化学
甲酰胺
乳腺癌
药品
药理学
联苯
癌症
立体化学
内科学
医学
有机化学
作者
Chaofan Wang,Yan Fang,Zi-Qin Zhou,Zhuoheng Liu,Fang Fěng,Xuan Wan,Yan Li,Shuang Liu,Jian Ding,Zhimin Zhang,Hua Xie,Xiaoyun Lu
标识
DOI:10.1021/acs.jmedchem.4c01458
摘要
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.
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