Insilico Medicine nominated ISM6200, a potential 'best-in-class' NR3C1 selective antagonist, for use in a broad range of disease areas including oncology, metabolism, and ophthalmology

· The NR3C1 gene regulates the glucocorticoid receptor (GR), which plays a role instress response, metabolism, immune function, and inflammationand offers therapeutic potential for various human diseases associated with excessive cortisol levels

· ISM6200 is a powerful, selective NR3C1 antagonist developed using Insilico Medicine's Pharma.AI platforma potent, selective NR3C1 antagonistwith low drug-drug interaction (DDI) risk, demonstrating superior efficacy in various animal disease models. It also exhibits favorable ADME/PK properties, with a predicted low effective dose in humans, showing best-in-class potential

· Combination therapy with ISM6200 demonstrateddose-dependent anti-tumor effects, and the US FDA has approved a proof-of-concept clinical study of an NR3C1 antagonist combined with paclitaxel for cancer treatment.

· ISM6200 has demonstrated excellent efficacy in preclinical models of Cushing's syndrome, cortisol-related obesity, and glaucoma.demonstrated excellent efficacy.。

· Since 2021, Insilico Medicine has nominated 29 PCCs, obtained clinical trial approvals for 12 candidate drugs, and advanced three drugs into Phase II clinical trials, with one Phase IIa trial already completed. Additionally, the company has achieved over 10 business development partnerships since 2025, underscoring the high quality and standards of Insilico Medicine’s proprietary programs.

The glucocorticoid receptor (GR), encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, is a key nuclear receptor essential for maintaining physiological homeostasis.Inhibition of NR3C1 can enhance the sensitivity of cancer cells to chemotherapy, showing particularly significant potential in ovarian cancer. Previously, the US FDA approved a proof-of-concept clinical study combining an NR3C1 antagonist with paclitaxel for cancer treatment. Beyond oncology, NR3C1 inhibitors hold promise inneurological, cardiovascular, immune, and metabolic diseaseshas also shown broad therapeutic potential.

Currently, NR3C1 selective inhibitors have addressed the off-target toxicity issues of first-generation drugs. However, in non-oncology indications such as metabolic and immune diseases, the balance between clinical benefits and safety risks still requires further evaluation. Therefore, designing and developingsafer and more effective NR3C1 inhibitorsto address the 'pain points' in clinical applications remains a significant challenge for the pharmaceutical industry.

Recently, Insilico Medicine (03696.HK), a clinical-stage biotechnology company driven by generative artificial intelligence (AI)announced the nomination of ISM6200, a potent, potentially best-in-class NR3C1 inhibitor, as a preclinical candidate compound (PCC) for the treatment ofovarian cancer, Cushing's syndrome, and other diseases related to excessive cortisol, including glucocorticoid-associated obesity.The discovery and optimization of this candidate drug were driven by Chemistry42, the generative chemistry engine under Insilico Medicine's Pharma.AI platform, along with its core modules.

Dr. Ren Feng, Co-CEO and Chief Scientific Officer of Insilico Medicine, stated,'For patients with platinum-resistant ovarian cancer, the overall survival is only about one year, highlighting an urgent need for new therapies to extend patient survival and improve quality of life. With the assistance of AI technology, Insilico Medicine's research team has found that ISM6200 exhibits excellent drug-like properties and significantly improves DDI characteristics. It has the potential to be compatible with background treatments, expand the scope of combination therapy, and may achieve stronger efficacy at lower human doses, thereby greatly enhancing safety.'

Preclinical data shows that ISM6200 is aLow drug-drug interaction (DDI) risksmall-molecule NR3C1 antagonist, demonstratingsuperior in vivo efficacyIn preclinical CDX tumor xenograft mouse models, ISM6200, when used in combination with paclitaxel, showed significantdose-dependent enhancement of antitumor efficacyMeanwhile, itsfavorable ADME properties and pharmacokinetic (PK) profileenable sufficient systemic exposure at lower doses, leading to better safety-patient benefit expectations. Additionally, ISM6200 also exhibitsgood physicochemical properties, stability, and developabilitylaying a solid foundation for subsequent clinical development.

Alex Zhavoronkov, founder and CEO of Insilico Medicine, statedWe initially discovered NR3C1 as a target through our dual research on diseases and aging.It has demonstrated high potential in various age-related diseases.Based on this, we have developed a series of small-molecule drug projects around NR3C1 with the aim of fully exploring its therapeutic potential while effectively avoiding known target-related risks. The nomination of ISM6200 further demonstrates the transformative value of generative AI in drug discovery. Not only can it help us address complex medicinal chemistry challenges, but it also reduces traditional R&D risks such as metabolic instability and off-target toxicity. What excites me most about ISM6200 is thatit holds broad application potential and may function across multiple systems in the human body,even surpassing Insilico Medicine’s long-standing dual-target expectations for addressing both aging and other diseases. With the power of AI, we are able to discover high-quality molecules with broad potential at unprecedented speeds and advance more R&D pipelines with higher efficiency.

Previously, the NR3C1 project made its debut as part of Insilico Medicine’s pipeline at the BIO-Europe 2025 conference and was positioned as a key pipeline within Insilico Medicine's metabolic disease portfolio. The main point of interest lies in its potential to reverse cortisol-driven metabolic dysfunction and enhance semaglutide-mediated weight loss effects.

In a diet-induced obesity (DIO) mouse model, ISM6200 demonstrated significant weight loss effects by primarily reducing fat while better preserving muscle mass. After 28 days of dosing, compared to the control group, monotherapy with ISM6200achieved noticeable weight reduction,, achieving a weight loss of 8.8% relative to the baseline. When ISM6200 is used in combination with Semaglutide, the weight loss effect is further enhanced,reaching 23.8% within the same dosing period., while the DIO control group showed a 2.4% increase in body weight. The above data provides strong support for subsequent clinical development.

In a rat model of Cushing's syndrome, ISM6200 significantly alleviated insulin resistance and high blood pressure issues, showing effects shortly after short-term administration., reducing the level of insulin resistance by 68%.Blood pressure alsoapproached the levels of the healthy control group.. Additionally, in a therapeutic glaucoma mouse model, after three days of dexamethasone injection followed by three days of ISM6200 treatment, tests revealeda significant decrease in intraocular pressure in mice,providing leads for subsequent clinical development.

Notably, since 2021, Insilico Medicine has nominated 29 PCCs, with 12 candidate drugs receiving clinical trial approvals, and three drugs advancing to Phase II clinical trials, one of which has already completed Phase IIa. Meanwhile, the company has achieved more than ten business development partnerships since 2025, fully demonstrating the high quality and standards of Insilico Medicine's self-developed projects.

About Insilico Medicine

Insilico Medicine is a global pioneer in biotechnology, dedicated to integrating artificial intelligence and automation technologies to accelerate drug discovery and drive innovation in the life sciences, empowering humans to live longer and healthier lives. On December 30, 2025, the company was listed on the Main Board of the Hong Kong Stock Exchange, with the stock code: 03696.HK.

Using its self-developed Pharma.AI platform and advanced automated biology laboratories, Insilico Medicine is providing innovative drug solutions for unmet disease areas such as fibrosis, oncology, immunology, pain, obesity, and metabolic disorders. Additionally, Insilico Medicine continues to expand the application of Pharma.AI into diverse fields, including advanced materials, agriculture, nutritional products, and veterinary drugs. For more information, please visit www.insilico.com.

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