Abstract 2790: Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors

Abstract

Abstract Growing evidences of covalent irreversible inhibitors in clinical treatments of solid tumors with KRAS G12C mutation have recently emerged after FDA-approved AMG510 (Sotorasib) for NSCLC chemotherapies. ZG19018 is an irreversible KRAS G12C inhibitor with novel structure that shows promising preclinical results for in vitro molecular and biological studies and in vivo G12C-mutated cancer models and safety studies in animals. For instance, ZG19018 rapidly and selectively forms covalent bonds with G12C-GDP, which accounts for lock-in KRAS protein as the inactive GDP-bound state but inhibits the activation of numerous downstream signaling pathways like RAF/MEK on ERK phosphorylation. ZG19018 showed highly inhibition of a 3D growth panel for human cancer cell lines harboring the KRAS G12C mutation, e.g. H358 (NSCLCs), MIA PaCa-2 (pancreatic) and SW837 (colorectal), etc. For pharmacodynamics, a battery of in vitro and in vivo ADME/DMPK studies indicated a high plasma protein binding (>99.6%) of ZG19018 with over 40% bioavailability in rat and dog via oral administration for the adequate drug levels in various tissues including lung, crossing BBB to reach brain, and accumulation in tumors. For in vivo anti-tumor efficacy, ZG19018 exhibited significant dose-dependent inhibition of tumor growth of G12C-driven subcutaneous models in nude mouse like H358 NSCLC cells but induced further tumor regression in pancreatic cancer MIA PaCa-2 xenograft. ZG19018 also showed an enhanced anti-tumor activities as combined with chemo-reagent Donafinib, a broad tyrosine kinase inhibitor blocking RAF/MEK/ERK signaling pathways of tumor cells, in the same H358 xenograft model. The general toxicology studies in rat under 28 days repeated oral administration (q.d.) showed NOAEL and STD10 values at 75 and 150 mg/kg/day, respectively. The safety pharmacological studies showed no notable effects of ZG19018 on the cardiovascular, respiratory and CNS systems. The genotoxic potential studies indicated ZG19018 without mutagenesis. Collectively, ZG19018 is now in phase I/II clinical trials for the treatments of solid tumors with KRAS G12C mutation in China. Citation Format: Bing Zhu, Dawei Cui, Ruifeng Liu, Weidong Feng, Zelin Sheng, Binhua Lv. Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors [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 2790.