Breaking the Safety Barrier: Insilico Medicine Nominates ISM1354, Next-Gen Small-Molecule GIPR Antagonist

Powered by its generative-AI platform, Insilico Medicine nominated ISM1354—a novel small-molecule PCC targeting GIPR—for obesity, type 2 diabetes and cardiovascular indications; preclinical data show 75%–104% oral bioavailability, at least 18-fold greater plasma exposure than a clinical-stage benchmark, and a markedly wider safety window.

Amid accelerating population aging and surging demand for obesity and metabolic-disease treatments, GLP-1 receptor agonist (GLP-1RA) drugs are experiencing explosive growth—with tirzepatide becoming the new 'top drug' on 2025 sales of US$36.507 billion. To make weight management longer-acting and more precise, the industry has proposed combining a GIPR (glucose-dependent insulinotropic polypeptide receptor) antagonist with GLP-1 therapy to reduce fat while preserving muscle mass; yet several GIPR candidates have recently stumbled in the clinic due to toxicity and tolerability, underscoring the development challenge.

Insilico Medicine (HKEX: 3696), a clinical-stage biotech powered by generative AI, announced the nomination of ISM1354—an AI-driven, novel small-molecule preclinical candidate (PCC) targeting GIPR—for potential intervention in obesity, type 2 diabetes, and related metabolic disorders, with potential expansion into cardiovascular disease. Notably, Insilico nominated another GIPR antagonist, ISM0676, in January this year, which showed up to 31.3% weight loss in humanized mouse models when combined with semaglutide; ISM1354 retains robust weight-loss efficacy while delivering multidimensional improvements in pharmacokinetics and in vitro/in vivo safety.

Generative AI is demonstrating immense potential in cracking complex drug discovery challenges. Given the structural complexity and intricate functional mechanisms of GIPR, the identification of viable small-molecule GIPR antagonists and the optimization of their drug-like properties remain major challenges in drug development. However, by leveraging the highly efficient molecular generation and optimization capabilities of our Pharma.AI platform, we successfully overcame these bottlenecks in a very short time and nominated the next-generation GIPR antagonist, ISM1354. This breakthrough, balancing both speed and quality, is truly encouraging.

Leveraging its proprietary generative chemistry platform Chemistry42, the R&D team integrated multiple prediction modules into molecular generation and optimization—balancing potency, selectivity, and safety. A drug-induced liver injury (DILI) prediction model pre-filtered candidates with improved safety profiles, while free-energy perturbation (FEP) supported affinity prediction and ranking; after multiple design-make-test-analyze (DMTA) iterations, ISM1354 emerged as the candidate.

Preclinical studies showed that ISM1354 exhibits excellent and consistent pharmacokinetics across mice, rats, dogs, and monkeys, with oral bioavailability of 75%–104%. At the same dose, its plasma exposure was at least 18-fold greater than a clinical-stage benchmark compound. In vitro, ISM1354 showed substantially weaker OATP1B1 inhibition; in primary human and monkey hepatocytes it had minimal effect on viability even at 200 μM, whereas the benchmark compound showed cytotoxicity with IC50 of ~25 μM (human) and ~20 μM (monkey)—indicating a markedly wider safety window and lower hepatotoxicity risk. A non-GLP monkey toxicology assessment showed no significant toxicity signals, with a margin of safety (MOS) of about 45x.

Obesity is not an isolated health issue; it is also a driver of many diseases, and lipid metabolic disorder itself is one of the core hallmarks of biological aging. I believe GLP-1 class therapies have the potential to become among the first scalable 'longevity drugs,' a monumental opportunity that is hard to quantify in monetary terms. However, we must not sacrifice physical function and muscle mass for weight loss—this is a long-standing industry pain point.

About Insilico Medicine

Insilico Medicine is a global pioneering biotech dedicated to integrating artificial intelligence and automation to accelerate drug discovery and advance innovation across the life sciences, enabling longer and healthier lives. The company listed on the Main Board of the Hong Kong Stock Exchange on 30 December 2025 under the stock code 03696.HK. Using its proprietary Pharma.AI platform and advanced automated biology laboratories, Insilico delivers innovative drug solutions for underserved areas including fibrosis, oncology, immunology, pain, obesity, and metabolic disorders, while extending Pharma.AI into advanced materials, agriculture, nutrition, and veterinary medicine. Learn more at www.insilico.com.