AI breakthrough "unmakeable" INSILICO(03696) pan-KRAS inhibitor ISM6166 achieves preclinical tumor regression

KRAS belongs to the RAS oncogene family, is one of the genes with the highest mutation rate in cancer, but its surface is abnormally smooth, lacks drug binding pockets, and has a high affinity for GTP/GDP, making it a traditionally "undruggable" target. Current KRAS inhibitors have made some progress by targeting specific mutations such as KRAS G12C, but still cannot provide effective treatment for a large number of patients with other KRAS mutation types, and the development of acquired resistance with long-term use remains a difficult barrier to overcome. Addressing the pain points of the industry, INSILICO (03696) has a broad KRAS inhibition strategy that can target multiple key mutations, nominating the oral small molecule ISM6166 that can simultaneously target the ON/OFF status of the KRAS protein. It is expected to cover a variety of KRAS-driven solid tumors such as lung cancer, pancreatic cancer, colorectal cancer, and gastric cancer, with significant potential for indication expansion. Importantly, ISM6166 has shown significant tumor inhibition and regression effects in preclinical studies, while maintaining high selectivity and good pharmacokinetic (PK) properties, and achieving a balanced drug-like profile. Its discovery and optimization process is empowered by the INSILICOChemistry42 and AIchemistry platforms. In lung cancer models, ISM6166 achieved a tumor growth inhibition rate (TGI) of 86.2% at a dose of 10 mg/kg, and tumor regression of 55.1% at a dose of 30 mg/kg. The anti-tumor efficacy in gastric cancer models was even more significant, with a TGI of 99.5% at a dose of 5 mg/kg, and inducing tumor regression of up to 65.8% at higher doses. These data indicate that ISM6166 not only inhibits tumor growth but also effectively reduces tumor size in various KRAS-mutant tumor models. Furthermore, ISM6166 maintains high selectivity for other RAS family proteins, providing crucial support for reducing off-target toxicity risks and minimizing potential side effects. In four preclinical species, ISM6166 has demonstrated good plasma clearance rates and acceptable oral bioavailability, fully supporting its potential as the best oral therapy of its kind. This is not the first time that INSILICO has ventured into the "undruggable" field using its proprietary AI advantages. In 2025, INSILICO made it to the annual top ten research advancements list of Nature Biotechnology for its KRAS-related research conducted in collaboration with academic partners, and even featured on the cover of that issue. In this study, the team combined quantum computing with classical computing methods to design small molecules targeting KRAS, ultimately synthesizing 15 candidate molecules and identifying 2 with good activity for further optimization.