Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic

被引：55

作者：

Furet, P ^{[1
]}

García-Echeverria, C ^{[1
]}

Gay, B ^{[1
]}

Schoepfer, J ^{[1
]}

Zeller, M ^{[1
]}

Rahuel, J ^{[1
]}

机构：

[1] Novartis Pharma Inc, Oncol Res Dept, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 13期

关键词：

D O I：

10.1021/jm991013u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Previous efforts in the search for molecules capable of blocking the associations between the activated tyrosine kinase growth factor receptors and the SH2 domain of Grb2 had resulted in the identification of 3-amino-Z-pTyr-Ac(6)c-Asn-NH2, a high-affinity and selective antagonist of this SH2 domain. In the present paper, we report the successful replacement of asparagine in this compound by a beta-amino acid mimetic, which brings us closer to our objective of identifying a Grb2-SH2 antagonist suitable for pharmacological investigations.

引用

页码：2358 / 2363

页数：6

共 27 条

[1]

Atherton E., 1989, SOLID PHASE PEPTIDE

[2] SH2 domain protein interaction and possibilities for pharmacological intervention [J].

Beattie, J .

CELLULAR SIGNALLING, 1996, 8 (02) :75-86

[3]

BRUNGER AT, 1992, XPLOR VERSION 3 1 SY

[4] THE GRB2 ADAPTER [J].

CHARDIN, P ;

CUSSAC, D ;

MAIGNAN, SB ;

DUCRUIX, A .

FEBS LETTERS, 1995, 369 (01) :47-51

[5] THE GRB2/SEM-5 ADAPTER PROTEIN [J].

DOWNWARD, J .

FEBS LETTERS, 1994, 338 (02) :113-117

[6] REDUCTION N-CHLOROSULFONYL BETA-LACTAMS TO BETA-LACTAMS WITH SODIUM SULFITE [J].

DURST, T ;

OSULLIVA.MJ .

JOURNAL OF ORGANIC CHEMISTRY, 1970, 35 (06) :2043-&

[7] Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain [J].

Furet, P ;

Gay, B ;

GarciaEcheverria, C ;

Rahuel, J ;

Fretz, H ;

Schoepfer, J ;

Caravatti, G .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (22) :3551-3556

[8] Structure-based design and synthesis of nigh affinity tripeptide ligands of the Grb2-SH2 domain [J].

Furet, P ;

Gay, B ;

Caravatti, G ;

García-Echeverría, C ;

Rahuel, J ;

Schoepfer, J ;

Fretz, H .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (18) :3442-3449

[9] Potent antagonists of the SH2 domain of Grb2:: Optimization of the X+1 position of 3-Amino-Z-Tyr(PO3H2)-X+1-Asn-NH2 [J].

García-Echeverría, C ;

Furet, P ;

Gay, B ;

Fretz, H ;

Rahuel, J ;

Schoepfer, J ;

Caravatti, G .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (11) :1741-1744

[10]

Gishizky ML, 1995, ANNU REP MED CHEM, V30, P247

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