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

<i>CCNE1</i> amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for <i>CCNE1</i> amplification holds promise for the treatment of <i>CCNE1</i>-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 <b>8ma</b> exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the <i>CCNE1</i>-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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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2024-08-20
DOI
https://doi.org/10.1021/acs.jmedchem.4c01458
Citations
11
Primary Topic
Advanced Breast Cancer Therapies
Type
article
Field-Weighted Citation Impact
4.61

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article

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

Fang Fěng, Xiaoyun Lu, Ziqin Zhou, Yan Fang et al.
11 citations
Journal of Medicinal Chemistry
Advanced Breast Cancer Therapies
4.61
article

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

Fang Fěng, Xiaoyun Lu, Ziqin Zhou, Yan Fang, Zhimin Zhang, Zhuoheng Liu, Chaofan Wang, Xuan Wan, Yan Li, Hua Xie, Shuang Liu, Jian Ding
article en
11 citations

Abstract

<i>CCNE1</i> amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for <i>CCNE1</i> amplification holds promise for the treatment of <i>CCNE1</i>-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 <b>8ma</b> exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the <i>CCNE1</i>-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.

Journal of Medicinal ChemistryVol. 67(17)
Jinan University (CN), Chinese Academy of Sciences (CN), Shanghai Institute of Materia Medica (CN), Guangdong Provincial People's Hospital (CN), University of Chinese Academy of Sciences (CN)
National Natural Science Foundation of China, Changjiang Scholar Program of Chinese Ministry of Education, Basic and Applied Basic Research Foundation of Guangdong Province
Good health and well-being
Openalex Percentile: Top 5%
Advanced Breast Cancer Therapies
4.61
DOIOpen Access PDFOpenAlex
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