Current Status of PTP-Based Therapeutics

He, Rongjun; Zhang, Zhong-Yin

doi:10.1007/978-1-4939-3649-6_13

Cited by 3 publications

(2 citation statements)

References 134 publications

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“…Another strategy is to develop mechanism-based inhibitors, which inactivate the PTP catalytic cysteine residue through oxidation or other modifications. This strategy has been employed in quinone-based CDC25 inhibitors [11] . However, quinone compounds may induce reactive oxygen species, which may inactivate various redox-sensitive enzymes and cause in vivo toxicity [271,272] .…”

Section: Strategies To Modulate Ptp Activitymentioning

confidence: 99%

Protein tyrosine phosphatases as potential therapeutic targets

et al. 2014

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Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.

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Section: Strategies To Modulate Ptp Activitymentioning

confidence: 99%

Protein tyrosine phosphatases as potential therapeutic targets

et al. 2014

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“…It remains unclear how other phosphatases interact with the Hippo pathway in many other biological processes. In addition, although many drugs targeting oncogenic kinases have been used for the treatment of cancers, only a few drugs targeting PTPs (e.g., PTP1B, SHP2, CDC25, and PRLs) are under clinical trials [ 204 ]. Given the roles of Hippo in tumorigenesis, angiogenesis, metastasis, drug resistance, and immune response [ 2 , 5 , 6 , 7 , 37 ], further elucidation of novel interactions between phosphatases and the Hippo pathway will provide very useful information for the targeting of phosphatases alone or in combination with Hippo-targeted drugs for the effective treatment of drug-resistant or metastasis cancers in the future.…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Emami

Zhang

Yang

2020

Cancers

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The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

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Protein Tyrosine Phosphatase-Prospective Target against Cancer: A Mini Review

Kanagarethinam¹,

Mahapatra²,

Jabalia³

et al. 2017

Cancer Surg

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Contemporary quantum leap on functional characterization of Protein Tyrosine Phosphatase (PTP) superfamily provides an incipient perspective on regulating signal transduction. PTPs are required in the regulation of several cellular processes; especially under stressed and pathogenic conditions leading to sundry human diseases. Concrete inhibition of PTP by oxyanions and active-site directed inhibitors (alkylating agents) may provide implements for human disease treatment involving them. The physiological paramountcy for the advancement of Protein Tyrosine Phosphatase, Non-receptor Type 1 (PTP1B) -predicated therapeutics is a prominent target for diabetes and inordinate corpulence treatment. PTPs are exhilarating quarry for active-site-mediated inhibitors generation. There, proneness to oxidation often create problem on high throughput screens, further the propensity for highly charged potent inhibitors, like non-hydrolysable pTyr mimetics, test with reverence to bioavailability. Subsequent preliminary concerns about specificity and quandaries with deference to hydrophilicity of phosphormimetics, promising successes attained by structure-predicated drug design, mainly the one exploit identical surface topology circumventing the catalytic pocket of each PTP. In PTP1B, it was found that a particular pTyr binding site could be habituated to succeed highly concrete bidentate inhibitors that bind both sites. This conventional approach can avail us to target highly categorical and efficacious inhibitors. Tyrosine phosphorylation increases 1-2% of total protein phosphorylation in tumorigenic transformation or magnification factor simulation essential for a controlled cellular event. This event is controlled by two molecular switches of enzymes protein tyrosine kinase and protein tyrosine phosphatase. Eccentric tyrosine phosphorylation is considered as one of the hallmarks of cancer. PTP has been recommended as next generation drug targets and a sum of PTP have been embroiled in sundry human disease, like cancer. The catalytic mechanism of PTP was demystified by site-directed mutagenesis then kinetic analyses with structural information. They have loss/ gain of function in cancer signaling events leading to dearth of inhibitors to control gain of function including modification of loss of function of PTP cognate genes. This review is about the consequentiality of tyrosine phosphatase enzyme and its role in the mundane cellular event and how it modifies the active site to agonise substrate and alter its action ultimately leading to tumorigenesis.

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Current Status of PTP-Based Therapeutics

Cited by 3 publications

References 134 publications

Protein tyrosine phosphatases as potential therapeutic targets

Protein tyrosine phosphatases as potential therapeutic targets

Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Protein Tyrosine Phosphatase-Prospective Target against Cancer: A Mini Review

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