WRN has been identified as a synthetic lethal target in highly microsatellite unstable (MSI-H) cancer cells, with therapeutic potential for MSI-H tumor patients who do not respond to existing therapies.

The innovative module Alchemisty under Yingsi Intelligent Chemistry42 utilizes non-equilibrium switching method to accurately and quickly estimate the binding free energy of protein ligand complexes, simplifying and accelerating the optimization process of ISM2196.

In preclinical studies, ISM2196 has demonstrated strong in vivo anti-tumor efficacy in various MSI-H cancer models, with good selectivity, safety, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) characteristics.

Yingsi Intelligent, a clinical stage biopharmaceutical technology company driven by generative artificial intelligence (AI), announced the nomination of preclinical candidate drug ISM2196, a potential "best in class" WRN inhibitor discovered by AI, aimed at treating advanced metastatic microsatellite instability (MSI) cancer through synthetic lethal strategies.

The DNA helicase Werner (WRN) is a member of the RecQ helicase family and plays a crucial role in maintaining genome integrity and promoting DNA damage repair. Recent studies have found that WRN deficiency selectively kills MSI-H cancer cells without affecting the survival of microsatellite stable (MSS) cells, making WRN a synthetic lethal target for MSI-H tumors. Represented by colorectal cancer, endometrial cancer, and gastric cancer, MSI-H status has been observed in over 20 different types of cancer, with hundreds of thousands of confirmed cases of MSI-H cancer worldwide each year.

ISM2196 is an innovative and potent WRN inhibitor, whose design and optimization process are empowered by Alchemisty, a module under Chemistry42. Alchemy utilizes non-equilibrium switching methods to accurately and rapidly estimate the binding free energy of protein ligand complexes, providing assistance for drug discovery and development processes. In the development of the WRN project, most of the AI predicted compounds showed better activity than the reference compounds. Afterwards, the R&D team of Yingsi Intelligent further integrated and analyzed the sorting results, ADMT activity, and PK/PD properties of candidate compounds from Alchemy, and quickly screened promising candidate molecules for subsequent synthesis and testing.

ISM2196 has shown promising research results in preclinical trials, demonstrating strong in vivo anti-tumor efficacy in various cancer models including colorectal cancer, endometrial cancer, and gastric cancer. In addition, it also demonstrates ideal drug like properties, including excellent in vitro ADMET characteristics, good in vivo exposure, low plasma clearance, and good oral bioavailability in multiple species models. These findings highlight the potential of ISM2196 as a potential best in class WRN inhibitor for the treatment of MSI-H tumors. Yingsi Intelligent has disclosed some preclinical key data about this project at the AACR Annual Meeting in 2024.

Although immune checkpoint inhibitors have been approved for the treatment of MSI-H tumors, there is still a considerable number of patients who do not respond to existing therapies, and some patients suffer from the toxicity of existing drugs. WRN inhibitors are expected to bring them new hope, and we are accelerating the IND ablation research of ISM2196. We look forward to working with experienced partners to advance the clinical validation of this candidate drug and provide innovative treatment options for patients

Dr. Alex Zhaovoronkov, founder and CEO of Insilicon Intelligence, said, "We have never stopped developing and researching the Pharma.AI platform, and new AI modules that integrate cutting-edge technologies are showing great potential. In the WRN project, the experience of optimizing the precursor compound series with these modules once again demonstrates the potential of AI technology to drive drug discovery. We look forward to bringing the next generation of innovative therapies to patients with unmet medical needs as soon as possible

In 2016, British Silicon Intelligence first introduced the concept of using generative artificial intelligence to design novel molecules in a peer-reviewed journal, aiming to commercialize pharmaceuticals covering fields such as generative biology, chemistry, and medicine The AI platform has laid the foundation. Since 2021, Yingsi Intelligence has been using its own artificial intelligence platform Pharma With the support of AI, more than 30 rich self-developed pipeline combinations have been established, and 19 preclinical candidate projects have been nominated from them, of which 9 compounds have obtained clinical trial permits.

At the recent IMGIAA (Insilico Medicine Generative AI Action) online seminar, Insilicon Intelligent released its own Pharma The AI platform update focuses on the debut of innovative applications, including Biology42: PandaOmics Box hardware for privacy computing, Precius-3 GPT for virtual data generation and biomedical research, and Science42: DORA research assistant for scientific document drafting. Based on this, Yingsi Intelligent expects to lead more socially responsible and sustainable technological breakthroughs. If you are interested in trying out the above platform, please contact BD@insilicomedicine.com .