Covalent Inhibition of the Lymphoid Tyrosine Phosphatase

Ahmed, Vanessa; Bottini, Nunzio; Barrios, Amy

doi:10.1002/cmdc.201300404

Cited by 6 publications

(3 citation statements)

References 84 publications

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“…14). 124 Kinetic analysis of these two compounds is consistent with covalent capture of the enzyme, with nanomolar K I and reciprocal millisecond k inact values, indicating the best k inact / K I ratios compared to other reported covalent LYP inhibitors. The anti-inflammatory compound BAY-11-7082 (Fig.…”

Section: Covalent Ptp Inhibitorssupporting

confidence: 64%

Covalent inhibition of protein tyrosine phosphatases

Ruddraraju

Zhang

2017

Mol. BioSyst.

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Protein tyrosine phosphatases (PTPs) are a large family of 107 signaling enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in a target protein. The phosphorylation status of tyrosine residues on proteins serve as a ubiquitous mechanism for cellular signal transduction. Aberrant function of PTPs can lead to many human diseases, such as diabetes, obesity, cancer, and autoimmune diseases. As the number of disease relevant PTPs increases, there is urgency in developing highly potent inhibitors that are selective towards specific PTPs. Most current efforts have been devoted to the development of active site-directed and reversible inhibitors for PTPs. This review summarizes recent progress made in the field of covalent inhibitors to target PTPs. Here, we discuss the in vivo and in vitro inactivation of various PTPs by small molecule-containing electrophiles, such as Michael acceptors, α-halo ketones, epoxides, and isothiocyanates, etc. as well as oxidizing agents. We also suggest potential strategies to transform these electrophiles into isozyme selective covalent PTP inhibitors.

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Section: Covalent Ptp Inhibitorssupporting

confidence: 64%

Covalent inhibition of protein tyrosine phosphatases

Ruddraraju

Zhang

2017

Mol. BioSyst.

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“…The experimental conditions of these assays were as follows: 1 nM LAR, 20 μM DiFMUP, 2–40 μM IA-30, and incubation times of 15–120 min. k obs values were calculated by curve fitting the data to the following: , where V ∞ is the enzyme velocity after an infinite amount of time. The k obs values were then plotted against the inhibitor concentrations using the following equation to obtain K I and k inact values: …”

Section: Methodsmentioning

confidence: 99%

“…The experimental conditions of these assays were as follows: 1 nM LAR, 20 μM DiFMUP, 2−40 μM IA-30, and incubation times of 15−120 min. k obs values were calculated by curve fitting the data to the following: 28,29 The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00663.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Synthesis and PTP Inhibitory Activity of Illudalic Acid and Its Methyl Ether, with Insights into Selectivity for LAR PTP over Other Tyrosine Phosphatases under Physiologically Relevant Conditions

et al. 2019

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The protein tyrosine phosphatase (PTP) family of enzymes includes many attractive therapeutic targets, such as those in the leukocyte common antigen-related (LAR) subfamily of receptor PTPs. Synthesis and PTP inhibitory activity of illudalic acid and its methyl ether are described, with a focus on selective inhibition of LAR PTP relative to a small collection of other representative PTPs. The synthesis comprises 16 steps and provides illudalic acid in up to 12% overall yield from neopentylene-fused benzoate 1 (20 steps from commercial materials). Illudalic acid dose-dependently (measured IC 50 = 2.1 ± 0.2 μM) and time-dependently inhibits LAR consistent with previous reports of covalent binding. The kinetics of LAR inhibition by illudalic acid are consistent with a two-step mechanism in which the inhibitor and enzyme first interact noncovalently (K I = 130 ± 50 μM), followed by covalent ligation at a rate k inact = 1.3 ± 0.4 min −1 . The k inact /K I ratio of 10 4 corresponds to a t ∞ 1/2 of 0.5 min, as discussed herein. The phenol methyl ether of illudalic acid was found to be less potent in our dose−response assays (measured IC 50 = 55 ± 6 μM) but more selective for LAR, with a weaker initial noncovalent interaction and faster covalent ligation of LAR as compared to illudalic acid itself. A truncated analogue of illudalic acid that lacks the neopentylene ring fusion was found to be devoid of significant activity under our assay conditions, in contrast to previous reports. These observations collectively help inform further development of illudalic acid analogues as potent and selective inhibitors of the LAR subfamily of tyrosine phosphatases.

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Identification of a benzo imidazole thiazole derivative as the specific irreversible inhibitor of protein tyrosine phosphatase

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Covalent Inhibition of the Lymphoid Tyrosine Phosphatase

Cited by 6 publications

References 84 publications

Covalent inhibition of protein tyrosine phosphatases

Covalent inhibition of protein tyrosine phosphatases

Synthesis and PTP Inhibitory Activity of Illudalic Acid and Its Methyl Ether, with Insights into Selectivity for LAR PTP over Other Tyrosine Phosphatases under Physiologically Relevant Conditions

Identification of a benzo imidazole thiazole derivative as the specific irreversible inhibitor of protein tyrosine phosphatase

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