Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR

Mengmeng Zheng; Chunpu Li; Mi Zhou; Ru Jia; Gang Cai; Fengyu She; Lulu Wei; Shaohui Wang; Jie Yu; Dingyan Wang; Laurent Calcul; Xingmin Sun; Xiaomin Luo; Feng Cheng; Qi Li; Yan Wang; Jianfeng Cai

doi:10.1021/acs.jmedchem.1c00607

Discovery of Cyclic Peptidomimetic Ligands Targeting the Extracellular Domain of EGFR

J Med Chem. 2021 Aug 12;64(15):11219-11228. doi: 10.1021/acs.jmedchem.1c00607. Epub 2021 Jul 23.

Authors

Mengmeng Zheng¹, Chunpu Li^{1

2}, Mi Zhou¹, Ru Jia², Gang Cai², Fengyu She¹, Lulu Wei¹, Shaohui Wang³, Jie Yu⁴, Dingyan Wang⁴, Laurent Calcul¹, Xingmin Sun³, Xiaomin Luo⁴, Feng Cheng⁵, Qi Li^{2

6}, Yan Wang^{2

6}, Jianfeng Cai¹

Affiliations

¹ Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
² Department of Medical Oncology & Cancer Institute of Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
³ Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
⁴ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida 33612, United States.
⁶ Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

PMID: 34297567
DOI: 10.1021/acs.jmedchem.1c00607

Abstract

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 γ-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Ligands
Molecular Structure
Peptidomimetics / chemical synthesis
Peptidomimetics / chemistry
Peptidomimetics / pharmacology*
Structure-Activity Relationship

Substances

Ligands
Peptidomimetics
EGFR protein, human
ErbB Receptors