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

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...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2009-05, Vol.19 (10), p.2693-2698
Hauptverfasser: Jiang, Sheng, Liao, Chenzhong, Bindu, Lakshman, Yin, Biaolin, Worthy, Karen W., Fisher, Robert J., Burke, Terrence R., Nicklaus, Marc C., Roller, Peter P.
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Sprache:eng
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Zusammenfassung: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 μM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.03.134