957471-86-2Relevant academic research and scientific papers
N-Terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding
Burke Jr, Terrence R,Yao, Zhu-Jun,Gao, Yang,Wu, Jane X,Zhu, Xiaofeng,Luo, Juliet H,Guo, Ribo,Yang, Dajun
, p. 1439 - 1445 (2001)
High affinity binding of peptides to Src homology 2 (SH2) domains, often requires the presence of phosphotyrosyl (pTyr) or pTyr-mimicking moieties in the N-terminal position of the binding ligand. Several reports have shown that Nα-acylation of the critical pTyr residue can result in increased SH2 domain binding potency. For Grb2 SH2 domains which recognize pTyr-Xxx-Asn-NH2 motifs, significantly potency enhancement can be incurred by Nα-(3-amino)Z derivatization of tripeptides such as pTyr-Ile-Asn-NH2. Using ligands based on the high affinity pY-Ac6c-Asn-(naphthylpropylamide) motif, (where Ac6c= 1-aminocyclohexanecarboxylic acid), additional reports have shown moderate potentiating effects of Nα-oxalyl derivatization. The current study examined variations of the Nα oxalyl theme in the context of a Xxx-Ac6c-Asn-(naphthylpropylamide) paltform, where Xxx = the hydrolytically stable pTyr mimetics phosphonomethyl phenylalanine (Pmp) or carboxymethyl phenylalanine (Cmf). The effects of Nα(3-amino)Z derivatization were also investigated for this platform, to ascertain whether the large binding enhancement reported for tripeptides such as pTyr-Ile-Asn-NH2 could be observed. In ELISA-based extracellular Grb2 SH2 domain binding assays, it was found for the pmp-based series, that extending the oxalyl carboxyl out by one methylene unit or replacing carboxyl functionality with a tetrazole isostere, resulted in binding potency greater than the parent Nα-acetyl-containing compound, with enhancement approximately that observed for the NNα-oxalyl derivative. When Cmf was used as the pTyr mimetic, only modest differences in IC50 approximating values were obsered for the series. Examination of the Nα-(3-amino)Z derivatized Pmp-Ac6c-Asn-(naphthylpropylamide), showed that binding affinity was reduced relative to the parent Nα-acetyl analogue, in contrast to the reported significant enhancement of affinity observed with other peptide ligands. Treatment of MDA-453 tumor cells, which are mitogenically driven through erbB-2 tyrosine kinase-dependent pathways, with Pmp-containing inhibitors resulted in growth inhibition, with the Nαoxalyl and Nα-malonyl-containing compounds exhibiting IC50 values (4.3 and 4.6 μM, respectively) approximately five-fold lower than the parent Nα-acetyl-containing compound. Tetrazole and Nα-(3-amino)Z-containing inhibitors were from two- to four-fold less potent than these latter analogues in the growth inhibition assays. Copyright
