Insilico Medicine announced on Apr. 8 the nomination of ISM6200 as a new preclinical drug candidate targeting NR3C1, for the treatment of ovarian cancer, Cushing's syndrome, and other disorders related to excess cortisol including obesity.
The development is significant as NR3C1 inhibitors are seen as promising therapies across several disease areas but have faced challenges with selectivity and safety in non-cancer uses. The company said that ISM6200 was discovered using its generative AI platform Chemistry42, which is part of Insilico's Pharma.AI suite.
According to Insilico Medicine, ISM6200 is a small molecule with low risk of drug-drug interactions and showed higher efficacy in animal models. In preclinical studies combining ISM6200 with paclitaxel in cell line-derived xenograft models, the compound enhanced anti-tumor effects in a dose-dependent manner. The company also reported favorable pharmacokinetic properties and stability supporting its potential as an effective therapeutic agent.
Alex Zhavoronkov, PhD, Founder and Co-CEO of Insilico Medicine said: "We originally identified NR3C1 utilizing dual target research related to aging – it scored in multiple age-related diseases. We started working on a portfolio of small molecule drugs targeting NR3C1 to help unlock the full potential of this target while avoiding the known on-target liabilities. The nomination of ISM6200 highlights the transformative power of generative AI in addressing complex medicinal chemistry challenges while reducing traditional risks such as metabolic instability and off-target toxicity." He added: "I am especially encouraged by multi-purpose candidates like this one, as it is indicated in systems across the body, even exceeding our expectation of targeting both aging and certain diseases. By using AI, we can identify high-quality molecules with broad potential, in record time, and we are advancing more pipelines with AI-driven efficiency."
In animal testing relevant to obesity treatment (the DIO mouse model), ISM6200 alone led to an average weight loss of 8.8%, while combination therapy with Semaglutide resulted in a greater reduction at 23.8%. In rat models simulating Cushing's syndrome conditions, insulin resistance dropped by 68% after six days' treatment with ISM6200; blood pressure levels approached those found in healthy animals.
ISM6200 represents Insilico’s 29th preclinical or developmental candidate nomination since 2021. Of these nominations over that period, twelve received clearance for investigational new drug applications (IND), three entered Phase II trials—including one completed Phase IIa study—and more than ten business development deals were signed.
