Abstract 1660: Preclinical investigation of orally bioavailable, potent KRASMulti inhibitor JAB-23425

Abstract

Abstract Background: Mutant KRAS is an important driver of tumor and has remained an undruggable target for decades. Despite the success of mutant-specific KRASG12C inhibitors, there is limited therapeutics for most KRAS-mutated patients (e.g., KRASG12D, KRASG12V and KRASG13D). Developing KRASMulti inhibitor targeting a broad range of KRAS-driven cancers is another promising strategy. Methods: The Induced Allosteric Drug Discovery Platform (IADDP) integrating medicinal chemistry, biophysical studies and computational techniques was applied for the development of JAB-23425. Surface Plasmon Resonance (SPR) was applied to determine JAB-23425 binding affinity on KRAS. Guanine nucleotide exchange assays and effector interaction assays were applied to determine the functional inhibition of GDP- and GTP-bound KRAS in biochemical level. ERK phosphorylation assays and CellTiter-Glo assays in both KRAS-dependent and KRAS-independent cells were performed to evaluate the inhibitory activities of downstream signaling of KRAS and cell viability. In vivo PK-PD study was conducted to evaluate the relationship between drug concentration and the level of tumor ERK phosphorylation. Antitumor activity of JAB-23425 was evaluated in multiple mouse models of KRAS mutant cancer. Results: Affinity measurement by SPR indicated strong binding of JAB-23425 to KRASG12D, KRASG12V, KRASG13D, KRASG12A, KRASG12R and KRASQ61H mutants as well as wild-type KRAS in both GDP- and GTP-bound states, with most KD in the sub-nanomolar range. Biochemical assays consistently demonstrated high potency of JAB-23425 on multiple KRAS mutants, and good selectivity over HRAS and NRAS. At the cellular level, JAB-23425 significantly reduced downstream ERK phosphorylation (most IC50 around 1 nM) and inhibited cell viability (most IC50 lower than 10 nM) on KRAS-dependent tumor cells harboring various KRAS mutations and amplification, with good selectivity against normal cells and KRAS-independent tumor cells (e.g., NRASmut and BRAFV600E). Above in vitro data showed that JAB-23425 is a potent and selective KRASMulti inhibitor and can spare HRAS and NRAS inhibition. In vivo PK-PD study showed that JAB-23425 exposure in plasma and tumor has good correlation with inhibition of tumor ERK phosphorylation. Furthermore, JAB-23425 monotherapy by oral administration showed potent antitumor activity and good tolerability in multiple KRASG12D, KRASG12V and KRASG13D mouse models. Conclusions: Our preclinical results identified JAB-23425 as a highly potent, orally bioavailable KRASMulti inhibitor, that can target multiple KRAS-driven cancers. Citation Format: Peng Wang, Yanping Wang, Xin Sun, Dan Liu, Xiaoyu Liu, Wei Zhang, Xueting He, Rui Zhou, Cunbo Ma, Amin Li, Yiwei Lin, Wei Long. Preclinical investigation of orally bioavailable, potent KRASMulti inhibitor JAB-23425 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1660.