image: In diet-induced obese (DIO) humanized GIPR mice, ISM0676 treatment led to significant body weight reduction along with improved body composition, as indicated by a higher lean mass-to-body weight ratio. After 27 days of dosing, ISM0676 achieved a 10.4% reduction in body weight from baseline, compared to 3% increase in the DIO vehicle group. Furthermore, when combined with Semaglutide, ISM0676 led to a substantially enhanced body weight loss of 31.3%.
Credit: Insilico Medicine
- Targeting glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising strategy against obesity and related diseases through the “incretin effect” and regulation of other biological processes.
- Empowered by the comprehensive abilities of Chemistry42, Insilico nominates ISM0676, the novel, oral available GIPR antagonist, as a clinical candidate compound (PCC) with both monotherapy and combination potential. The process from project initiation to PCC took 14 months, with less than 200 molecules synthesized and tested.
- Preclinical studies have highlighted up to 31.3% body weight loss in diet-induced obese (DIO) humanized GIPR mice when co-administered with semaglutide. ISM0676 also demonstrated excellent in vivo metabolic stability, low drug-drug interaction risk, favorable safety profiles, and low predicted human efficacious dose, supporting future development.
The global demand for effective obesity treatments has been surging, with a market size projected to reach USD 60.53 billion by 2030, yet latest therapies including GLP-1 receptor agonists (GLP-1RAs) still face challenges represented by lean mass loss, efficacy plateaus, rapid weight regain upon withdrawal, and patient adherence.
The GIP receptor (GIPR), activated by its ligand GIP, which plays a crucial role in metabolism by regulating insulin secretion, controlling fat storage in tissues, maintaining bone composition and turnover, and influencing appetite through the central nervous system. By targeting GIPR in combination with GLP-1 therapies, novel drug candidates could possibly overcome the key shortcomings of current obesity treatments and deliver more sustainable, patient-friendly solutions for weight management.
Insilico Medicine ("Insilico"), a generative artificial intelligence (AI)-driven clinical-stage drug discovery company, today announces the nomination of ISM0676 as a Preclinical Candidate (PCC) targeting the Glucose-dependent Insulinotropic Polypeptide Receptor (GIPR). Developed as an orally bioavailable small molecule antagonist, ISM0676 is designed for the treatment of obesity and associated diseases, including Type 2 diabetes, with broad potential expanding into obesity-associated cardiovascular diseases, such as heart failure.
"The nomination of ISM0676 further enriches Insilico’s cardiometabolic pipeline programs driven by generative AI exploration, which is currently one of the core strategies of the company," said Feng Ren, Ph.D., Co-CEO and Chief Scientific Officer of Insilico Medicine. "From highly novel mechanisms to well validated targets, from fibrosis and cancer to cardiometabolic diseases, Insilico has proved how AI can accelerate diversified areas, and we look forward to advancing this program to further development stages, aiming to induce breakthroughs to chronic disease management with AI."
Empowered by Chemistry42, Insilico’s proprietary generative AI engine, and its affiliated applications including Alchemistry, ISM0676 was nominated 14 months after project initiation, with less than 200 molecules synthesized and tested. Compared to leading available therapies or drug candidates in development, ISM0676 has demonstrated excellent in vivo metabolic stability, superior in vivo efficacy at low doses, low drug-drug interaction (DDI) risk, favorable safety profile, and low predicted human efficacious dose.
In diet-induced obese (DIO) humanized GIPR mice, ISM0676 treatment led to significant body weight reduction along with improved body composition, as indicated by a higher lean mass-to-body weight ratio. After 27 days of dosing, ISM0676 achieved a 10.4% reduction in body weight from baseline, compared to 3% increase in the DIO vehicle group. Furthermore, when combined with Semaglutide, ISM0676 led to a substantially enhanced body weight loss of 31.3%. These collective results support its further clinical development.
“Metabolism involves fundamental biological processes in human life and has long been considered one of the key aging hallmarks. To achieve longer, healthier lives, Insilico has been investing into metabolic disease research with AI-driven speed and precision, as we believe efforts in this area could produce the first health span extension therapies at scale,” said Alex Zhavoronkov, PhD., Founder and CEO, CBO of Insilico Medicine, “The nomination of ISM0676 reflects how our Pharma.AI platform can rapidly design and optimize promising molecules to address urgent needs, bringing benefits for patients worldwide.”
Insilico Medicine continues to expand the application of its Pharma.AI platform into the high-demand area of cardiometabolic diseases, announcing multiple novel programs featuring both well-validated and rather innovative targets with novel chemical design, including ISM0676, the novel, oral available GIPR antagonist with favorable druggability and promising weight management potential.
Meanwhile, cutting-edge exploration is securing major partnerships as acknowledgement of Insilico’s technology-integrated R&D workflow. In January 2026 alone, Insilico announced two collaborations to further advance its cardiometabolic strategy, namely, the USD $66 million co-development collaboration with Hygtia Therapeutics to accelerate ISM8969, a brain-penetrant inhibitor targeting NLRP3 as a highly potential target at the intersection of inflammation and metabolism modulation, as well as the strategic partnership with Qilu Pharmaceutical targeting novel small molecule options for cardiometabolic disease management, with a total deal value approaching USD $120 million.
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