Insilico Medicine has nominated ISM6166 as a preclinical candidate, a potent, oral pan-KRAS inhibitor designed to treat a broad spectrum of solid tumours. 

Among the Ras family of oncogenes, KRAS is one of the most frequently altered drivers in human cancer, playing a key role in regulating the proliferation and survival of tumour cells. 

While the first-generation of KRAS inhibitors have shown success against specific mutations such as G12C, their clinical impact is constrained by rapidly acquired resistance and a limited patient population. 

By targeting a broader spectrum of major KRAS alterations and binding the protein in both ‘ON’ (GTP-bound) and ‘OFF’ (GDP-bound) states, Insilico hopes that ISM6166 offers broader patient population coverage and a more durable response for patients who have exhausted current therapeutic options. 

In a preclinical lung cancer model, oral administration of ISM6166 achieved 86.2% tumour growth inhibition (TGI) and 55.1% tumour regression at 10mg/kg and 30mg/kg, respectively. In a gastric cancer model, a 5mg/kg dose reached 99.5% TGI, and higher doses induced up to 65.8% tumour regression. These findings suggest that ISM6166 does not merely halt cancer growth but can effectively shrink tumours with diverse KRAS alterations. 

ISM6166 also maintained high selectivity against other RAS family members and showed favourable plasma clearance and acceptable oral bioavailability across four preclinical species. 

Feng Ren, Co-CEO and Chief Scientific Officer of Insilico Medicine, commented: “By leveraging AI and Chemistry42 to rapidly explore and optimise 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 tumours.” 

Looking ahead, Insilico plans to accelerate IND-enabling studies for ISM6166 and advance the programme into clinical trials, either independently or in collaboration with partners.