(Press-News.org) NLRP3 is a validated anti-inflammatory target that mediates the release of proinflammatory cytokines IL-1β and IL-18, and ISM5059 targets systemic inflammatory conditions by targeting NLRP3 and blocking the inflammatory cascade at its source.
Unlike ISM8969, Insilico’s brain-penetrant NLRP3 pipeline already with FDA IND clearance, ISM5059 features a completely different chemical core designed for peripheral-restricted potency.
Empowered by AI, ISM5059 demonstrated robust efficacy, excellent safety profiles in preclinical studies, and low predicted human efficacious dose, with high potential in multiple indications including autoimmune and chronic cardiometabolic diseases with no obvious CNS (central nervous system) related toxicity observed in preclinical studies.
The NOD-like receptor protein 3 (NLRP3) inflammasome is a validated target for anti-inflammatory drug development. Upon activation by internal and external stimuli, NLRP3 mediates the release of proinflammatory cytokines IL-1β and IL-18, thereby driving a form of inflammatory cell death called pyroptosis. NLRP3 plays an important role in a variety of inflammatory diseases, including metabolic and cardiovascular disorders. Currently, there is a significant unmet clinical need in the treatment of systemic inflammatory diseases, highlighting the urgent demand for innovative drug options with greater efficacy and a wider safety margin.
Insilico Medicine (3696.HK), a clinical-stage, generative AI-driven drug discovery company, today announced the nomination of ISM5059, an AI-empowered, peripherally restricted small molecule inhibitor targeting NLRP3 as preclinical candidate compound (PCC). Guided by Pharma.AI, Insilico’s proprietary generative platform covering the whole cycle of drug discovery, ISM5059 features a novel core structure, was specifically designed to inhibit NLRP3 conformational changes and oligomerization, while maintaining exceptional safety profiles.
“Targeting NLRP3 offers tremendous potential across a pipeline-in-a-drug model. Beyond classic immune and inflammatory diseases, NLRP3 overactivation is a key driver in lifestyle-associated and metabolic disorders such as obesity, hyperlipidemia, diabetes, and cardiovascular disease.” said Feng Ren, Ph.D., Co-CEO and Chief Scientific Officer of Insilico Medicine. “More importantly, ISM5059 comes with peripheral-restricted trait and a novel chemical core structure, demonstrating how generative AI can produce highly potential molecules with desired properties and innovative structures.”
In preclinical studies, ISM5059 has demonstrated high potency and selectivity, favorable safety profiles and excellent in vivo efficacy across animal disease models, supporting broad indication potential expanding into autoimmune and inflammatory diseases, metabolic diseases, cardiovascular diseases and ophthalmology diseases. Moreover, ISM5059 is predicted to be efficacious at a low dose in humans, providing a high safety margin for future validation.
the in vivo peritonitis model, ISM5059 demonstrated a robust, dose-dependent inhibition of Interleukin-1β (IL-1β), a potent pro-inflammatory cytokine as a master regulator of the inflammatory response. Notably, even at the lowest tested dose of 0.3 mg/kg, IL-1β levels were nearly halved compared to the vehicle control group. This was followed by a steep, progressive reduction at higher dose levels, highlighting ISM5059‘s high potency in suppressing acute inflammatory responses.
This nomination follows the recent FDA IND approval for Insilico’s other NLRP3 program, ISM8969, a potential best-in-class, brain-penetrant candidate discovered and optimized through Insilico Medicine’s Pharma.AI platform and intended for the treatment Parkinson’s disease. To accelerate the development of ISM8969, Insilico has entered into a co-development collaboration with Hygtia Therapeutics, where both parties hold 50% of the global rights, and Insilico is eligible to receive up to $66 million in upfront and milestone payments.
Harnessing state-of-the-art AI and automation technologies, Insilico has significantly improved the efficiency of preclinical drug development, setting a benchmark for AI-driven drug R&D. While traditional early-stage drug discovery typically requires an average of 4.5 years, Insilico has nominated 20 preclinical candidates from 2021 to 2024, with an average timeline—from project initiation to preclinical candidate (PCC) nomination—of just 12 to 18 months per program, with only 60 to 200 molecules synthesized and tested in each program.
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 healthy 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
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