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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-20 , DOI: 10.1021/acs.jmedchem.4c01458
Chaofan Wang ₁ , Yan Fang _{2,

3} , Ziqin Zhou ₁ , Zhuoheng Liu ₁ , Fang Feng ₂ , Xuan Wan _{2,

3} , Yan Li ₂ , Shuang Liu ₄ , Jian Ding _{2,

3} , Zhi-Min Zhang ₁ , Hua Xie _{3,

5,

6} , Xiaoyun Lu _{1,

4}

Affiliation

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.

中文翻译：

2-氨基-[1,1'-联苯]-3-甲酰胺衍生物的基于结构的药物设计作为选择性 PKMYT1 抑制剂用于治疗 CCNE1 扩增的乳腺癌

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。

更新日期：2024-08-20

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