Using small molecules to target protein phosphatases

Vintonyak, Viktor V.; Waldmann, Herbert; Rauh, Daniel

doi:10.1016/j.bmc.2011.02.047

Cited by 45 publications

(32 citation statements)

References 126 publications

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“…14 In contrast to PTP, the inositol 5-phosphatase catalytic (IPP5C) domain, common to Synj1 and 5-phosphatases, is composed of an active site His and Asp pair coordinating a cation (typically Mg 2+ ) resembling the active site of serine/threonine-protein phosphatases. 15,16 However, the catalytic domain lacks the classical CX 5 R(T/S) motif present in other protein and lipid phosphatases. 36,37 Despite the common IPP5C shared by 5′-phosphatases, SHIP2 inhibitors display 30-fold higher affinity for SHIP2 over SHIP1 and Synj1.…”

Section: Discussionmentioning

confidence: 99%

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Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

et al. 2014

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Elevation of amyloid β-peptide (Aβ) is critically associated with Alzheimer’s disease (AD) pathogenesis. Aβ-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aβ-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aβ-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aβ-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1’s substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors which have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

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Section: Discussionmentioning

confidence: 99%

“…14,15 However, ample target validation studies have revealed the biological significance of phosphatases in various human disease. 10,14–19 For example, the tyrosine phosphatase STEP has been suggested as a candidate therapeutic target in AD.…”

Section: Introductionmentioning

confidence: 99%

Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

et al. 2014

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“…It is a public database contains validated chemical structures and detailed information of drugs. The test set was selected from literature consist of 59 compounds [34][35][36][37].…”

Section: Dataset Collectionmentioning

confidence: 99%

In Silico Approach for Lead Identification and Optimization Of Antidiabetic Compounds

2013

IOSR-JPBS

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“…The compelling biochemical evidence above-depicted has resulted in a plethora of efforts by academia and the pharmaceutical community toward the production of PTPs inhibitors [20, 21]. However, among the numerous inhibitors indentified during the past decade, only a few candidates have entered clinical trials while no commercial drugs have been approved till date due mainly to their insufficient selectivity over homologous PTPs and especially, limited bioavailability.…”

Section: Ptps As Drug Targetsmentioning

confidence: 99%

CuAAC Click Chemistry Accelerates the Discovery of Novel Chemical Scaffolds as Promising Protein Tyrosine Phosphatases Inhibitors

Xie

Tang

et al. 2012

CMC

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Protein tyrosine phosphatases (PTPs) are crucial regulators for numerous biological processes in nature. The dysfunction and overexpression of many PTP members have been demonstrated to cause fatal human diseases such as cancers, diabetes, obesity, neurodegenerative diseases and autoimmune disorders. In the past decade, considerable efforts have been devoted to the production of PTPs inhibitors by both academia and the pharmaceutical industry. However, there are only limited drug candidates in clinical trials and no commercial drugs have been approved, implying that further efficient discovery of novel chemical entities competent for inhibition of the specific PTP target in vivo remains yet a challenge. In light of the click-chemistry paradigm which advocates the utilization of concise and selective carbon-heteroatom ligation reactions for the modular construction of useful compound libraries, the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC) has fueled enormous energy into the modern drug discovery. Recently, this ingenious chemical ligation tool has also revealed efficacious and expeditious in establishing large combinatorial libraries for the acquisition of novel PTPs inhibitors with promising pharmacological profiles. We thus offer here a comprehensive review highlighting the development of PTPs inhibitors accelerated by the CuAAC click chemistry.

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Using small molecules to target protein phosphatases

Cited by 45 publications

References 126 publications

Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

In Silico Approach for Lead Identification and Optimization Of Antidiabetic Compounds

CuAAC Click Chemistry Accelerates the Discovery of Novel Chemical Scaffolds as Promising Protein Tyrosine Phosphatases Inhibitors

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