151608-48-9Relevant academic research and scientific papers
Development of non-peptide ligands of growth factor receptor-bound protein 2-src homology 2 domain using molecular modeling and NMR spectroscopy
Orcajo-Rincón, ángel L.,Ortega-Gutiérrez, Silvia,Serrano, Pedro,Torrecillas, Ivan R.,Wüthrich, Kurt,Campillo, Mercedes,Pardo, Leonardo,Viso, Alma,Benhamú, Bellinda,López-Rodríguez, María L.
supporting information; experimental part, p. 1096 - 1100 (2011/04/26)
We report a novel series of non-peptide ligands that inhibit the growth factor receptor-bound protein 2 (Grb2)-Src homology 2 (SH2) domain binding, designed using a combined computational and NMR-driven approach. We have identified a new lead compound, 1n (IC50 = 56 μM), which is cytotoxic in HER2-positive breast cancer cells and disrupts the interaction between HER2 and Grb2. Thus, 1n can be used as a scaffold for the development of efficient Grb2-SH2 domain binding inhibitors.
Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56(lck) SH2 domain
Llinàs-Brunet, Montse,Beaulieu, Pierre L.,Cameron, Dale R.,Ferland, Jean-Marie,Gauthier, Jean,Ghiro, Elise,Gillard, James,Gorys, Vida,Poirier, Martin,Rancourt, Jean,Wernic, Dominik,Betageri, Raj,Cardozo, Mario,Jakes, Scott,Lukas, Suzanne,Patel, Usha,Proudfoot, John,Moss, Neil
, p. 722 - 729 (2007/10/03)
Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56(lck) (Lck) with an affinity of 0.1 μM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.
