Insilico Medicine Nominates Pan-KRAS Preclinical Candidate ISM6166 to Tackle “Undruggable” Solid Tumors, Showing Tumor Regression in Preclinical Studies

● Tackling “undruggable” target: ISM6166 was nominated as a PCC as an oral, broad-spectrum pan‑KRAS ON/OFF inhibitor, designed to cover multiple KRAS alterations and has the potential to overcome drug resistance associated with current KRAS therapies

● Promising efficacy and balanced properties: ISM6166 showed not only tumor growth inhibition but also pronounced tumor regression, along with strong selectivity and favorable PK profiles in preclinical study.

● Insilico is advancing IND-enabling studies for ISM6166 and aims to bring this potential best-in-class candidate into the clinic, either independently or with experienced partners

Shanghai, China — February 27, 2026 — Insilico Medicine (“Insilico”, 3696.HK), a clinical-stage, generative artificial intelligence (AI)-driven drug discovery company, today 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, playing a key role in regulating the proliferation and survival of tumor cells. For decades, the KRAS protein was considered an "undruggable" target due to its exceptionally smooth surface and high affinity for GTP, which left few "pockets" for traditional drugs to bind to. 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.

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

By using Insilico’s Chemistry42 and AIchemistry platforms to enable parallel multi-parameter optimization of potency, selectivity, ADMEPT properties and developability, ISM6166 was discovered with a well-balanced profile that features robust anti-tumor activity and favorable pharmacokinetic (PK) properties.

In preclinical studies, ISM6166 demonstrated exceptional anti-tumor efficacy. In lung cancer model, oral administration of ISM6166 achieved 86.2% tumor growth inhibition (TGI) and 55.1% tumor regression at 10 mg/kg and 30 mg/kg, respectively. The anti-tumor efficacy was even more pronounced in gastric cancer model, where a 5 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 effectively shrink tumors with diverse KRAS alterations.

Beyond its high potency, ISM6166 maintained high selectivity against other RAS family members, which is critical for reducing potential side effects. Moreover, the compound showed favorable plasma clearance and acceptable oral bioavailability across four preclinical species, supporting its potential as a best-in-class pan-KRAS inhibitor.

“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,” 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.