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

Abstract：

: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)=0.359microM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Jiang S,Liao C,Bindu L,Yin B,Worthy KW,Fisher RJ,Burke TR Jr,Nicklaus MC,Roller PP

doi

10.1016/j.bmcl.2009.03.134

subject

Has Abstract

pub_date

2009-05-15 00:00:00

pages

2693-8

issue

10

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(09)00458-2

journal_volume

19

pub_type

杂志文章

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