Structure-activity relationships of 2-substituted phenyl- N -phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)

Liu, Zhiqing; Zhu, Yixin; Chen, Haiying; Wang, Pingyuan; Mei, Fang; Ye, Na; Cheng, Xiaodong; Zhou, Jia

doi:10.1016/j.bmcl.2017.10.056

Cited by 9 publications

(13 citation statements)

References 31 publications

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“…In conclusion, we have shown that modulation of cellular EPAC2 protein significantly impacts cellular responses and viral replication in two airway epithelial models of RSV infection, suggesting EPAC2 is a promising therapeutic target for RSV infection. Given the importance of EPAC in cancer, diabetes, heart failure, inflammation, and neurological disorders, EPAC-specific modulators are being urgently investigated to explore their physiological functions, mechanisms of regulation, and therapeutic applications (55,56). We are currently investigating the antiviral spectrum of other EPAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection

Choi

Ren

Chen

et al. 2018

J Virol

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Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children and high-risk adults. However, a specific treatment for this viral infection is not currently available. In this study, we discovered that an exchange protein directly activated by cyclic AMP (EPAC) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, treatment with EPAC inhibitor (ESI-09), but not protein kinase A inhibitor (H89), significantly inhibits RSV replication and proinflammatory cytokine/chemokine induction. In addition, RSV-activated transcriptional factors belonging to the NF-κB and IRF families are also suppressed by ESI-09. Through isoform-specific gene knockdown, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. Experiments using both EPAC2 knockout and EPAC2-specific inhibitor support such roles of EPAC2. Therefore, EPAC2 is a promising therapeutic target to regulate RSV replication and associated inflammation. RSV is a serious public health problem, as it is associated with bronchiolitis, pneumonia, and asthma exacerbations. Currently no effective treatment or vaccine is available, and many molecular mechanisms regarding RSV-induced lung disease are still significantly unknown. This project aims to elucidate an important and novel function of a protein, called EPAC2, in RSV replication and innate inflammatory responses. Our results should provide an important insight into the development of new pharmacologic strategies against RSV infection, thereby reducing RSV-associated morbidity and mortality.

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Section: Discussionmentioning

confidence: 99%

Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection

Choi

Ren

Chen

et al. 2018

J Virol

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“…Finally, since many GEFs are regulated by protein-protein interactions and post-translational modifications, it may be possible to identify drugs that block these mechanisms. In an excellent example of this approach, cAMP is a potent activator of the Rapl GEFs, Exchange Proteins directly Activated by cAMP (EPAC1 and 2) and high throughput screens to identify small molecules that displace cAMP binding led to the discovery of several inhibitors or partial agonists for these GEFs (Brown, et al, 2014;Z. Liu, et al, 2017;Parnell, et al, 2017).…”

Section: 22mentioning

confidence: 99%

Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure

Dee

Mangum

Xue

et al. 2019

Pharmacology & Therapeutics

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The prevalence of high blood pressure (also known as hypertension) has steadily increased over the last few decades. Known as a silent killer, hypertension increases the risk for cardiovascular disease and can lead to stroke, heart attack, kidney failure and associated sequela. While numerous hypertensive therapies are currently available, it is estimated that only half of medicated patients exhibit blood pressure control. This signifies the need for a better understanding of the underlying cause of disease and for more effective therapies. While blood pressure homeostasis is very complex and involves the integrated control of multiple body systems, smooth muscle contractility and arterial resistance are important contributors. Strong evidence from pre-clinical animal models and genome-wide association studies indicate that smooth muscle contraction and BP homeostasis are governed by the small GTPase RhoA and its downstream target, Rho kinase. In this review, we summarize the signaling pathways and regulators that impart tight spatial-temporal control of RhoA activity in smooth muscle cells and discuss current therapeutic strategies to target these RhoA pathway components. We also discuss known allelic variations in the RhoA pathway and consider how these polymorphisms may affect genetic risk for hypertension and its clinical manifestations.

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“…It was established that, all compounds produced through bioisosteric substitution of tert-butyl isoxazole ring with tert-butyl phenyl group reserved EPAC2 inhibitory activities. 48 Liu et al formulated and synthesized novel series of 2-substituted phenyl-Nphenyl-2-oxoacetohydrazonoyl cyanides as EPAC2 inhibitors through ingenuous chemistry with low-cost maiden material as well as synthetic affluence appropriate for scale up. 48 ZL0524 was the utmost potent EPAC2 inhibitory (Figure 2) activities with IC50 values of 1.2 mM.…”

Section: Epac2 Inhibitionmentioning

confidence: 99%

EPAC2: A new and promising protein for glioma pathogenesis and therapy

Richard¹

2020

Oncol Rev

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Gliomas are prime brain cancers which are initiated by malignant modification of neural stem cells, progenitor cells and differentiated glial cells such as astrocyte, oligodendrocyte as well as ependymal cells. Exchange proteins directly activated by cAMP (EPACs) are crucial cyclic adenosine 3’,5’-monophosphate (cAMP)-determined signaling pathways. Cyclic AMP-intermediated signaling events were utilized to transduce protein kinase A (PKA) leading to the detection of EPACs or cAMP-guanine exchange factors (cAMP-GEFs). EPACs have been detected as crucial proteins associated with the pathogenesis of neurological disorders as well as numerous human diseases. EPAC proteins have two isoforms. These isoforms are EPAC1 and EPAC2. EPAC2 also known as Rap guanine nucleotide exchange factor 4 (RAPGEF4) is generally expression in all neurites. Higher EAPC2 levels was detected in the cortex, hippocampus as well as striatum of adult mouse brain. Activation as well as over-secretion of EPAC2 triggers apoptosis in neurons and EPAC-triggered apoptosis was intermediated via the modulation of Bcl-2 interacting member protein (BIM). EPAC2 secretory levels has proven to be more in low-grade clinical glioma than high-grade clinical glioma. This review therefore explores the effects of EPAC2/RAPGEF4 on the pathogenesis of glioma instead of EPAC1 because EPAC2 and not EPAC1 is predominately expressed in the brain. Therefore, EPAC2 is most likely to modulate glioma pathogenesis rather than EPAC1.

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Structure-activity relationships of 2-substituted phenyl- N -phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs)

Cited by 9 publications

References 31 publications

Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection

Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection

Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure

EPAC2: A new and promising protein for glioma pathogenesis and therapy

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