Development of a Phosphatase-Stable Phosphotyrosyl Mimetic Suitably Protected for the Synthesis of High-Affinity Grb2 SH2 Domain-Binding Ligands

Wei, Chang Qing; Li, Bihua; Guo, Ribo; Yang, Dajun; Burke, Terrence R.

doi:10.1016/s0960-894x(02)00527-9

Cited by 27 publications

(40 citation statements)

References 16 publications

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“…Burke et al designed and synthesized a series of open-chain and macrocyclic Grb SH2 mimetics such as 89 (IC 50 ¼ 9 nM, ELISA assay; IC 50 ¼ 20 nM SPR assay, Figure 8.35). 204,205 Compound 89 also showed activity (IC 50 ¼ 5 mM) in a whole cell assay with MDA-MB-453 breast cancer cell line where the erb-2 gene is amplified. 204 The cyclohexylglycine residue at the iþ2 position of the b-turn of 89 greatly stabilizes the bioactive conformation.…”

Section: Sh2 Domains: Macrocyclic Modulators Of Grb2mentioning

confidence: 97%

“…204,205 Compound 89 also showed activity (IC 50 ¼ 5 mM) in a whole cell assay with MDA-MB-453 breast cancer cell line where the erb-2 gene is amplified. 204 The cyclohexylglycine residue at the iþ2 position of the b-turn of 89 greatly stabilizes the bioactive conformation. Through macrocyclization using a ring-closing metathesis reaction, this conformation was subsequently further stabilized in compound 90 (IC 50 ¼ 2 nM, ELISA assay, Figure 8 196 B: X-ray structure of Cyclosporin A bound to calcineurin and cyclophilin.…”

Section: Sh2 Domains: Macrocyclic Modulators Of Grb2mentioning

confidence: 97%

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Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

Ermert

Moehle

Obrecht

2014

Macrocycles in Drug Discovery

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This chapter summarizes some highlights of macrocyclic drug discovery in the area of GPCRs, integrins, and protein–protein interactions spanning roughly the last 30 years. Several examples demonstrate that incorporation of pharmacophores derived from natural peptide ligands into the context of a constrained macrocycle (“lock of the bioactive conformation”) has proven a powerful approach for the discovery of potent and selective macrocyclic drugs. In addition, it will be shown that macrocycles, due to their semi-rigid nature, can exhibit unique properties that can be beneficially exploited by medicinal chemists. Macrocycles can adapt their conformation during binding to a flexible protein target surface (“induced fit”), and due to their size, can interact with larger protein interfaces (“hot spots”). Also, macrocycles can display favorable ADME properties well beyond the rule of 5 in particular exhibiting favorable cell penetrating properties and oral bioavailability.

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Section: Sh2 Domains: Macrocyclic Modulators Of Grb2mentioning

confidence: 97%

Section: Sh2 Domains: Macrocyclic Modulators Of Grb2mentioning

confidence: 97%

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

Ermert

Moehle

Obrecht

2014

Macrocycles in Drug Discovery

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“…In this phosphopeptide the α,α-cycloamino acid stabilized the β-turn conformation required for efficient recognition by the Grb2-SH2 domain. Further modifications at different parts of the molecule resulted in a series of inhibitors (27)(28)(29)(30), some incorporating phosphonate and malonyl phosphotyrosyl mimetics, and others indole derivatives instead of the naphthalene moiety, which showed potent activity in cell-based assays and improved stability to cellular phosphatases [105][106][107][108].…”

Section: Antagonists Of the Sh2 Domain Of Grb2mentioning

confidence: 99%

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Vega

Martı́n-Martı́nez²,

González‐Muñiz

2007

CTMC

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In view of the crucial role of protein-protein intercommunication both in biological and pathological processes, the search of modulators of protein-protein interactions (PPIs) is currently a challenging issue. The development of rational strategies to imitate key secondary structure elements of protein interfaces is complementary to other approaches based on the screening of synthetic or virtual libraries. In this sense, the present review provides representative examples of compounds that are able to disturb PPIs of therapeutic relevance, through the stabilization or the imitation of peptide hot-spots detected in contact areas of the interacting proteins. The review is divided into three sections, covering mimetics of the three main secondary structural elements found in proteins, in general, and in protein-protein interfaces, in particular (alpha-helices, beta-sheets, and reverse turns). Once the secondary element has been identified, the first approach typically involves the translation of the primary peptide structure into different cyclic analogues. This is normally followed by gradual decrease of the peptide nature through combination of peptide and non-peptide fragments in the same molecule. The final step usually consists in the development of pertinent organic scaffolds for appending key functional groups in the right spatial disposition, as a means towards totally non-peptide small molecule PPI modulators.

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“…The synthesis of the macrocycles 40 was undertaken in an effort to reduce binding entropy penalties by constraining the peptide backbone, and introducing side chain rotational constraints [119,120] besides the bend-inducing effect afforded by the cyclohexane moiety [116,120]; thus the effects of macrocyclization and the influence of an acidic functionality at the tyrosyl alpha-amino group were studied in both extracellular and in whole cell systems [119][120][121].…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

Costantino¹,

Barlocco

2004

CMC

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Reversible phosphorylation of Tyr residues in proteins plays a central role in the transduction of signals. For both SH2 domains and for protein tyrosine phosphatases (PTPs) the phosphate group of phosphotyrosine (pTyr) of peptides provides a key affinity element, but its highly charged nature and its hydrolytic lability render it unsuitable in inhibitor design. The research in the recent years has been addressed to find pTyr bioisosters devoid of the phenylphosphate moiety and more potent inhibitors with less peptidic character. Several derivatives were prepared as pTyr bioisosters, and their activity appears to depend on the nature of the substrate, peptidic or low-molecular weight compounds, in which they are placed. In the field of PTPs, the research was mainly focused on new and selective PTP1B inhibitors, possibly useful in the treatment of Type 2 diabetes. The discovery of non-peptidic low molecular weight compounds able to inhibit PTP1B, by means of docking procedures and HTS screening, and the presence of secondary binding sites on PTP1B afforded new potent and selective inhibitors; several leads devoid of negative charges were also found. To date, however, few compounds have been tested In vivo and found to show a significant activity in diabetic mouse models. Other neutral compounds, mainly quinones, were found to inhibit CD45 and Cdc25. Several papers have appeared in recent years on the discovery of new Grb2, Src, Syk, and Lck SH2 domains binding antagonists. In this field very good inhibitors derived from high affinity peptides were found, with less peptidic character and with a reduced number of negative charges; however the presence of some negative charges, especially the one present on the pTyr bioisoster moiety, seems to be indispensable. As regards Grb2, Src and Lck SH2 domains, rigidification of the starting high affinity binding peptides afforded derivatives with improved affinity; cellular activity was achieved by modification of the side chains of these inhibitors.

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Development of a Phosphatase-Stable Phosphotyrosyl Mimetic Suitably Protected for the Synthesis of High-Affinity Grb2 SH2 Domain-Binding Ligands

Cited by 27 publications

References 16 publications

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

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