KT5720

KT5720 is an antagonist of protein kinase A. Protein kinase A (PKA) is a group of kinases that are cAMP-dependent that primarily phosphorylate serine or threonine residues in target proteins. PKA is a tetramer consisting of two catalytic subunits and two regulatory subunits, with the later holding the catalytic subunits in an inactive state. The binding of two cAMP molecules to each regulatory subunit causes an allosteric change that detaches the regulatory subunits from the catalytic subunits.{{Cite journal |last1=Turnham |first1=Rigney E. |last2=Scott |first2=John D. |date=February 2016 |title=Protein kinase A catalytic subunit isoform PRKACA; History, function and physiology |url=https://doi.org/10.1016/j.gene.2015.11.052 |journal=Gene |volume=577 |issue=2 |pages=101–108 |doi=10.1016/j.gene.2015.11.052 |pmid=26687711 |pmc=4713328 |issn=0378-1119}} This exposes the ATP-binding site of the kinase. KT5720 binds competitively to the ATP-binding site of the catalytic subunit of PKA and its effects are dependent on the cellular concentration of ATP.{{Cite journal |last=Murray |first=Andrew J. |date=2008-06-03 |title=Pharmacological PKA Inhibition: All May Not Be What It Seems |url=https://doi.org/10.1126/scisignal.122re4 |journal=Science Signaling |volume=1 |issue=22 |pages=re4 |doi=10.1126/scisignal.122re4 |pmid=18523239 |issn=1945-0877}}

There have been several studied effects on the inhibition of PKA through the binding of KT5720. KT5720 has been shown to effect dorsal root ganglion neurons through the inhibition of PKA. It reduced intracellular concentration of calcium ions as well as decrease the H-current in the HCN channels which decreased the excitability of rat neurons.{{Cite journal |last1=Cheng |first1=Qiuping |last2=Zhou |first2=Yanhong |date=June 2013 |title=Novel Role of KT5720 on Regulating Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Activity and Dorsal Root Ganglion Neuron Excitability |url=https://doi.org/10.1089/dna.2013.2021 |journal=DNA and Cell Biology |volume=32 |issue=6 |pages=320–328 |doi=10.1089/dna.2013.2021 |pmid=23713946 |pmc=3666193 |issn=1044-5498}} Additionally, there is evidence to suggest that the inhibition of KT5720 affects endothelial cell response to irradiation. It has been shown to decrease irradiation-induced apoptosis in human pulmonary microvascular endothelial cells.{{Cite journal |last1=Boittin |first1=François-Xavier |last2=Guitard |first2=Nathalie |last3=Toth |first3=Maeliss |last4=Riccobono |first4=Diane |last5=Théry |first5=Hélène |last6=Bobe |first6=Régis |date=2024-02-14 |title=The Protein Kinase A Inhibitor KT5720 Prevents Endothelial Dysfunctions Induced by High-Dose Irradiation |journal=International Journal of Molecular Sciences |volume=25 |issue=4 |pages=2269 |doi=10.3390/ijms25042269 |doi-access=free |pmid=38396945 |pmc=10889412 |issn=1422-0067}}

The purported target of KT5720 is PKA, however, it has displayed effects on other proteins. KT5720 has been shown to inhibit other protein kinases such as phosphorylase kinase (PHK) and pyruvate dehydrogenase kinase 1 (PDK1). One study determined that the IC₅₀ was 11nM and 300nM for PHK and PDK1, respectively. This was significantly lower than the IC₅₀ for PKA, determined to be 3.3µM in the same study.{{Cite web |last=Kane |first=Larry |date=2011-11-16 |title=Faculty Opinions recommendation of Specificity and mechanism of action of some commonly used protein kinase inhibitors. |doi=10.3410/f.13361028.14731161 |doi-access=free }} This establishes that KT5720 can significantly affect other kinases, however, it cannot be used to determined the absolute specificity of KT5720 due to differing ATP concentrations in vitro and in vivo.

KT5720 has also been shown to affect platelet aggregation in rabbits. It's mechanism of action favored the inhibition of certain molecules such as serotonin but did not inhibit other platelets aggregation factors such as thrombin and collagen.{{Cite journal |last1=Yamada |first1=Koji |last2=Ishii |first2=Akio |date=1989 |title=KT5720, a new selective inhibitor of PAF-induced platelet responses without receptor antagonism |url=https://doi.org/10.1016/s0021-5198(19)56624-0 |journal=Japanese Journal of Pharmacology |volume=49 |pages=263 |doi=10.1016/s0021-5198(19)56624-0 |issn=0021-5198|doi-access=free }}

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Category:Indole alkaloids

Category:Protein kinase inhibitors

Category:Indolocarbazoles

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