Discovery of Thioazepinone Ligands for Src SH2: From Non-specific to Specific Binding

Lesuisse, Dominique; Deprez, Pierre; Albert, Eva; Duc, Tran Thien; Sortais, Benoît; Gofflo, Dominique; Jean‐Baptiste, Véronique; Marquette, Jean‐Pierre; Schoot, Bernard; Sarubbi, Edoardo; Lange, Gudrun; Broto, Pierre; Mandine, Eliane

doi:10.1016/s0960-894x(01)00386-9

Cited by 22 publications

(15 citation statements)

References 11 publications

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“…Beneficial hydrophobic interaction with the (pY+0)-binding pocket was demonstrated in this approach by use of a monobenzyl phosphate pY+0 function [165]. Efforts have also been made to exploit the Cys C3 residue [155] of the pTyr-binding pocket, by introduction of a 3 -formyl electrophile to the pTyr [166] aryl motif of 117 to give 129 [143].…”

Section: Targeting Of Sh2-domain Of Pp60 C-srcmentioning

confidence: 99%

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

Wardle¹,

Bligh²,

Hudson³

2008

CMC

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Literature publications reporting the development of organophosphorus compounds, targeting aspects of signal transduction to the titled therapeutic ends, are reviewed. With respect to extracellular targets, the development of ligands to purinergic (P2), and endothelial differentiation-gene receptors (of S1P- and LPA-receptor subtypes) is charted, along with inhibitors of the production and release of tumour necrosis factor-alpha (TNF-alpha). Reported also are inhibitors of the ectoenzymes aminopeptidase N, aminopeptidase A and dipeptidyl peptidase IV, the proteolytic enzyme thrombin, ligands to "apoptosis-receptors" and gammadelta T-cell activators. In addition, disruption of intracellular signalling chains mediated through reversible coupling of proteins via phosphorylation of Tyr residues and docking of pTyr residues in SH2-binding domains is covered. In particular, the development of ligands to SH2-binding domains in tyrosine kinases Src and lck, adaptor protein Grb2, and also ZAP70 protein are reported along with inhibitors to relevant phosphatases. SAR studies of ligands to Ins(1,4,5)-P3- and ryanodine-type receptors of intracellular Ca2+-storage organelles are described including analogues to secondary messengers cyclic-ADP-ribose (cADPR) and myo-inositol-1,4,5-triphosphate. Inhibitors of phosphatidyl inositol 3-kinase (PI3K) and sphingomyelinase are also reported, as are inhibitors of farnesyl transferase, the enzyme involved in protein-prenylation.

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Section: Targeting Of Sh2-domain Of Pp60 C-srcmentioning

confidence: 99%

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

Wardle¹,

Bligh²,

Hudson³

2008

CMC

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“…Replacement of the phosphate group in pTyr with less acidic carboxylic acids has also been found to be favourable in terms of cell permeability [202,203]. Essentially non-peptidic inhibitors such as 13.4a have also been developed [191,[204][205][206][207]. The presence of a thiol group from Cys 188 in Src SH2 was exploited for the design of covalent inhibitors.…”

Section: Adaptor Proteinsmentioning

confidence: 99%

The Design of Drug Candidate Molecules as Selective Inhibitors of Therapeutically Relevant Protein Kinases

Fischer¹

2004

CMC

109

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The human genome encompasses some 2,000 proteins that utilize adenosine 5'-triphosphate (ATP) in one way or another and some 500 of these are protein-tyrosine and protein-serine/threonine kinases (PTKs & PSTKs). Substrate phosphorylation by these enzymes is nature's predominant molecular way of organizing cellular signal transduction and regulating biochemical processes in general. It is not surprising, therefore, that abnormal phosphorylation of cellular proteins is a hallmark of disease and that there has been a growing interest in the use of kinase inhibitors as drugs. In fact the search for such agents has recently culminated in the approval of the first kinase inhibitor drugs for medical use. Although it has been demonstrated exhaustively that potent and structurally diverse ATP-antagonistic small molecule kinase inhibitors can be found through mass screening and structure-guided design, the question of biochemical, cellular, and in vivo selectivity of such inhibitors remains much less clear. Here the medicinal chemistry of kinase inhibitors is reviewed critically with particular emphasis on target selectivity and specificity. Approaches based on chemical genomics, combinatorial target-guided ligand assembly, computational chemistry, and structural biology techniques, which aim at classifying both inhibitors and kinase targets, are given special emphasis. The various strategies in which differences in biochemical mechanism of kinase function can be exploited in order to attain selective inhibition are also discussed. Furthermore, recent developments in the design of inhibitors to selected individual validated therapeutic kinase targets, including cell cycle kinases and receptor PTKs, etc. are summarised.

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“…Since molecular modelling indicated that neither of the two aromatic rings on the benzothioazepinone moiety were involved in the binding, simplified compounds were designed, in order to lower the lipophilicity. The best affinity was displayed by compound 43 (R 1 = CH 2 PhPh; X = S; IC 50 = 90 nM vs. pYEEI IC 50 = 150 nM, SPA assay [124]). X-ray studies on the complex of 43 showed that the compound binds Src SH2 in the same way as the parent tetrapeptide [124].…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

“…The best affinity was displayed by compound 43 (R 1 = CH 2 PhPh; X = S; IC 50 = 90 nM vs. pYEEI IC 50 = 150 nM, SPA assay [124]). X-ray studies on the complex of 43 showed that the compound binds Src SH2 in the same way as the parent tetrapeptide [124].…”

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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Discovery of Thioazepinone Ligands for Src SH2: From Non-specific to Specific Binding

Cited by 22 publications

References 11 publications

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

The Design of Drug Candidate Molecules as Selective Inhibitors of Therapeutically Relevant Protein Kinases

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

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