Non-peptide itam mimics as ZAP-70 antagonists

Révész, Láśzló; Blum, Ernst; Manning, Ute; Demange, B.Jachez; Widmer, Armin; Zuber, Jean-François

doi:10.1016/s0960-894x(97)10102-0

Cited by 6 publications

(4 citation statements)

References 6 publications

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“…Specifically, substitution of the D-Hcy-NH 2 by various disubstituted amines provided lead compounds of the generic structure Ac-pTyr-Glu-NRRЈ (wherein R and RЈ represented independent alkyl groups or are cyclized to form a pyrrolidine ring). 34 Of these dipeptides, the most potent analogues included C-terminal amide modifications such as NMe-(CH 2 ) 3 -cyclohexyl (43) and 2-(cyclohexylethyl)-pyrrolidine (44). Further substitutions at the pTyr and pYϩ1 positions resulted in decreased Src SH2 binding potencies, but did provide prototype lead compounds Ac-pTyr-Abu-NMe-(CH 2 ) 3 )-cyclohexyl (45) and Ac-F 2 Pmp-Abu-NMe-(CH 2 ) 3 -cyclohexyl) (46) having potentially improved cell permeability properties by virtue of the fact that the only ionic functionalities of such compounds were derived from the pTyr (or pTyr mimetic) side chain.…”

Section: Sh2 Domain Drug Discoverymentioning

confidence: 99%

“…nonpeptide 44 inhibitors of Zap70 N/C-SH2 binding exemplify the fact that mono-pTyr (or mimetics thereof) containing ligands may provide prototype leads to the design of yet more potent inhibitors. Specifically, a combinatorial library-based approach 43 led to the identification of a prototype multi-N-substituted tetrapeptide of the generic structure acyl-NR 1 Gly-NR 2 Gly-NR 3 Gly-NR 4 Gly-amide (see 68 -70, Figure 17).…”

Section: Figure 16mentioning

confidence: 99%

“…In the case of the recent discovery 44 of nonpeptide inhibitors of Zap70 N/C-SH2 binding, a steroid-based template was functionalized to incorporate pTyr-like substructural features to provide both monodentate and bidentate ligands (see 71-74, Figure 18). Examination of the structure-activity properties of this novel series of nonpeptide ligands revealed that the bidentate analogues (73 and 74) were about 10-fold more potent than the monodentate analogues (71 and 72) as based on their binding to Zap70 N/C-SH2.…”

Section: Figure 16mentioning

confidence: 99%

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Src homology-2 domains: Structure, mechanisms, and drug discovery

Sawyer¹

1998

Biopolymers

129

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Src homology‐2 (SH2) domains and their associated catalytic or noncatalytic proteins constitute critical signal transduction targets for drug discovery. Such SH2 proteins are found in the regulation of a number of cellular processes, including growth, mitogenesis, motility, metabolism, immune response, and gene transcription. From the relationship of tyrosine phosphorylation and intracellular regulation by protein–tyrosine kinases (PTKs) and protein–tyrosine phosphatases (PTPs), the dynamic and reversible binding interactions of SH2 domain containing proteins with their cognate phosphotyrosine (pTyr) containing proteins provide a third dimensionality to the orchestration of signal transduction pathways that exist as a result of pTyr formation, degradation, and molecular recognition events. This review highlights several key research achievements impacting our current understanding of SH2 structure, mechanisms, and drug discovery that underlie the role(s) of SH2 domains in signal transduction processes, cellular functions, and disease states. © 1998 John Wiley & Sons, Inc. Biopoly 47: 243–261, 1998

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Section: Sh2 Domain Drug Discoverymentioning

confidence: 99%

Section: Figure 16mentioning

confidence: 99%

Section: Figure 16mentioning

confidence: 99%

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Src homology-2 domains: Structure, mechanisms, and drug discovery

Sawyer¹

1998

Biopolymers

129

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“…The lead structures for these efforts are usually phosphotyrosine-containing peptides, and most of the reported ligands are at least doubly charged at physiological pH and often retain some peptidic character. These two features are considered impediments to cell permeation, and, although ligands with good binding affinity to various SH2 domains are available, prodrug 3c,8 and more exotic approaches 9 have generally been needed to deliver these ligands into cells . Recently, cellular activity that does not rely on these approaches has been reported for a monocharged ligand of the src SH2 domain …”

Section: Introductionmentioning

confidence: 99%

Nonpeptidic, Monocharged, Cell Permeable Ligands for the p56lck SH2 Domain

Proudfoot¹,

Betageri²,

Cardozo³

et al. 2001

J. Med. Chem.

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p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.

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Peptoid-Peptide Hybrids That Bind Syk SH2 Domains Involved in Signal Transduction

et al. 2001

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Peptoid-peptide hybrids are oligomeric peptidomimetics that contain one or more N-substituted glycine residues. In these hybrids, the side chains of one or several amino acids are "shifted" from the alpha-carbon atom to the amide nitrogen atom. A library of phosphorylated peptoid-peptide hybrids derived from the sequence pTyr-Glu-Thr-Leu was synthesized and tested for binding to the tandem SH2 domain of the protein tyrosine kinase Syk. A considerable influence of the side chain position was observed. Compounds 19-21, 24, and 25 comprising a peptoid NpTyr and/or NGlu residue did not show any binding. Compounds 22, 23, and 26 containing an NhThr (hThr=homothreonine) and/or NLeu peptoid residue showed binding with IC(50) values that were only five to eight times higher than that of the tetrapeptide lead compound 18. These data show that side chain shifting is possible with retention of binding capacity, but only at the two C-terminal residues of the tetramer. This method of a peptoid scan using peptoid-peptide hybrids appears to be very useful to explore to what extent a peptide sequence can be transformed into a peptoid while retaining its affinity.

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Non-peptide itam mimics as ZAP-70 antagonists

Cited by 6 publications

References 6 publications

Src homology-2 domains: Structure, mechanisms, and drug discovery

Src homology-2 domains: Structure, mechanisms, and drug discovery

Nonpeptidic, Monocharged, Cell Permeable Ligands for the p56lck SH2 Domain

Peptoid-Peptide Hybrids That Bind Syk SH2 Domains Involved in Signal Transduction

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