Discovery of 4-Aminoquinazoline Derivatives as Potent PKMYT1 Inhibitors via Hydrogen Bond Donor-To-Acceptor Conversion for CCNE1 -Amplified Cancers

Abstract

PKMYT1 is a critical regulator of the cell cycle and has emerged as a promising synthetic lethal target for CCNE1-amplified cancers. In this study, we report the design, synthesis, and biological evaluation of a novel series of 4-aminoquinazoline-based PKMYT1 inhibitors. A hydrogen bond donor-to-acceptor conversion strategy was successfully employed to reduce the hydrogen bond donor (HBD) count, thereby improving the drug-likeness of this series. Among them, compound 12f exhibited nanomolar inhibitory activity against PKMYT1 and potent antiproliferative activity in the OVCAR-3 ovarian cancer cell line. Furthermore, compound 12f demonstrated synergistic antiproliferative effects when combined with PARP inhibitors. Along with an acceptable oral pharmacokinetic profile, compound 12f demonstrated robust in vivo efficacy in OVCAR-3 xenograft models. Notably, compound 12f was well-tolerated, demonstrating no significant body weight loss or apparent toxicity to major organs. Collectively, these results underscore the therapeutic potential of compound 12f as a promising PKMYT1 inhibitor against CCNE1-amplified cancers.