Insilico Medicine has nominated ISM6166 as a preclinical candidate, positioning the oral pan-KRAS inhibitor to target a broad range of solid tumours historically considered difficult to treat.

The Hong Kong-listed company (3696.HK) said ISM6166 is designed as a broad-spectrum, pan-KRAS ON/OFF inhibitor, covering multiple KRAS alterations and aiming to address resistance seen with first-generation KRAS-targeted therapies. The compound was generated and optimised using Insilico’s Chemistry42 platform.

KRAS remains one of the most frequently altered oncogenes in human cancer, driving tumour proliferation and survival in indications including lung, pancreatic, colorectal and gastric cancers. For decades, the protein was widely described as “undruggable” due to its smooth surface topology and high affinity for GTP and GDP, which limited opportunities for small-molecule binding. Although mutation-specific inhibitors such as G12C agents have reached the market, their clinical benefit is restricted to defined patient subsets and resistance commonly emerges.

Insilico said ISM6166 was engineered to bind KRAS in both its GTP-bound ‘ON’ and GDP-bound ‘OFF’ conformations. By targeting a broader spectrum of major KRAS alterations, the company believes the candidate could expand treatment coverage and support more durable responses, including in patients who have progressed on existing therapies.

According to preclinical data disclosed by the company, ISM6166 demonstrated tumour growth inhibition and regression across multiple models. In a lung cancer model, oral administration achieved 86.2% tumour growth inhibition at 10 mg/kg and 55.1% tumour regression at 30 mg/kg. In a gastric cancer model, a 5 mg/kg dose resulted in 99.5% tumour growth inhibition, while higher doses induced tumour regression of up to 65.8%.

The company said the compound also showed strong selectivity over other RAS family members, a factor considered important in limiting off-target effects. In addition, ISM6166 demonstrated favourable pharmacokinetic properties, including acceptable oral bioavailability and plasma clearance across four preclinical species, supporting further development.

Feng Ren, co-CEO and chief scientific officer at Insilico, said: “Due to the shallow binding pocket and high affinity for GTP/GDP, KRAS has long been regarded as an undruggable target in oncology, and it has challenged generations of drug developers. By leveraging AI and Chemistry42 to rapidly explore and optimize chemical space against demanding requirements, we aim to produce novel therapies with higher speed and quality, delivering a differentiated pan-KRAS candidate that supports durable responses through rational treatment combinations and provides better options for patients with KRAS-altered tumors.”

Insilico is advancing IND-enabling studies for ISM6166 and plans to move the programme into clinical trials, either independently or in partnership with experienced collaborators.

Beyond ISM6166, the company said it continues to explore advanced computational approaches for difficult drug targets. In earlier KRAS-focused research conducted with academic partners and published in Nature Biotechnology in 2025, the team combined quantum computing, artificial intelligence and classical computational methods to design small molecules against KRAS. Fifteen candidates were synthesised, with two progressing for further optimisation after demonstrating promising activity.

The nomination of ISM6166 adds to the growing pipeline of AI-enabled oncology programmes seeking to address historically challenging molecular targets, as companies attempt to broaden the impact of KRAS inhibition beyond mutation-specific approaches.