Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR(L858R/T790M/C797S))

Shen Jiayi; Zhang Tao; Zhu Su-Jie; Sun Min; Tong Linjiang; Lai Mengzhen; Zhang Rong; Xu Wei; Wu Ruibo; Ding Jian; Yun Cai-Hong; Xie Hua; Lu Xiaoyun; Ding Ke

首页> 外文期刊>Journal of Medicinal Chemistry >Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR(L858R/T790M/C797S))

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Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR(L858R/T790M/C797S))

机译：5-甲基吡啶吡啶酮衍生物的基于结构的设计，作为表皮生长因子受体三重突变体的新型野生型备用抑制剂（EGFR（L858R / T790M / C797S））

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Tertiary EGFRc797s mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFR(L858R/T790M/C797S) inhibitors. A representative compound, 8r-B, exhibited an ICso of 27.5 nM against the EGFR(L858R/T790M/C797S) mutant, while being a significantly less potent for EGFRwr (IC50 > 1.0 NM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

机译：第三次EGFRC797S突变诱导对Osimertinib（1）的抗性是非小细胞肺癌（NSCLC）患者的新兴的“未满足临床需要”。设计并合成了一系列5-甲基吡啶吡啶衍生物作为新选择性EGFR（L858R / T790M / C797S）抑制剂。代表性化合物8R-B对EGFR（L858R / T790M / C797S）突变体表现出27.5nm的ICSO，同时为EGFRWR（IC50> 1.0nm）表示较小的有效性。进行了共晶结构的确定和计算调查，以阐明其目标选择性。

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来源
《Journal of Medicinal Chemistry》 |2019年第15期|共7页
作者
Shen Jiayi; Zhang Tao; Zhu Su-Jie; Sun Min; Tong Linjiang; Lai Mengzhen; Zhang Rong; Xu Wei; Wu Ruibo; Ding Jian; Yun Cai-Hong; Xie Hua; Lu Xiaoyun; Ding Ke;
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作者单位

Jinan Univ Sch Pharm Guangzhou City Key Lab Precis Chem Drug Dev Minis Int Cooperat Lab Tradit Chinese Med Modernizat &

601 Huangpu Ave West Guangzhou 510632 Guangdong Peoples R China;

Chinese Acad Sci Div Antitumor Pharmacol State Key Lab Drug Res Shanghai Inst Mat Med 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

Qingdao Univ Inst Translat Med Coll Med Qingdao 266021 Shandong Peoples R China;

Jiangsu Aosaikang Pharmacceut Co Ltd 699 Kejian Rd Jiangsu Sci Pk Nanjing 211112 Jiangsu Peoples R China;

Chinese Acad Sci Div Antitumor Pharmacol State Key Lab Drug Res Shanghai Inst Mat Med 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

Chinese Acad Sci Div Antitumor Pharmacol State Key Lab Drug Res Shanghai Inst Mat Med 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

Sun Yat Sen Univ Sch Pharmaceut Sci Guangzhou 510006 Guangdong Peoples R China;

Jinan Univ Sch Pharm Guangzhou City Key Lab Precis Chem Drug Dev Minis Int Cooperat Lab Tradit Chinese Med Modernizat &

601 Huangpu Ave West Guangzhou 510632 Guangdong Peoples R China;

Sun Yat Sen Univ Sch Pharmaceut Sci Guangzhou 510006 Guangdong Peoples R China;

Chinese Acad Sci Div Antitumor Pharmacol State Key Lab Drug Res Shanghai Inst Mat Med 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

Peking Univ Hlth Sci Ctr Dept Biochem &

Biophys Inst Syst Biomed Sch Basic Med Sci Beijing 100191 Peoples R China;

Chinese Acad Sci Div Antitumor Pharmacol State Key Lab Drug Res Shanghai Inst Mat Med 555 Zuchongzhi Rd Shanghai 201203 Peoples R China;

Jinan Univ Sch Pharm Guangzhou City Key Lab Precis Chem Drug Dev Minis Int Cooperat Lab Tradit Chinese Med Modernizat &

601 Huangpu Ave West Guangzhou 510632 Guangdong Peoples R China;

Jinan Univ Sch Pharm Guangzhou City Key Lab Precis Chem Drug Dev Minis Int Cooperat Lab Tradit Chinese Med Modernizat &

601 Huangpu Ave West Guangzhou 510632 Guangdong Peoples R China;

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1. Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR(L858R/T790M/C797S)) [J] . Shen Jiayi, Zhang Tao, Zhu Su-Jie, Journal of Medicinal Chemistry . 2019,第15期

机译：5-甲基吡啶吡啶酮衍生物的基于结构的设计，作为表皮生长因子受体三重突变体的新型野生型备用抑制剂（EGFR（L858R / T790M / C797S））
2. Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors [J] . Zhang Mingguang, Wang Yunyun, Wang Jia, Chemical and Pharmaceutical Bulletin . 2020,第10期

机译：喹唑啉衍生物的设计，合成和生物学评价为L858R / T790M / C797S三重突变表皮生长因子受体酪氨酸激酶抑制剂
3. Discovery of 5-(methylthio)pyrimidine derivatives as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors [J] . Xiao Qiang, Qu Rong, Gao Dingding, Bioorganic and medicinal chemistry . 2016,第12期

机译：发现5-（甲硫基）嘧啶衍生物作为L858R / T790M突变体选择表皮生长因子受体（EGFR）抑制剂
4. QSAR Study of Quinazoline Derivatives as Inhibitor of Epidermal Growth Factor Receptor-Tyrosine Kinase (EGFR-TK) [C] . La Ode Aman, Widisusanti Abdulkadir, Julitha Geybie Rembet, International Conference on Computation for Science and Technology . 2015

机译：喹唑啉衍生物作为表皮生长因子受体 - 酪氨酸激酶（EGFR-TK）抑制剂的QSAR研究
5. Modeling the consequences of epidermal growth factor receptor inhibition in vivo using the classical EGFR⟨wa2⟩ mutant mouse. [D] . Roberts, Reade Bruce. 2003

机译：使用经典的EGFR〈wa2〉突变小鼠对体内表皮生长因子受体抑制的后果进行建模。
6. Structure-Guided Design of C4-alkyl-14-dihydro-2H-pyrimido45-d13oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors [O] . Yongjia Hao, Jiankun Lyu, Rong Qu, -1

机译：C4-烷基-14-二氢-2H-嘧啶45-d 13恶嗪-2-酮作为有效和突变体选择性表皮生长因子受体（EGFR）L858R /的结构指导设计T790M抑制剂
7. Structure-Based Design of 5Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S) [O] . -1

机译：5甲基吡啶吡啶酮衍生物的基于结构的设计作为表皮生长因子受体三重突变体的新型野生型腐败抑制剂（EGFR1858R / T790M / C797S）

Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR(L858R/T790M/C797S))

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