Polycarboxylic fullerene derivatives as protein tyrosine phosphatase inhibitors (original) (raw)
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Tapping the therapeutic potential of protein tyrosine phosphatase 4A with small molecule inhibitors
Bioorganic & Medicinal Chemistry Letters, 2019
The post-translational phosphorylation of protein tyrosine residues, and their subsequent dephosphorylation, is essential for controlled cellular signaling in many biological pathways. 1 An equilibrium is maintained by the opposing roles of protein tyrosine kinases (PTKs), which catalyze tyrosine phosphorylations, and protein tyrosine phosphatases (PTPs), which catalyze the removal of phosphate group(s). Unlike many Ser and Thr phosphorylations, most Tyr phosphorylations are very short-lived because of extremely active phospho-tyrosine-specific phosphatases (PTPs). 1 Not surprisingly, aberrant tyrosine phosphorylation and dephosphorylation events have been linked to many pathophysiological conditions, including inflammatory disorders, metabolic diseases, and cancer. 2 Hence, both PTKs and PTPs represent promising therapeutic targets for treating a variety of maladies. PTKs have already been extensively investigated, 3 and to date, the FDA has approved 35 PTK inhibitors. In fact, over the past four decades, small molecule inhibitors (SMIs) of kinases, in addition to the other two major "druggable" protein families, GPCRs and ion channels, have proven to be particularly successful in providing new anticancer drugs with fewer side effects than traditional, broadly cytotoxic agents. 4 Moreover, it is notable that the development of targeted inhibitors employing reversible or irreversible covalent binding strategies has reemerged as a viable drug design strategy in the kinase field. 5 In stark contrast, research exploring the untapped potential of PTPs as novel drug targets has been slow to emerge, with many in the pharmaceutical community still considering PTPs to be "undruggable". 6,7 Historically, one impediment for the development of SMIs of PTPs was an assumption that these enzymes lacked regulatory roles in disease, and were purely tumor
Protein Tyrosine Phosphatase-Prospective Target against Cancer: A Mini Review
Cancer Surgery, 2017
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.
Discovery of a Novel Shp2 Protein Tyrosine Phosphatase Inhibitor
Molecular Pharmacology, 2006
Shp2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. It is involved in growth factor-induced activation of mitogen-activated protein (MAP) kinases Erk1 and Erk2 (Erk1/2) and has been implicated in the pathogenicity of the oncogenic bacterium Helicobactor pylori (H. pylori). Moreover, gain-of-function Shp2 mutations have been found in childhood leukemias and Noonan syndrome. Thus, small molecule Shp2 PTP inhibitors are much needed reagents for evaluation of Shp2 as a therapeutic target and for chemical biology studies of Shp2 function. By screening the National Cancer Institute (NCI) Diversity Set chemical library, we identified NSC-87877 as a potent Shp2 PTP inhibitor. Molecular modeling and site-directed mutagenesis studies suggested that NSC-87877 binds to the catalytic cleft of Shp2 PTP. NSC-87877 cross-inhibited Shp1 in vitro, but it was selective for Shp2 over other PTPs (PTP1B, HePTP, DEP1, CD45, and LAR). Importantly, NSC-87877 inhibited EGFinduced activation of Shp2 PTP, Ras, and Erk1/2 in cell cultures but did not block EGF-induced Gab1 tyrosine phosphorylation or Gab1-Shp2 association. Furthermore, NSC-87877 inhibited Erk1/2 activation by a Gab1-Shp2 chimera but did not affect the Shp2-independent Erk1/2 activation by phorbol 12-myristate 13-acetate (PMA). These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. Our study also provides the first pharmacological evidence that Shp2 mediates EGFinduced Erk1/2 MAP kinase activation.
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
Nature, 2016
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS-ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conform...
A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors
Journal of Biological Chemistry, 2020
The non-receptor protein tyrosine phosphatase (PTP) SHP2 is encoded by the proto-oncogene PTPN11 and is a ubiquitously expressed key regulator of cell signaling, acting on a number of cellular processes and components, including the Ras/Raf/Erk, PI3K/Akt, and JAK/STAT pathways and immune check point receptors. Aberrant SHP2 activity has been implicated in all phases of tumor initiation, progression, and metastasis. Gain-of-function PTPN11 mutations drive oncogenesis in several leukemias and cause developmental disorders with increased risk of malignancy such as Noonan syndrome. Until recently, small molecule-based targeting of SHP2 was hampered by the failure of orthosteric active-site inhibitors to achieve selectivity and potency within a useful therapeutic window. However, new SHP2 allosteric inhibitors with excellent potency and selectivity have sparked renewed interest in the selective targeting of SHP2 and other PTP family members. Crucially, drug discovery campaigns focusing o...
BMB Reports, 2017
Protein tyrosine phosphatases (PTPs) play crucial roles in signal transduction and their functional alteration has been detected in many diseases. PTP inhibitors have been developed as therapeutic drugs for diseases that are related to the activity of PTPs. In this study, PTP inhibitor XIX, an inhibitor of CD45 and PTEN, was investigated whether it inhibits other PTPs. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was selectively inhibited by the inhibitor in a competitive manner. Drug affinity responsive target stability (DARTS) analysis showed that the inhibitor induces conformational changes in PTPN2. Phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) at Tyr-705, a crucial site for STAT3 activation and target site of PTPN2, decreased upon exposure to the inhibitor. Our results suggest that PTP inhibitor XIX might be considered as an effective regulator of PTPN2 for treating diseases related to PTPN2. [BMB Reports 2017; 50(6): 329-334]
Protein-tyrosine phosphatases and cancer
Nature Reviews Cancer, 2006
Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.
Journal of Neurology & Neurophysiology, 2014
Protein-Tyrosine Phosphatase1B (PTP1B) is a negative regulator of the insulin signaling pathway and is a potential therapeutic target for treatment of type 2 diabetes, cardiovascular disease, metabolic syndrome and cancer. It has been postulated that CNB-001 [4-((1E)-2-(5-(4-hydroxy-3methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl) vinyl)-2-methoxy-phenol)] may regulate PTP1B activity suggested by a computer-based active site docking recognition model. This possibility was studied using a human recombinant PTP1B assay, and a phospho-peptide fragment of the insulin receptor β subunit domain (IR5). The positive control, suramin, inhibited PTP1B with an IC50 (half minimal (50%) inhibitory concentration) value of 16.34 µM; CNB-001 did not affect enzyme activity across the range of 1nM-0.1mM. This study suggests that PTP1B inhibition is not involved in the beneficial effects of CNB-001 in obese type 2 diabetic mice.