phosphorylation assay and CellTiter-Glo assay were performed to evaluate KRAS downstream signaling inhibition and cell viability, respectively, in both KRAS-dependent and -independent tumor cells. In vivo PK/PD study was conducted to evaluate the relationship between drug concentration and the level of ERK phosphorylation in tumor. The antitumor activity of JAB-23E73 was evaluated in multiple CDX and PDX models carrying different KRAS mutations. Results: Affinity measurement by SPR indicated strong binding of JAB-23E73 to KRAS mutants (such as G12A/D/V and G13D) as well as wild-type KRAS in both GDP- and GTP-bound states, with most KDs in the sub-nanomolar range. Biochemical assays demonstrated high potency of JAB-23E73 on multiple KRAS mutants including G12A/D/V, G13D, and Q61H in either “off” state (with sub-nanomolar to nanomolar IC50s) or “on” state (with double-digit nanomolar IC50s), with more than 1000-fold selectivity over HRAS and NRAS. JAB-23E73 significantly inhibited ERK phosphorylation (with sub-nanomolar to nanomolar IC50s) and reduced viability (with single-digit nanomolar IC50s) of tumor cells harboring various KRAS driver mutations or amplification. In vivo PK/PD study showed that JAB-23E73 exposure in plasma and tumor has good correlation with inhibition of tumor ERK phosphorylation. Furthermore, JAB-23E73 monotherapy by oral administration showed potent antitumor activity and was well tolerated in multiple KRAS G12D, KRAS G12V, KRAS G12A and KRAS G13D mouse models. Conclusions: JAB-23E73 is a highly potent, orally bioavailable pan-KRAS (ON/OFF) inhibitor with strong selectivity to spare HRAS and NRAS inhibition. It exhibited superior antitumor activity and good tolerability in KRAS-driven mouse tumor models. JAB-23E73 is currently in Phase I clinical trials for patients with advanced solid tumors harboring KRAS gene alterations (NCT06959615 in China and NCT06973564 in the US). Citation Format: Peng Wang, Xiaoyu Liu, Wei Zhang, Dan Liu, Xueting He, Cunbo Ma, Amin Li, Yiwei Lin, Xin Sun, Wei Long, Yanping Wang. Preclinical investigation of orally bioavailable, potent pan-KRAS (ON/OFF) inhibitor JAB-23E73 [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 A068.