Design and Biological Evaluation of Novel Imidazolyl Flavonoids as Potent and Selective Protein Tyrosine Phosphatase Inhibitors

2020 ◽  
Vol 16 (4) ◽  
pp. 563-574 ◽  
Author(s):  
Rong Y. Han ◽  
Yu Ge ◽  
Ling Zhang ◽  
Qing M. Wang
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Structural Features ◽  
Biological Evaluation ◽  
Cell Protein ◽  
Phosphatase Inhibitors ◽  
Protein Tyrosine ◽  
Therapeutic Development ◽  
Chemical Studies

Background: Protein tyrosine phosphatases 1B are considered to be a desirable validated target for therapeutic development of type II diabetes and obesity. Methods: A new series of imidazolyl flavonoids as potential protein tyrosine phosphatase inhibitors were synthesized and evaluated. Results: Bioactive results indicated that some synthesized compounds exhibited potent protein phosphatase 1B (PTP1B) inhibitory activities at the micromolar range. Especially, compound 8b showed the best inhibitory activity (IC50=1.0 µM) with 15-fold selectivity for PTP1B over the closely related T-cell protein tyrosine phosphatase (TCPTP). Cell viability assays indicated that 8b is cell permeable with lower cytotoxicity. Molecular modeling and dynamics studies revealed the reason for selectivity of PTP1B over TCPTP. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. Conclusion: Compound 8b should be a potential selective PTP1B inhibitor.

scholarly journals Crystal Structure of the Trypanosoma cruzi Protein Tyrosine Phosphatase TcPTP1

2014 ◽  
Vol 70 (a1) ◽  
pp. C824-C824
Author(s):  
George Lountos ◽  
Joseph Tropea ◽  
David Waugh
Keyword(s):  
Crystal Structure ◽  
Drug Design ◽  
Trypanosoma Cruzi ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Large Population ◽  
Protein Tyrosine Phosphatases ◽  
Structure Based Drug Design ◽  
Phosphatase Inhibitors ◽  
Protein Tyrosine

Chagas' disease is a neglected tropical disease transmitted by the flagellated protozoan, Trypanosoma cruzi, which affects millions of people particularly in Latin America. Only two approved drugs are available to treat the disease but they can present several side effects and are not very effective during the chronic stage of the disease. Therefore, given the large population that is at risk, there is a need to discover new molecular targets for drug design efforts. Recently, the T. cruzi protein tyrosine phosphatase, TcPTP1, was shown to play a role in the cellular differentiation and infectivity of the parasite, and therefore, raises its profile as a potential new therapeutic target. Although drug development targeting protein tyrosine phosphatases is challenging and not as advanced as in other targets such as kinases, structure-based drug design methods have shown to be vital in aiding the discovery of novel phosphatase inhibitors with high potency and improved specificity. Here, we present the 2.1 Angstroms resolution X-ray crystal structure of the T. cruzi TcPTP1 that provides structural insights into the active site environment that may be exploited in order to initiate structure-based drug design efforts to develop novel TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also presented that may make it feasible to develop compounds that are specific for TcPTP1.

scholarly journals Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) β-Receptor but Not the PDGF α-Receptor

2006 ◽  
Vol 17 (11) ◽  
pp. 4846-4855 ◽  
Author(s):  
Susann Karlsson ◽  
Katarzyna Kowanetz ◽  
Åsa Sandin ◽  
Camilla Persson ◽  
Arne Östman ◽  
...  
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Cell Protein ◽  
Protein Tyrosine ◽  
Β Receptor

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) β-receptor. Here, we show that the increased PDGF β-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF β-receptors and delayed receptor degradation, suggesting PDGF β-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF β-receptor, because PDGF α-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF αβ-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF β-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF β-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

Structure-Based Design and Discovery of Protein Tyrosine Phosphatase Inhibitors Incorporating Novel Isothiazolidinone Heterocyclic Phosphotyrosine Mimetics

2005 ◽  
Vol 48 (21) ◽  
pp. 6544-6548 ◽  
Author(s):  
Andrew P. Combs ◽  
Eddy W. Yue ◽  
Michael Bower ◽  
Paul J. Ala ◽  
Brian Wayland ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Phosphatase Inhibitors ◽  
Protein Tyrosine

scholarly journals The YRD Motif Is a Major Determinant of Substrate and Inhibitor Specificity in T-cell Protein-tyrosine Phosphatase

2001 ◽  
Vol 276 (28) ◽  
pp. 26036-26043 ◽  
Author(s):  
Ernest Asante-Appiah ◽  
Kristen Ball ◽  
Kevin Bateman ◽  
Kathryn Skorey ◽  
Rick Friesen ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Major Determinant ◽  
Cell Protein ◽  
Inhibitor Specificity ◽  
Protein Tyrosine ◽  
The Yrd
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