The difluoromethylenesulfonic acid group as a monoanionic phosphate surrogate for obtaining PTP1B inhibitors

Leung, Chun Sing; Grzyb, Justyna A.; Lee, Jason; Meyer, N.; Hum, Gabriel; Jia, Chenguo; Liu, Shifeng; Taylor, Scott D.

doi:10.1016/s0968-0896(02)00062-7

Cited by 37 publications

(30 citation statements)

References 29 publications

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“…Incorporating pTyr mimics into peptide templates is one method to improve the activity of inhibitors. 15,19,22,24 PTP1B contains a second noncatalytic pTyr binding site that is formed mainly by Arg24, Arg254, Gly259, Gln262 and Met258. 25 These residues, except for Arg254 and Gln262, are not as conserved in many PTPs compared to the residues that make up the active site.…”

Section: Ptp Inhibitorsmentioning

confidence: 99%

A two stage click-based library of protein tyrosine phosphatase inhibitors

Xie

Seto

2007

Bioorganic & Medicinal Chemistry

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Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono-and diynes. After hydrolysis of the methyl esters, the resulting α-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono-and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR and CD45. The best bis(α-ketocarboxylic acid) inhibitor 34 had an IC 50 value of 550 nM against the Yersinia PTP, and an IC 50 value of 710 nM against TCPTP. The most potent inhibitor containing a single α-ketocarboxylic acid group 32 had IC 50 values of 2.1, 5.7 and 2.6 μM against the Yersinia PTP, PTP1B and TCPTP, respectively.

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Section: Ptp Inhibitorsmentioning

confidence: 99%

A two stage click-based library of protein tyrosine phosphatase inhibitors

Xie

Seto

2007

Bioorganic & Medicinal Chemistry

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“…All obtained results relied on increasing hydrophobic interactions of these groups with enzyme side groups of Ile219, Val49, Tyr46, Arg47 and Phe182 Several attempts were made in order to increase the potency of low molecular inhibitors of PTP1B deriving from compound 66. Analogues with extended aromatic portion of the molecule were prepared and evaluated [114][115][116][117][118][119]. Among all synthesised compounds, the most potent were those with aromatic or unsaturated substituents placed in meta position of the first aromatic ring (for example compounds 81-84, Fig.…”

Section: Protein Tyrosine Phosphatase 1bmentioning

confidence: 99%

Computer-Aided Analysis and Design of Phosphonic and Phosphinic Enzyme Inhibitors as Potential Drugs and Agrochemicals

Berlicki¹,

Kafarski

2005

COC

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A structure-based approach to design potent and selective inhibitors is an important component of the modern drug development process. As the altered activity of certain enzymes is associated with variety of pathologies, the design and synthesis of inhibitors for enzymes playing the key role in pathogenesis may result in potential therapeutic agents. Nowadays, the development of new inhibitors is often based on computer assisted design process. Although threedimensional structure of the enzyme and mechanism of enzymatic reaction are most important for accurate design, the mode of action of already known lead compounds as well as their characteristic structural features also have to be considered.This review summarises the current progress in computer-aided design of phosphonic and phosphinic acids and their short peptides as inhibitors of chosen enzymes of medical and agrochemical importance. Despite the mechanism of inhibitory activity two approaches for their design are presented. First one relies on the use of the crystal structure of enzymes as well as enzymes complexed with some ligands for structure-based search for novel inhibitory structures. Second enables prediction of activity of new enzyme groups of inhibitors based on the building-up relation of observed activity to specific structural features of sets of compounds of known biological activity.

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“…1)] are less active (100 fold) than the corresponding phosphono(difluoromethyl) phenylalanine [F 2 Pmp, 3, (Fig. 1)] but the comparison with analogous peptides bearing monoanionic pTyr mimetics indicated that F 2 Smp is more effective than other monoanionic pTyr mimetics [34]. When F 2 Pmp and F 2 Smp are inserted in non-peptidic, low molecular weight biaryl compounds, the difference in activity between F 2 Smp and F 2 Pmp is much smaller (3 to 8-fold) than that observed when these groups are present in peptide scaffolds [34].…”

Section: Phosphotyrosine Mimeticsmentioning

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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The difluoromethylenesulfonic acid group as a monoanionic phosphate surrogate for obtaining PTP1B inhibitors

Cited by 37 publications

References 29 publications

A two stage click-based library of protein tyrosine phosphatase inhibitors

A two stage click-based library of protein tyrosine phosphatase inhibitors

Computer-Aided Analysis and Design of Phosphonic and Phosphinic Enzyme Inhibitors as Potential Drugs and Agrochemicals

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

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