Insilico Medicine (“Insilico”), a clinical-stage, generative artificial intelligence (AI)-driven drug discovery company, recently announced the nomination of ISM6166 as a Preclinical Candidate (PCC), a potent, oral pan-KRAS inhibitor designed to treat a broad spectrum of solid tumors, including lung, pancreatic, colorectal, and gastric cancers, generated and optimized using its Chemistry42 platform.

Among the Ras family of oncogenes, KRAS is one of the most frequently altered drivers in human cancer, modulating how tumor cells multiply and survive. For decades, the KRAS protein was considered an "undruggable" target due to its exceptionally smooth surface and high affinity for energy molecules like GTP, which left few "pockets" for traditional drugs to bind to. While first-generation KRAS inhibitors have shown success against specific mutations such as G12C, their clinical impact is constrained by rapid acquired resistance and a limited patient population.

To overcome these limitations, Insilico developed ISM6166, a potential best-in-class pan-KRAS inhibitor. By targeting a broader spectrum of major KRAS mutations and locking the protein in both its 'ON' (GTP-bound) and 'OFF' (GDP-bound) states, ISM6166 offers the potential to expand treatment indications and provide a more durable response for patients who have exhausted current therapeutic options.

Discovered and optimized using Insilico’s Chemistry42 and AIchemistry platforms to enable parallel multi-parameter optimization of potency, selectivity, and developability, ISM6166 was engineered with a balanced druggability profile that pairs robust anti-tumor activity with favorable pharmacokinetic (PK) properties.

In preclinical studies, ISM6166 demonstrated exceptional anti-tumor efficacy. In lung cancer models, a 10 mg/kg dose achieved an 86.2% tumor growth inhibition (TGI), while a 30 mg/kg dose resulted in 55.1% actual tumor regression. Results were even more pronounced in gastric cancer models, where a 10 mg/kg dose reached 99.5% TGI, and higher doses induced up to 65.8% tumor regression. These findings suggest that ISM6166 does not merely halt cancer growth but can actively shrink tumors across diverse genetic backgrounds.

Beyond its high potency, ISM6166 maintained strong selectivity against related proteins like HRAS and NRAS, which is critical for reducing potential side effects. Across four preclinical species, the compound showed favorable plasma clearance and oral bioavailability, supporting its potential as best-in-class oral therapy.

“Due to the smooth surface 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,” said Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. “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.”

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

Insilico is also exploring advanced computing for hard drug targets. In earlier KRAS research with academic partners, published in Nature Biotechnology in 2025 and selected as one of the year’s “Top 10” research advances, the team combined quantum computing, AI, and classical methods to generate KRAS small-molecule designs, synthesized 15 candidates, and identified 2 with promising activity for further optimization.

About Insilico Medicine

Insilico Medicine is a pioneering global biotechnology company dedicated to integrating artificial intelligence and automation technologies to accelerate drug discovery, drive innovation in the life sciences, and extend health longevity to people on the planet. The company was listed on the Main Board of the Hong Kong Stock Exchange on December 30, 2025, under the stock code 03696.HK.

By integrating AI and automation technologies and deep in-house drug discovery capabilities, Insilico is delivering innovative drug solutions for unmet needs including fibrosis, oncology, immunology, pain, and obesity and metabolic disorders. Additionally, Insilico extends the reach of Pharma.AI across diverse industries, such as advanced materials, agriculture, nutritional products and veterinary medicine. For more information, please visit www.insilico.com