Insilico Medicine, a clinical-stage pharmaceutical research company based on generative artificial intelligence (AI), recently published an early study identifying MYT1 as a promising new therapeutic target for breast and gynecological cancers. The company also discovered a series of novel, effective, and highly selective inhibitors specifically targeting MYT1. These results were supported by Insilico’s AI-driven generative biology and chemistry engine and were published in the Journal of Medicinal Chemistry in December 2023.
Globally, breast and gynecological cancers pose a serious threat to women’s health, fertility, and overall quality of life. To identify potential targets for new therapeutics, Insilico’s research team utilized the company’s proprietary AI-driven target identification platform, PandaOmics, to analyze data from five types of gynecological cancers, including ovarian, endometrial, cervical, and breast cancers, specifically triple-negative breast cancer. Remarkably, MYT1 consistently ranked at the top in terms of relevance across all diseases.
MYT1, a member of the Wee1 kinase family, is rarely expressed in most normal tissues but highly expressed in most cancers. MYT1 inhibition and CCNE1 amplification, a condition known as synthetic lethality, play a crucial role in regulating the cell cycle, suggesting that MYT1 inhibition is a promising synthetic lethal therapy for treating cancers with genomic instability (e.g., CCNE1 amplification).
However, MYT1 is highly homologous to Wee1, making the development of selective MYT1 inhibitors challenging. In this study, Insilico, with the support of Chemistry42, Insilico’s AI-driven small molecule generation platform, addressed the gap in selective MYT1 inhibitors. Using structure-based drug design strategies (SBDD) and applying stringent filters for similarity and selectivity, Insilico developed a series of compounds targeting MYT1 from scratch. Among these novel compounds, several proved to be successful.
Subsequently, Insilico conducted X-ray crystal structure analysis of the complex and found that subtle chemical structure modifications had a significant impact on the activity. This knowledge provided guidance for further molecular optimization and led Insilico to discover the lead compound, Compound 21. Compound 21 showed good MYT1 activity and excellent selectivity over Wee1 and the other kinase panel, reducing the potential risk of off-target effects and translating into a safer profile. It also demonstrated effective in vivo antitumor efficacy in preclinical studies 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 pipeline of synthetic lethal drugs and paves the way for a safer and more effective therapeutic future for patients suffering from gynecological cancers and breast cancer.
Yazhou Wang, Ph.D., Medical Chemistry Leader of the MYT1 Program at Insilico Medicine and lead author of this article
Wang, S., et al. (2023). Discovery of Tetrahydropyrazolopyrazine Derivatives as Effective and Selective MYT1 Inhibitors for Cancer Treatment. Journal of Medicinal Chemistry. doi.org/10.1021/acs.jmedchem.3c01476