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

Proudfoot, John; Betageri, Rajashehar; Cardozo, Mario; Gilmore, Thomas A.; Glynn, Susan; Hickey, Eugene R.; Jakes, Scott; Kabcenell, Alisa K.; Kirrane, Thomas M.; Tibolla, Annette K.; Lukas, Susan; Patel, Usha; Sharma, Rajiv P.; Moss, Neil; Beaulieu, Pierre L.; Cameron, Dale R.; Ferland, Jean-Marie; Gauthier, Jean; Gillard, James; Gorys, Vida; Poirier, Martin; Rancourt, James D.; Wernic, Dominik; Llinàs‐Brunet, Montse

doi:10.1021/jm000446q

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…Compound 53f inhibited receptor-mediated increase in intracellular calcium concentration with an EC 50 = 10 µM. The R enantiomer had a much weaker effect (EC 50 > 50 µM), thus supporting action of 53f via antagonism of the Lck SH2 domain [145].…”

Section: Sh2 Inhibitorsmentioning

confidence: 84%

“…Even if the replacement of the doubly charged phosphate group present in compound 51 with the mono-charged acetic acid group (comp. 52) decreased binding affinity, this decrease was partially compensated by the positive effect exerted by the lipophilic substituent placed at the N-terminus of the inhibitor [145], an effect well known in this field [146]. On the whole, peptide 52 showed a 50-fold lower affinity than 41 but, despite the reduced negative charges, was still very poorly cell permeable [145].…”

Section: Sh2 Inhibitorsmentioning

confidence: 95%

“…Inhibitors of the SH2 domain of p56lck have the potential to control the immune response and have therefore become an important target [31,129,144,145].…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

“…The α,α-dimethyl substitution in compound 53a (to obtain 53b) was meant to enhance the cell permeation properties, by shielding the polar carboxylate functionality. Additional dimethylation at the P-1 amide led to compound 53d, which showed the best cell permeability (Caco-2 model of cell permeation) [145], though accompanied by a small decrease in binding affinity versus 53c. Compound 53d w a s separated into its two enantiomers and the S-enantiomer 53f proved to be the eutomer and it is also provided by a good cell permeation.…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

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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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Section: Sh2 Inhibitorsmentioning

confidence: 84%

Section: Sh2 Inhibitorsmentioning

confidence: 95%

“…Inhibitors of the SH2 domain of p56lck have the potential to control the immune response and have therefore become an important target [31,129,144,145].…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

Section: Sh2 Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Costantino¹,

Barlocco

2004

CMC

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“…Such esters are readily hydrolysed by cellular enzymes, furnishing the free and biologically active diacid precursors following efficient cellular delivery [199]. 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].…”

Section: Adaptor Proteinsmentioning

confidence: 99%

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

Fischer¹

2004

CMC

110

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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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An Overview of Caco‐2 and Alternatives for Prediction of Intestinal Drug Transport and Absorption

Ungell

Artursson

2008

Methods and Principles in Medicinal Chemistry

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

Cited by 14 publications

References 41 publications

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

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

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

An Overview of Caco‐2 and Alternatives for Prediction of Intestinal Drug Transport and Absorption

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