CCNE1 扩增发生在乳腺癌中，目前缺乏有效的治疗方法。 PKMYT1 作为 CCNE1 扩增的合成致死靶标有望治疗 CCNE1 扩增的乳腺癌。在此，我们使用基于结构的药物设计发现了一系列 2-氨基-[1,1'-联苯]-3-甲酰胺衍生物作为有效的选择性 PKMYT1 抑制剂。代表性化合物 8ma 对 PKMYT1 表现出优异的效力，同时不影响 WEE1。它还抑制 CCNE1 扩增的 HCC1569 乳腺癌细胞系的增殖，并与吉西他滨联合显示出协同细胞毒性。 PKMYT1 X 射线共晶体证实，抑制剂与 PKMYT1 残基 Asp251 和 Tyr121 之间关键结合相互作用的引入大大增强了化合物的效力和选择性。

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.