Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Jiang, Sheng¹  Liao, Chenzhong²  Bindu, Lakshman³  Yin, Biaolin¹  Worthy, Karen W.³  Fisher, Robert J.³  Burke, Terrence R., Jr.²  Nicklaus, Marc C.²  Roller, Peter P.² 

[1] Chinese Acad Sci, Lab Regenerat Biol, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China

[2] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA

[3] SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA

关键词: Grb2-SH2 domain;    Cyclic peptides;    G1TE analogs;    Phosphotyrosine;    Grb2-SH2 antagonist;   

DOI  :  10.1016/j.bmcl.2009.03.134

来源: Elsevier

【 摘 要 】

Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d) = 0.359 mu M, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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