P2X7 Antagonists for CNS Indications: Recent Patent Disclosures

Pevarello, Paolo; Bovolenta, Silvia; Tarroni, Paola; Za, Lorena; Severi, Elda; Torino, Domenica; Vitalone, Rocco

doi:10.4155/ppa-2016-0044

Cited by 25 publications

(20 citation statements)

References 19 publications

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“…Polymorphism and multicellular expression of TSPO, as well as the lack of a specific brain region of negative control, led to identifying other molecular biomarkers of activated microglia that would likely be complementary to TSPO PET imaging. Among the targets of interest summarized in the present review, P2X7 receptor appears to be the most promising one regarding: (1) its implication in neurodegenerative diseases’ pathophysiology, highlighted by numerous current clinical trials aiming at evaluating P2X7 antagonists in CNS indications [176]; (2) the recent development of efficient dedicated radiopharmaceuticals that are currently coming available for clinical trials; (3) its implication on M1 microglial polarization. Thus, a multi-targets approach for PET imaging of microglia activation, combining TSPO radiopharmaceuticals with new probes specific of P2X7 expression may help to characterize the involvement of neuroinflammation over the CNS disorder’s progression, as well as to follow the effects of clinical treatments on microglia polarization.…”

Section: Discussionmentioning

confidence: 99%

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Tronel

Largeau

Ribeiro

et al. 2017

IJMS

114

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Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals’ binding affinity, or similar expression in activated microglia regardless of its polarization (pro- or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians’ expectations.

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Section: Discussionmentioning

confidence: 99%

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Tronel

Largeau

Ribeiro

et al. 2017

IJMS

114

View full text Add to dashboard Cite

show abstract

“…Several pharmaceutical organizations have engaged in the development of both small-molecules and biologics directed against P2X7 (Mehta et al, 2014;Baudelet et al, 2015;Jacobson and Muller, 2016) (Table 3). These developments can be seen in the increasing number of filed patents for P2X7 targeted treatment (Gunosewoyo and Kassiou, 2010;Sluyter and Stokes, 2011;Park and Kim, 2017;Pevarello et al, 2017). Early development of small molecule inhibitors targeted the P2X7 orthosteric site to compete ATP mediated P2X7 activation.…”

Section: Therapeutic Approaches Taken To Target P2x7mentioning

confidence: 99%

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and posttranslational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.

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“…The role of P2X7R in diseases related to neuroinflammation and the use of centrally penetrant antagonists has been highlighted [ 1 , 11 , 14 , 18 , 91 – 94 ]. Blockade of P2X7R may serve as a therapeutic target in alleviating the degree of inflammation seen in neurodegenerative and neoplastic conditions [ 95 ].…”

Section: P2x7r and Diseases Of The Cnsmentioning

confidence: 99%

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Burnstock

Knight

2017

Purinergic Signalling

198

166

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Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.

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P2X7 Antagonists for CNS Indications: Recent Patent Disclosures

Cited by 25 publications

References 19 publications

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

Molecular Targets for PET Imaging of Activated Microglia: The Current Situation and Future Expectations

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

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