Insilico Medicine("Insilico"), a clinical-stage generative artificial intelligence (AI)-driven biotechnology company, today announced the nomination of ISM2196, an AI-driven, potential best-in-class small molecule WRN inhibitor targeting advanced metastatic microsatellite instability (MSI) cancers guided by synthetic lethality strategy.
Werner helicase (WRN) is a member of the RecQ helicase family, which plays a critical role in maintaining genome integrity and promoting DNA damage repair. Recent studies identified that WRN deficiency selectively impairs the viability of MSI-H but not microsatellite stable (MSS) cancer cells, which indicates WRN is a synthetic lethal target for MSI-H tumors. MSI-H condition is observed in more than 20 different types of cancers, especially in colorectal cancer, endometrial cancer, gastric cancer and others, with hundreds of thousands of cases diagnosed globally each year.
ISM2196 is a novel, potent WRN inhibitor, designed with the assistance of Alchemistry, one of the latest modules of Chemistry 42. Alchemistry enhances drug R&D by leveraging non-equilibrium switching to accurately and rapidly compute binding free-energy estimates for protein-ligand complexes. In developing the WRN program, most predicted compounds demonstrated superior activity to the reference compounds. Insilico's scientists further integrated and analyzed the ranking results from Alchemistry, ADMT activity and PK/PD properties of the candidates, enabling the rapid selection of promising molecules for synthesis and testing.
ISM2196 has shown promising results in preclinical studies, demonstrating potent in vivo anti-tumor efficacy across multiple cancer models, including colorectal, endometrial, and gastric cancers. Additionally, it showcased good drug-like properties, including excellent in vitro ADMET profiles, favorable in vivo exposure, low clearance, and optimal oral bioavailability across multiple preclinical species. These findings highlight the potential of ISM2196 as a best-in-class WRN inhibitor for treating MSI-H tumors. Insilico disclosed parts of the key preclinical data during AACR 2024.
"Although immune checkpoint inhibitors have been approved for the treatment of MSI-H tumors, a significant proportion of patients do not respond to available therapies and a subset of patients suffer from drug toxicity problems. WRN inhibitors are expected to be promising novel treatment options," says Feng Ren, Ph.D., Co-CEO and Chief Scientific Officer of Insilico Medicine. "We are conducting the IND-enabling study of ISM2196 and look forward to working with experienced partners to advance the candidate to clinical validation and providing innovative treatment options to patients."
We have never stopped developing the Pharma.AI platform, which is demonstrating even greater potential with the integration of new modules powered by cutting-edge technology. The experience of AI optimized drug candidates in the WRN program once again underscores the possibilities of AI technology to transform drug discovery and deliver next-generation therapeutics to patients with unmet medical needs."
Alex Zhavoronkov, Ph.D., Founder and CEO of Insilico Medicine
In 2016, Insilico first described the concept of using generative AI for the design of novel molecules in a peer-reviewed journal, which laid the foundation for the commercially available Pharma.AI platform. Since then, Insilico keeps integrating technical breakthroughs into Pharma.AI platform, which is currently a generative AI-powered solution spanning across biology, chemistry and clinical development. Powered by Pharma.AI, Insilico has nominated 19 preclinical candidates in its comprehensive portfolio of over 30 assets since 2021 and has received IND approval for 9 molecules.
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