Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer
Jinyu Yu, Haoyu Zhang, Chuanxu Su, Shizhe Yuan, Nian Liu, Yin Sun, Yixiang Sun, Zixuan Gao, Dongmei Zhao, Maosheng Cheng · Biomedicines · 2025
Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. The underlying mechanisms were investigated by means of pharmacological experiments and molecular simulations. Results: Compound MY-14 demonstrated optimal kinase inhibition (IC50 = 0.002 μM) and significant anti-proliferative efficacy against CCNE1-amplified cells (IC50-HCC1569 = 1.06 μM and IC50-OVCAR3 = 0.80 μM). Furthermore, MY-14 induced concentration-dependent apoptosis, inhibited colony formation, and effectively arrested cell-cycle progression at the S-phase through synthetic lethality. Molecular dynamics simulations, Hirshfeld surface analysis, dynamic cross-correlation matrix (DCCM), and MM/GBSA calculations elucidated the molecular mechanism underlying MY-14’s interaction with PKMYT1. Conclusions: MY-14 emerged as a promising compound for the development of a novel PKMYT1 inhibitor.