Identification of Biologically Active PDE11-Selective Inhibitors Using a Yeast-Based High-Throughput Screen

Ceyhan, Ozge; Birsoy, Kıvanç; Hoffman, Charles S.

doi:10.1016/j.chembiol.2011.12.010

Cited by 54 publications

(52 citation statements)

References 36 publications

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“…BC 11–38 is a recently identified potent and selective PDE11 inhibitor (IC 50 = 0.28 μM) with potential application for adrenal insufficiency (Ceyhan et al, 2012). …”

Section: Pde Inhibitors: Main Characteristics and Clinical Applicationsmentioning

confidence: 99%

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

Noël

Dhooghe²,

Leal

2012

Front. Pharmacol.

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Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

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“…BC 11–38 is a recently identified potent and selective PDE11 inhibitor (IC 50 = 0.28 μM) with potential application for adrenal insufficiency (Ceyhan et al, 2012). …”

Section: Pde Inhibitors: Main Characteristics and Clinical Applicationsmentioning

confidence: 99%

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

Noël

Dhooghe²,

Leal

2012

Front. Pharmacol.

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“…Therefore, PDE11 seems to fulfill a special role in the consolidation of social memories. Currently, the first PDE11 inhibitors have been developed [106], yet no clinical studies have been conducted yet.…”

Section: Phosphodiesterase 11mentioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

146

168

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Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…5FOA growth assays to screen for and to characterize PDE inhibitors were carried out using strains that express the PKA-repressed fbp1-ura4 + reporter as previously described [13, 20, 22–25]. Dose response profiling of BC54 and rolipram was carried out at concentrations of 0.05 μM to 50 μM.…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays

Medeiros

Wyman

Alaamery

et al. 2017

Cellular Signalling

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We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells. We further exploited PKA-regulated growth phenotypes in fission yeast to isolate two mutant alleles of the human PDE4B2 gene that encode enzymes possessing single amino acid changes that confer partial resistance to BC54. We confirm this resistance to both BC54 and rolipram via yeast-based assays and, for PDE4B2T407A, in vitro enzyme assays. Thus, we are able to use this system for both chemical screens to identify biologically-active PDE inhibitors and molecular genetic studies to characterize the interaction of these molecules with their target enzymes. Based on its potency, selectivity, and effectiveness in cell culture, BC54 should be a useful tool to study biological processes regulated by PDE4 and PDE7 enzymes.

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Identification of Biologically Active PDE11-Selective Inhibitors Using a Yeast-Based High-Throughput Screen

Cited by 54 publications

References 36 publications

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays

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