Using generative AI to identify potent and selective MYT1 inhibitors for cancer treatment

Recent research has identified MYT1 as a promising new therapeutic target for breast and gynecological cancer and discovered a series of novel, potent and highly selective inhibitors specifically targeting MYT1.

These results, published in the Journal of Medicinal Chemistrywere supported by Insilico Medicine’s AI-driven generative biology and chemistry engine.

Across the world, breast and gynecologic cancers pose serious threats to women’s health, fertility, and overall quality of life. To identify potential targets for new treatments, the research team leveraged PandaOmics, Insilico’s proprietary AI-based target identification platform, to analyze data on five forms of gynecological cancers, including ovarian, endometrial, cervical and breast cancer, particularly triple negative cancer. breast cancer.

Remarkably, MYT1 consistently ranked first across all diseases in terms of relevance.

MYT1 is a member of the Wee1-kinase family, rarely expressed in most normal tissues but highly expressed in most types of cancer. MYT1 inhibition and CCNE1 amplification, a condition known as synthetic lethality, have been reported to play crucial functions in cell cycle regulation, indicating that MYT1 inhibition is a strategy promising synthetic lethal therapeutic for the treatment of cancers exhibiting genome instability (e.g. CCNE1 amplification). .

However, MYT1 is highly homologous to Wee1, making it difficult to design selective MYT1 inhibitors. In this study, Insilico filled the gap in selective MYT1 inhibitors with the support of Chemsitry42, Insilico’s AI-driven small molecule generation platform.

Using structure-based drug design (SBDD) strategies and applying rigorous similarity and selectivity filters, Insilico designed a portfolio of MYT1-targeting compounds from scratch. Among these new compounds, one series proved to be a hit compound.

Insilico then performed an X-ray crystal structure analysis of the complex and found a significant impact on activity from subtle changes in 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 reduces the potential risk of off-target effects and could result in a safer profile. In preclinical studies, it also shows potent in vivo antitumor efficacy and a promising profile in ADME and PK/PD.

“This program’s innovative approach not only presented an efficient target identification method, but also led to the development of a promising selective MYT1 inhibitor,” said Yazhou Wang, Ph.D., head of the medicinal chemistry of Insilico’s MYT1 program. Medicine, and first author of this article. “Compound 21 expands Insilico’s lethal synthetic pipeline and paves the way for a safer and more effective therapeutic future for patients battling gynecologic and breast cancers. »