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Titolo:
N-terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding
Autore:
Burke, TR; Yao, ZJ; Gao, Y; Wu, JX; Zhu, XF; Luo, JH; Guo, RB; Yang, DJ;
Indirizzi:
NCI, Med Chem Lab, Div Basic Sci, NIH, Frederick, MD 21702 USA NCI Frederick MD USA 21702 b, Div Basic Sci, NIH, Frederick, MD 21702 USA Georgetown Univ, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 t Oncol, Washington, DC 20007 USA
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 6, volume: 9, anno: 2001,
pagine: 1439 - 1445
SICI:
0968-0896(200106)9:6<1439:NCATAA>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
STRUCTURE-BASED DESIGN; PHOSPHOTYROSINE-CONTAINING PEPTIDE; PHOSPHATE-CONTAINING LIGANDS; TYROSINE KINASE ZAP-70; HIGH-AFFINITY; SIGNAL-TRANSDUCTION; DRUG DESIGN; INHIBITORS; POTENT; DISCOVERY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
53
Recensione:
Indirizzi per estratti:
Indirizzo: Burke, TR NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 376,FCRDC, Frederick, MD 21702USA NCI Bldg 376,FCRDC Frederick MD USA 21702 Frederick, MD 21702USA
Citazione:
T.R. Burke et al., "N-terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding", BIO MED CH, 9(6), 2001, pp. 1439-1445

Abstract

High affinity binding of peptides to Src homology 2 (SH2) domains, often requires the presence of phosphotyrosyl (pTyr) or pTyr-mimicking moieties inthe N-terminal position of the binding ligand. Several reports have shown that N-alpha-acylation of the critical pTyr residue can result in increasedSH2 domain binding potency. For Grb2 SH2 domains which recognize pTyr-Xxx-Asn-NH2 motifs, significant potency enhancement can be incurred by N-alpha-(3-amino)Z derivatization of tripeptides such as pTyr-Xxe-Asn-NH2. Using ligands based on the high affinity pY-Ac(6)c-Asn-(naphthylpropylamide) motif,(where Ac(6)c = 1-aminocyclohex-anecarboxylic acid), additional reports have shown moderate potentiating effects of N-alpha-oxalyl derivatization. The current study examined variations of the N-alpha-oxalyl theme in the context of a Xxx-Ac(6)c-Asn-(naphthylpropylamide) platform, where Xxx = the hydrolytically stable pTyr mimetics phosphonomethyl phenylalanine (Pmp) or carboxymethyl phenylalanine (Cmf). The effects of N-alpha-(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 N-alpha-acetyl-containing compound, with enhancement approximating that observed for the N-alpha-oxalyl derivative. When Cmf was used as the pTyr mimetic, only modest differences in IC50 values were observed for the series. Examination of the N-alpha-(3-amino)Z derivatized Pmp-Ac(6)c-Asn-(naphthylpropylamide), showed that binding affinity was reduced relative to the parent N-alpha-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 N-alpha-oxalyl and N-alpha-malonyl-containing compounds exhibiting IC50 values (4.3 and 4.6 muM, respectively) approximately five-fold lower than the parent N-alpha-acetyl-containing compound. Tetrazole and N-alpha-(3-amino)Z-containing inhibitors were from two- to four-fold less potent thanthese latter analogues in the growth inhibition assays. (C) 2001 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 12:49:06