Identification of a Potent, State-Dependent Inhibitor of Nav1.7 with Oral Efficacy in the Formalin Model of Persistent Pain

Bregman, Howard; Berry, Loren; Buchanan, Joan L.; Chen, April; Du, Bingfan; Feric, Elma; Hierl, Markus; Huang, Liyue; Immke, David; Janosky, Brett; Johnson, Danielle; Li, Xingwen; Ligutti, Joseph; Liu, Dong; Malmberg, Annika B.; Matson, David J.; McDermott, Jeff S.; Miu, Peter; Nguyen, Hanh Nho; Patel, Vinod F.; Waldon, Daniel J.; Wilenkin, Ben; Zheng, Xiao Mei; Zou, Anruo; McDonough, Stefan I.; DiMauro, Erin F.

doi:10.1021/jm200018k

Cited by 49 publications

(46 citation statements)

References 43 publications

(91 reference statements)

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“…This finding has shed light on designs of sodium channel inhibitor screens. To date, only a few small molecule sodium channel inhibitors exhibit subtype selectivity (Jarvis et al, 2007;Bregman et al, 2011;McCormack et al, 2013). Screens using Phe mutant Nav channels may enrich subtype-selective inhibitors and identify inhibitors acting on novel sites with less conservation, such as the voltage sensor domain.…”

Section: Discussionmentioning

confidence: 99%

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Zhang

Zou

et al. 2014

Mol Pharmacol

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Voltage-gated sodium (Nav) channels are essential for membrane excitability and represent therapeutic targets for treating human diseases. Recent reports suggest that these channels, e.g., Nav1.3 and Nav1.5, are inhibited by multiple structurally distinctive small molecule drugs. These studies give reason to wonder whether these drugs collectively target a single site or multiple sites in manifesting such pharmacological promiscuity. We thus investigate the pharmacological profile of Nav1.5 through systemic analysis of its sensitivity to diverse compound collections. Here, we report a dual-color fluorescent method that exploits a customized Nav1.5 [calcium permeable Nav channel, subtype 5 (SoCal5)] with engineered-enhanced calcium permeability. SoCal5 retains wildtype (WT) Nav1.5 pharmacological profiles. WT SoCal5 and SoCal5 with the local anesthetics binding site mutated (F1760A) could be expressed in separate cells, each with a differentcolored genetically encoded calcium sensor, which allows a simultaneous report of compound activity and site dependence. The pharmacological profile of SoCal5 reveals a hit rate (.50% inhibition) of around 13% at 10 mM, comparable to that of hERG. The channel activity is susceptible to blockage by known drugs and structurally diverse compounds. The broad inhibition profile is highly dependent on the F1760 residue in the inner cavity, which is a residue conserved among all nine subtypes of Nav channels. Both promiscuity and dependence on F1760 seen in Nav1.5 were replicated in Nav1.4. Our evidence of a broad inhibition profile of Nav channels suggests a need to consider off-target effects on Nav channels. The site-dependent promiscuity forms a foundation to better understand Nav channels and compound interactions.

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Section: Discussionmentioning

confidence: 99%

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Zhang

Zou

et al. 2014

Mol Pharmacol

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“…Drugs that target Na v 1.7 activity could, thus, prove useful in conjunction with existing therapies. Na v -specific blockers are already in clinical use as local anaesthetics and, more recently, Na v 1.7-specific inhibitors are being developed for the treatment of pain (Bregman et al, 2011;Chowdhury et al, 2011;Clare, 2010;Ghelardini et al, 2010). Given its functional significance and marked upregulation in tumour tissue, we suggest that Na v 1.7 represents an important new target for therapeutic intervention and/or as a diagnostic and/or prognostic marker in NSCLC.…”

Section: -Test) Continuous Lines Indicatementioning

confidence: 96%

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Campbell¹,

Main²,

FitzGerald³

2013

Journal of Cell Science

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SummaryVarious ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, invasion and metastasis. Expression of functional voltage-gated Na + channels (Na v ) is implicated in the metastatic potential of breast, prostate, lung and colon cancer cells. However, the cellular mechanisms that regulate Na v expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, we examine the role of epidermal growth factor receptor (EGFR) signalling and Na v in non-small cell lung carcinoma (NSCLC) cell lines. We show unequivocally, that functional expression of the a subunit Na v 1.7 promotes invasion in H460 NSCLC cells. Inhibition of Na v 1.7 activity (using tetrodotoxin) or expression (by using small interfering RNA), reduces H460 cell invasion by up to 50%. Crucially, non-invasive wild type A549 cells lack functional Na v , whereas exogenous overexpression of the Na v 1.7 a subunit is sufficient to promote TTX-sensitive invasion of these cells. EGF/EGFR signalling enhances proliferation, migration and invasion of H460 cells but we find that, specifically, EGFR-mediated upregulation of Na v 1.7 is necessary for invasive behaviour in these cells. Examination of Na v 1.7 expression at mRNA, protein and functional levels further reveals that EGF/ EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of channel expression to promote cellular invasion. Immunohistochemistry of patient biopsies confirms the clinical relevance of Na v 1.7 expression in NSCLC. Thus, Na v 1.7 has significant potential as a new target for therapeutic intervention and/or as a diagnostic or prognostic marker in NSCLC.

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“…There are already several relatively selective smallmolecule inhibitors of Na v 1.7 that have shown efficacy in acute, inflammatory, and neuropathic pain models (Williams et al, 2007;London et al, 2008;Bregman et al, 2011;Chowdhury et al 2011). Although many conotoxins can also inhibit Na v 1.7 (see above), no highly selective antagonists have been identified to date, although analogs of the smaller -conotoxins have potential (see above).…”

Section: F Sodium Channel Inhibition In Pain Managementmentioning

confidence: 99%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

385

424

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Identification of a Potent, State-Dependent Inhibitor of Nav1.7 with Oral Efficacy in the Formalin Model of Persistent Pain

Cited by 49 publications

References 43 publications

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Conus Venom Peptide Pharmacology

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