2024-01-21 18:28:50
Insilico Medicine (“Insilico”), a clinical-stage artificial intelligence (AI)-driven drug discovery company, recently published preliminary research that identified MYT1 as a promising new therapeutic target for breast and gynecologic cancers, and discovered a series of novel, potent, and highly selective inhibitors that specifically target MYT1 . These findings were supported by Insilico’s artificial intelligence-driven generative biology and chemistry engine and published in Journal of Medicinal Chemistry In December 2023.
Worldwide, breast and gynecological cancer pose serious threats to women’s health, fertility and overall quality of life. In order to identify potential targets for new treatments, the research team is leveraging Insilico’s proprietary target identification platform, PandaOmics, to analyze data from five forms of gynecological cancer, including ovarian, endometrial, cervical and breast cancer, particularly triple-negative breast. Cancer. Remarkably, MYT1 consistently ranked at the forefront of all diseases in terms of relevance.
MYT1 is a member of the Wee1-kinase family, which is rarely expressed in most normal tissues but highly expressed in most cancers. It has been reported that inhibition of MYT1 and CCNE1 Amplification, a condition termed synthetic lethality, plays crucial roles in cell cycle regulation, indicating that MYT1 inhibition is a promising synthetic lethal therapeutic strategy to treat cancers with genome instability (e.g. amplification of CCNE1).
However, MYT1 is highly homologous to Wee1, making it challenging to design selective MYT1 inhibitors. In this study, Insilico addressed the gap in selective MYT1 inhibitors with the support of Chemsitry42, Insilico’s AI-driven small molecule manufacturing platform. Using structure-based drug design (SBDD) strategies and applying rigorous filters for similarity and selectivity, Insilico designed an array of MYT1-targeting compounds from scratch. Among these new compounds, one series emerged as hit compounds.
Insilico then performed an X-ray crystal structure analysis of the complex and found a significant effect on the activity of subtle changes in the chemical structure. This knowledge provided guidance for further molecular optimization, leading insilico to the discovery of the lead compound, compound 21. Compound 21 exhibits good MYT1 activity and excellent selectivity over Wee1 and the other panel of kinases which reduces the potential risk of off-target effects and may translate to a safer profile. In preclinical studies, it also shows strong alive Antitumor efficacy, and a promising profile in ADME and PK/PD.
The innovative approach of this program not only introduced a method for effective target identification but also led to the development of a promising selective MYT1 inhibitor. Compound 21 expands Insilico’s synthetic lethal pipeline and paves the way for a safer and more effective therapeutic future for patients battling gynecological and breast cancer.”
Yazhou Wang, Ph.D., medicinal chemistry leader of the MYT1 program at Insilico Medicine, and first author of this paper
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