Recent research has pinpointed MYT1 as a potential breakthrough therapeutic target for breast and gynecological cancers, unveiling a range of novel, potent, and highly selective inhibitors tailored to MYT1. These significant findings, featured in the Journal of Medicinal Chemistry, benefited from the support of Insilico Medicine's AI-driven generative biology and chemistry engine.
Globally, breast and gynecological cancers present substantial challenges to women's health, fertility, and overall well-being. To identify potential targets for innovative therapeutics, the research team harnessed Insilico's proprietary AI-driven target identification platform, PandaOmics. They analyzed data on five forms of gynecological cancers, including ovarian, endometrial, cervical, and the particularly challenging triple-negative breast cancer.
Remarkably, MYT1 consistently emerged as a top-ranking target across all these diseases in terms of relevance.
MYT1, belonging to the Wee1-kinase family, is seldom expressed in normal tissues but highly prevalent in most cancer types. Previous reports indicate that inhibiting MYT1 and amplifying CCNE1, a condition termed synthetic lethality, plays a pivotal role in regulating the cell cycle. This implies that MYT1 inhibition holds promise as a synthetic lethal therapeutic strategy for treating cancers with genome instability, such as those with CCNE1 amplification.
Yet, designing selective MYT1 inhibitors poses a challenge due to MYT1's high similarity to Wee1. In this study, Insilico tackled this hurdle with the assistance of Chemistry42, Insilico's AI-driven small molecule generation platform. Using structure-based drug design (SBDD) strategies and applying stringent filters for similarity and selectivity, Insilico crafted a range of compounds targeting MYT1 from scratch. Among these, one series emerged as promising hit compounds.
Insilico proceeded to conduct an X-ray crystal structure analysis of the complex, unveiling the substantial impact of subtle chemical structure modifications on activity. This valuable insight guided further molecular optimization, leading to the discovery of the lead compound, Compound 21.
Compound 21 exhibited robust MYT1 activity and excellent selectivity over Wee1 and other kinases in the panel, minimizing the risk of off-target effects and suggesting a potentially safer profile. In preclinical studies, it demonstrated potent in vivo antitumor efficacy and showcased a promising profile in ADME (Absorption, Distribution, Metabolism, Excretion) and PK/PD (Pharmacokinetics/Pharmacodynamics).
Dr. Yazhou Wang, the medicinal chemistry leader of the MYT1 program at Insilico Medicine and the first author of the paper expressed enthusiasm, stating, "The innovative approach of this program has not only presented a method for effective target identification but has also led to the development of a promising selective MYT1 inhibitor. Compound 21 expands Insilico's synthetic lethal pipeline and paves the way toward a safer, more effective therapeutic future for patients battling gynecological and breast cancers."
anhydrous definition
ai chemistry
ai chemistry solver
Absolutely outstanding
ReplyDeleteAwesome!!!!!
ReplyDelete