Structure-Based Drug Design of 2-Amino-[1,1′-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of <i>CCNE1</i>-Amplified Breast Cancer
Chaofan Wang, Yan Fang, Ziqin Zhou, Zhuoheng Liu, Fang Fěng, Xuan Wan, Yan Li, Shuang Liu, Jian Ding, Zhimin Zhang, Hua Xie, Xiaoyun Lu
Abstract
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.