2019
DOI: 10.1073/pnas.1822113116
|View full text |Cite
|
Sign up to set email alerts
|

Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Abstract: Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activat… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1

Citation Types

3
51
0
1

Year Published

2019
2019
2024
2024

Publication Types

Select...
8
1

Relationship

0
9

Authors

Journals

citations
Cited by 60 publications
(55 citation statements)
references
References 72 publications
3
51
0
1
Order By: Relevance
“…17 Recently, a small allosteric modulator that mimics the effect of PKA phosphorylation on PDE4 long forms was reported. 50 This prototypical PDE4 activator was shown to reduce the chronically elevated cAMP levels which drive abnormal cyst formation in animal and human cell models of autosomal dominant polycystic kidney disease. 50 These results suggest that such compound could constitute an alternative approach to gene therapy in HF.…”
Section: Discussionmentioning
confidence: 99%
“…17 Recently, a small allosteric modulator that mimics the effect of PKA phosphorylation on PDE4 long forms was reported. 50 This prototypical PDE4 activator was shown to reduce the chronically elevated cAMP levels which drive abnormal cyst formation in animal and human cell models of autosomal dominant polycystic kidney disease. 50 These results suggest that such compound could constitute an alternative approach to gene therapy in HF.…”
Section: Discussionmentioning
confidence: 99%
“…In contrast, PDE activators may be developed to treat cancers that are promoted by cAMP signaling. Recently, a small-molecule compound that allosterically activates PDE4 long isoforms has been developed [ 142 ]. This prototypical PDE4 activator compound is able to reduce intracellular cAMP levels and inhibit cyst formation in the kidney [ 142 ].…”
Section: Targeting Camp–pka Pathway For Cancer Therapymentioning
confidence: 99%
“…Recently, a small-molecule compound that allosterically activates PDE4 long isoforms has been developed [ 142 ]. This prototypical PDE4 activator compound is able to reduce intracellular cAMP levels and inhibit cyst formation in the kidney [ 142 ]. It remains to know whether such kinds of PDE activators may be repurposed to treat some types of cancer.…”
Section: Targeting Camp–pka Pathway For Cancer Therapymentioning
confidence: 99%
“…One allosteric activator compound of PDE4 has the potential to lower the cAMP levels and limit the cAMP-mediated signaling pathways. This inhibits the cyst formation after tests in human embryonic kidney (HEK) 293 and Madin Darby Canine Kidney (MDCK, ATCC) cells [ 58 ]. Manipulating the N -terminal regulatory modules or upstream interventions could give new insights into the regulating mechanism of PDE catalytic activity.…”
Section: Therapeutic Targeting Of Pdesmentioning
confidence: 99%