Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

Abstract

Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating the urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target for breast and gynecological cancer using PandaOmics, an AI-driven target discovery platform. The synthetic lethal relationship of MYT1 in tumor cell lines with CCNE1 amplification enhanced this rationale. Through structurebased drug design, we developed a series of novel, potent, and highly selective inhibitors specifically targeting MYT1. Importantly, our lead compound, featuring a tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over WEE1, a related kinase associated with bone marrow suppression upon inhibition. Optimization of potency and physical properties resulted in the discovery of compound 21, a novel MYT1 inhibitor, exhibiting optimal pharmacokinetic properties and promising in vivo antitumor efficacy.

The Science and Art of Structure-Based Virtual Screening

“…Encouragingly, compound 7 was reported to be the starting point toward discovery of the drug candidate, RP-6306, which is currently in clinical trials for treatment of various solid tumors . Following its development, Insilico Medicine recently reported the discovery of a novel MYT1 inhibior selective over WEE1 . Taken together, one may argue that structure-based VS is indeed a sustainable approach conferring novel chemotypes, with a demonstrated impact on drug discovery.…”