Therapeutic potential of targeting SHP2 in human developmental disorders and cancers

Shen, Dadong; Chen, Wenxia; Zhu, Jinlin; Wu, Guofeng; Shen, Runpu; Xi, Meiyang; Sun, Haopeng

doi:10.1016/j.ejmech.2020.112117

Cited by 62 publications

(62 citation statements)

References 144 publications

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“…Another MVP interactor is the Src homology 2 (SH2) domain-containing tyrosine phosphatase (SHP-2) [61], which in recent years has emerged as a major regulatory protein of RTK and cytokine receptor signaling [93]. SHP2 interacts with tyrosine phosphorylated MVP in a substrate-trapping manner-i.e., without the involvement of phosphatase activity.…”

Section: How the Vault Nanoparticle Participates In Diverse Cellular mentioning

confidence: 99%

The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy

Frascotti

Galbiati

Mazzucchelli

et al. 2021

Cancers

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The vault nanoparticle is a eukaryotic ribonucleoprotein complex consisting of 78 individual 97 kDa-“major vault protein” (MVP) molecules that form two symmetrical, cup-shaped, hollow halves. It has a huge size (72.5 × 41 × 41 nm) and an internal cavity, wherein the vault poly(ADP-ribose) polymerase (vPARP), telomerase-associated protein-1 (TEP1), and some small untranslated RNAs are accommodated. Plenty of literature reports on the biological role(s) of this nanocomplex, as well as its involvement in diseases, mostly oncological ones. Nevertheless, much has still to be understood as to how vault participates in normal and pathological mechanisms. In this comprehensive review, current understanding of its biological roles is discussed. By different mechanisms, vault’s individual components are involved in major cellular phenomena, which result in protection against cellular stresses, such as DNA-damaging agents, irradiation, hypoxia, hyperosmotic, and oxidative conditions. These diverse cellular functions are accomplished by different mechanisms, mainly gene expression reprogramming, activation of proliferative/prosurvival signaling pathways, export from the nucleus of DNA-damaging drugs, and import of specific proteins. The cellular functions of this nanocomplex may also result in the onset of pathological conditions, mainly (but not exclusively) tumor proliferation and multidrug resistance. The current understanding of its biological roles in physiological and pathological processes should also provide new hints to extend the scope of its exploitation as a nanocarrier for drug delivery.

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Section: How the Vault Nanoparticle Participates In Diverse Cellular mentioning

confidence: 99%

The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy

Frascotti

Galbiati

Mazzucchelli

et al. 2021

Cancers

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“…[29] Direct as well as allosteric inhibitors of Shp2 have been developed by various research groups; while direct active-site inhibition has proven challenging due to the polar nature of the catalytic PTP site and the active intermediate (Figure 3), allosteric inhibitors have demonstrated better potency and better pharmacokinetic properties. [30,31] It would be pertinent to state here, that anti-Shp2 drug discovery is more challenging than it seems. This is due to the fact that there is considerable homology between the catalytic domains of different members of the PTPN subfamily [15] and preferentially targeting Shp2 over other tyrosine phosphatases containing SH2 domains like Shp1 or PTP1B often results in undesired crossreactivity and off-targeted responses.…”

Section: Anti-shp2 Drug Development For Gbm: Opportunities and Challementioning

confidence: 99%

Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview

Mitra

Ayyannan

2020

ChemMedChem

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Glioblastoma multiforme (GBM) is a dreadful cancer characterised by poor prognosis, low survival rate and difficult clinical correlations. Several signalling pathways and molecular mediators are known to precipitate GBM, and small‐molecular targets of these mediators have become a favoured thrust area for researchers to develop potent anti‐GBM drugs. Shp2, an important phosphatase of the nonreceptor type protein tyrosine phosphatase (PTPN) subfamily is responsible for master regulation of several such signalling pathways in normal and glioma cells. Thus, inhibition of Shp2 is a logical strategy for the design and development of anti‐neoplastic drugs against GBM. Though tapping the full potential of Shp2 binding sites has been challenging, nevertheless, many synthetic and natural scaffolds have been documented as possessing potent and selective anti‐Shp2 activities in biochemical and cellular assays, through either active‐site or allosteric binding. Most of these scaffolds share a few common pharmacophoric features, a thorough study of which is useful in paving the way for the design and development of improved Shp2 inhibitors. This minireview summarizes the current scenario of potent small‐molecule Shp2 inhibitors and emphasizes the anti‐GBM potential of some important scaffolds that have shown promising GBM‐specific activity in in vitro and in vivo models, thus proving their efficacy in GBM therapy. This review could guide researchers to design new and improved anti‐Shp2 pharmacophores and develop them as anti‐GBM agents by employing GBM‐centric drug‐discovery protocols.

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“…SHP2 is a ubiquitous protein tyrosine phosphatase with conserved structure and function, and participates in many biological processes [17,18]. The dysregulation of SHP2 has been implicated in the pathogenesis of many human diseases, such as Noonan syndrome (NS), LEOPARD syndrome (LS), and multiple types of cancers, including leukemia, lung and breast cancer, liver cancer and neuroblastoma [17,[19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations

Wang

Zhao

et al. 2021

Molecules

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CagA is a major virulence factor of Helicobacter pylori. H. pylori CagA is geographically subclassified into East Asian CagA and Western CagA, which are characterized by the presence of a EPIYA-D or EPIYA-C segment. The East Asian CagA is more closely associated with gastric cancer than the Western CagA. In this study, molecular dynamic (MD) simulations were performed to investigate the binding details of SHP2 and EPIYA segments, and to explore the allosteric regulation mechanism of SHP2. Our results show that the EPIYA-D has a stronger binding affinity to the N-SH2 domain of SHP2 than EPIYA-C. In addition, a single EPIYA-D binding to N-SH2 domain of SHP2 can cause a deflection of the key helix B, and the deflected helix B could squeeze the N-SH2 and PTP domains to break the autoinhibition pocket of SHP2. However, a single EPIYA-C binding to the N-SH2 domain of SHP2 cannot break the autoinhibition of SHP2 because the secondary structure of the key helix B is destroyed. However, the tandem EPIYA-C not only increases its binding affinity to SHP2, but also does not significantly break the secondary structure of the key helix B. Our study can help us better understand the mechanism of gastric cancer caused by Helicobacter pylori infection.

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Therapeutic potential of targeting SHP2 in human developmental disorders and cancers

Cited by 62 publications

References 144 publications

The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy

The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy

Small‐Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview

Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations

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