Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR

被引：10

作者：

Zheng, Mengmeng ^{[1
]}

Li, Chunpu ^{[1
,2
,3
]}

Zhou, Mi ^{[1
]}

Jia, Ru ^{[2
,3
]}

Cai, Gang ^{[2
,3
]}

She, Fengyu ^{[1
]}

Wei, Lulu ^{[1
]}

Wang, Shaohui ^{[4
]}

Yu, Jie ^{[5
]}

Wang, Dingyan ^{[5
]}

Calcul, Laurent ^{[1
]}

Sun, Xingmin ^{[4
]}

Luo, Xiaomin ^{[5
]}

Cheng, Feng ^{[6
]}

Li, Qi ^{[2
,3
,7
]}

Wang, Yan ^{[2
,3
,7
]}

Cai, Jianfeng ^{[1
]}

机构：

[1] Univ S Florida, Dept Chem, Tampa, FL 33620 USA

[2] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Med Oncol, Shanghai 201203, Peoples R China

[3] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Canc Inst Med, Shanghai 201203, Peoples R China

[4] Univ S Florida, Morsani Coll Med, Dept Mol Med, Tampa, FL 33612 USA

[5] Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[6] Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, Tampa, FL 33612 USA

[7] Shanghai Univ Tradit Chinese Med, Acad Integrat Med, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 15期

基金：

中国国家自然科学基金;

关键词：

EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR; SIGNAL-TRANSDUCTION; GAMMA-AAPEPTIDES; PEPTIDE LIGAND; CANCER; BINDING; MUTATIONS; GEFITINIB; THERAPY;

D O I：

10.1021/acs.jmedchem.1c00607

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

It is very promising to target the extracellular domain of epidermal growth factor receptor (EGFR) for developing novel and selective anticancer therapies. Herein, we report the discovery of a novel small molecule, M-2-5, from a one-bead-two-compound (OBTC) cyclic gamma-AApeptide library. The molecule was found to bind tightly to the extracellular domain of EGFR. Intriguingly, this molecule could also effectively antagonize EGF-stimulated EGFR phosphorylation and downstream signal transduction. Furthermore, together with its remarkable resistance to proteolytic degradation, M-2-5 was shown to effectively inhibit cell proliferation and migration in vitro and suppresses the growth of tumor in the A549 xenograft model in vivo, highlighting its potential therapeutic application for cancer treatment.

引用

页码：11219 / 11228

页数：10

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