Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

被引：37

作者：

Shen, Jiayi ^{[1
]}

Zhang, Tao ^{[2
]}

Zhu, Su-Jie ^{[3
]}

Sun, Min ^{[4
]}

Tong, Linjiang ^{[2
]}

Lai, Mengzhen ^{[2
]}

Zhang, Rong ^{[5
]}

Xu, Wei ^{[1
]}

Wu, Ruibo ^{[5
]}

Ding, Jian ^{[2
]}

Yun, Cai-Hong ^{[6
]}

Xie, Hua ^{[2
]}

Lu, Xiaoyun ^{[1
]}

Ding, Ke ^{[1
]}

机构：

[1] 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

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

[3] Qingdao Univ, Inst Translat Med, Coll Med, Qingdao 266021, Shandong, Peoples R China

[4] Jiangsu Aosaikang Pharmacceut Co Ltd, 699 Kejian Rd,Jiangsu Sci Pk, Nanjing 211112, Jiangsu, Peoples R China

[5] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China

[6] Peking Univ, Hlth Sci Ctr, Dept Biochem & Biophys, Inst Syst Biomed,Sch Basic Med Sci, Beijing 100191, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 15期

基金：

中国国家自然科学基金;

关键词：

LUNG-CANCER; EGFR INHIBITORS; RESISTANCE; GEFITINIB; OPTIMIZATION; DISCOVERY; MUTATIONS; AZD9291;

D O I：

10.1021/acs.jmedchem.9b00576

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7302 / 7308

页数：7

共 49 条

[1] Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry
Lu, Xiaoyun
Yu, Lei
Zhang, Zhang
Ren, Xiaomei
Smaill, Jeff B.
Ding, Ke
MEDICINAL RESEARCH REVIEWS, 2018, 38 (05) : 1550 - 1581
[2] Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S
Li, Qiannan
Zhang, Tao
Li, Shiliang
Tong, Linjiang
Li, Junyu
Su, Zhicheng
Feng, Fang
Sun, Deheng
Tong, Yi
Wang, Xia
Zhao, Zhenjiang
Zhu, Lili
Ding, Jian
Li, Honglin
Xie, Hua
Xu, Yufang
ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (06): : 869 - 873
[3] Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFRdel19/T790M/C797S and EGFRL858R/T790M/C797S)
Fang, Haotian
Wu, Yingming
Xiao, Qitao
He, Dongbo
Zhou, Tongrui
Liu, Wenzhong
Yang, Chun-Hao
Xie, Yuli
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2022, 72
[4] Design, Synthesis and Biological Evaluation of the Quinazoline Derivatives as L858R/T790M/C797S Triple Mutant Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Zhang, Mingguang
Wang, Yunyun
Wang, Jia
Liu, Zhaogang
Shi, Jingmiao
Li, Mingxin
Zhu, Yongqiang
Wang, Shifa
CHEMICAL & PHARMACEUTICAL BULLETIN, 2020, 68 (10) : 971 - 980
[5] Synthesis and biological evaluation of anilide derivatives as epidermal growth factor receptor L858R/T790M and L858R/T790M/C797S inhibitors
Kim, Soo Lim
Yang, Yo-Sep
Lee, Sujin
Kim, Nam-Jung
BULLETIN OF THE KOREAN CHEMICAL SOCIETY, 2022, 43 (08) : 1032 - 1036
[6] Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR
Todsaporn, Duangjai
Zubenko, Alexander
Kartsev, Victor G.
Mahalapbutr, Panupong
Geronikaki, Athina
Sirakanyan, Samvel N.
Divaeva, Lyudmila N.
Chekrisheva, Victoria
Yildiz, Ilkay
Choowongkomon, Kiattawee
Rungrotmongkol, Thanyada
JOURNAL OF PHYSICAL CHEMISTRY B, 2024, 128 (50): : 12389 - 12402
[7] A sulfonyl fluoride derivative inhibits EGFRL858R/T790M/C797S by covalent modification of the catalytic lysine
Ferlenghi, Francesca
Scalvini, Laura
Vacondio, Federica
Castelli, Riccardo
Bozza, Nicole
Marseglia, Giuseppe
Rivara, Silvia
Lodola, Alessio
La Monica, Silvia
Minari, Roberta
Petronini, Pier Giorgio
Alfieri, Roberta
Tiseo, Marcello
Mor, Marco
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, 225
[8] Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors
Dou, Dou
Zhang, Xingsen
Wang, Jie
Wumaier, Gulinuer
Qiao, Yunjin
Xie, Lijuan
Jiang, Wenzhe
Sha, Wenjie
Li, Wenjie
Mei, Wenyi
Zhang, Chen
He, Huan
Wang, Caolin
Wu, Lingkang
Diao, Yanyan
Zhu, Lili
Zhao, Zhenjiang
Chen, Zhuo
Xu, Yufang
Li, Shengqing
Li, Honglin
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2024, 279
[9] Structure-Based Design of New LSD1/EGFRL858R/T790M Dual Inhibitors for Treating EGFR Mutant NSCLC Cancers
Zhang, Jingya
He, Pengxing
Wang, Wenwen
Wang, Yuxing
Yang, Han
Hu, Zhaoxin
Song, Yihui
Chang, Junbiao
Yu, Bin
JOURNAL OF MEDICINAL CHEMISTRY, 2025, 68 (05) : 5954 - 5972
[10] In silico design of EGFRL858R/T790M/C797S inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations
Hadni, Hanine
Elhallaouia, Menana
HELIYON, 2022, 8 (11)

← 1 2 3 4 5 →