New methods for the discovery and synthesis of PDE7 inhibitors as new drugs for neurological and inflammatory disorders

Safavi, Maliheh; Baeeri, Maryam; Abdollahi, Mohammad

doi:10.1517/17460441.2013.787986

Cited by 31 publications

(17 citation statements)

References 117 publications

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“…Three variant forms of PdE7A have been annotated: PdE7A1 and PdE7A2 are N-terminal variants, and PdE7A3 is a C-terminal variant (25,27). The expression of PDE7A is elevated in pro-inflammatory and immune cells, supporting the role of PdE7A as a therapeutic target for inflammation disorders (28). A recent study indicated that the PDE7A-specific inhibitor ASB16165 suppresses keratinocyte proliferation on TPA-induced skin inflammation (29).…”

Section: Discussionmentioning

confidence: 99%

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Yamamoto

Nishikawa

Chiyomaru

et al. 2015

International Journal of Oncology

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In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

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Section: Discussionmentioning

confidence: 99%

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

Yamamoto

Nishikawa

Chiyomaru

et al. 2015

International Journal of Oncology

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“…Together with the current findings, these results provide a strong rationale for cAMP elevation in the treatment of brain tumors. While there have not been any studies of specific PDE7B inhibitors in the context of cancer treatment, there has been work done evaluating PDE7B inhibition for the treatment of autoimmune disorders [53], [54]. Therefore future work should focus on taking specific inhibitors of PDE7B from the autoimmune studies and determining their efficacy in blocking glioma growth in vitro and in vivo with the hope of translating these findings to the clinic as quickly as possible.…”

Section: Discussionmentioning

confidence: 99%

PDE7B Is a Novel, Prognostically Significant Mediator of Glioblastoma Growth Whose Expression Is Regulated by Endothelial Cells

et al. 2014

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Cell-cell interactions between tumor cells and constituents of their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM) cells and endothelial cells (ECs) establish a purported cancer stem cell niche. We hypothesized that genes regulated by these interactions would be important, particularly as therapeutic targets. Using a computational approach, we deconvoluted expression data from a mixed physical co-culture of GBM cells and ECs and identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to direct contact with ECs. We further found that elevated PDE7B expression occurs in most GBM cases and has a negative effect on survival. PDE7B overexpression resulted in the expansion of a stem-like cell subpopulation in vitro and increased tumor growth and aggressiveness in an in vivo intracranial GBM model. Collectively these studies illustrate a novel approach for studying cell-cell interactions and identifying new therapeutic targets like PDE7B in GBM.

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“…• Inhibitors used for erectile dysfunction (Yuan et al, 2013), pulmonary hypertension (Oudiz et al, 2012), and benign prostatic hypertrophy (Gacci et al, 2014) • Inhibitors are being studied for diabetes, atherosclerosis and metabolic syndrome Lugnier, 2011), and lower urinary tract symptoms (LUTS) (Uckert and Oelke, 2011) • Inhibitors suppress the growth of breast cancer cells ( • Inhibitors are anti-inflammatory and neuroprotective (Safavi et al, 2013).…”

Section: Oral Diseasesmentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

et al. 2014

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By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.

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New methods for the discovery and synthesis of PDE7 inhibitors as new drugs for neurological and inflammatory disorders

Cited by 31 publications

References 117 publications

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

The tumor-suppressive microRNA-1/133a cluster targets PDE7A and inhibits cancer cell migration and invasion in endometrial cancer

PDE7B Is a Novel, Prognostically Significant Mediator of Glioblastoma Growth Whose Expression Is Regulated by Endothelial Cells

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

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