Structure-Based Drug Design of 2-Amino-[1,1′-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of CCNE1 -Amplified Breast Cancer

作者：Chaofan Wang, Yan Fang, Ziqin Zhou, Zhuoheng Liu, Fang Fěng, Xuan Wan, Yan Li, Shuang Liu, Jian Ding, Zhimin Zhang, Hua Xie, Xiaoyun Lu · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01458 · 被引用次数：19 · 研究领域：Advanced Breast Cancer Therapies、Peptidase Inhibition and Analysis、Click Chemistry and Applications

CCNE1 amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for CCNE1 amplification holds promise for the treatment of CCNE1 -amplified breast cancer. Herein, we discover a series of 2-amino-[1,1′-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound 8ma exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the CCNE1 -amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.