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PKG Inhibitors






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cGMP molecule

Cyclic GMP

Tools

Created by Dr. Luis Agulló (last update on 12-6-2007)



Inhibitors of Cyclic GMP-Dependent Protein Kinase or Protein Kinase G (PKG)



Rp-cGMPS

[Rp-Guanosine 3',5'-cyclic monophosphorothioate]

Potency: A competitive inhibitor of protein kinase G (PKG) 1a that blocks PKG and protein kinase A activation (Ki = 20 µM).

Membrane permeability: Y/N / Solubility: H2O / MW: 462.5

Comments: Exhibits low cell permeability. Resistant against cyclic nucleotide-dependent phosphodiesterases compared to cGMP, shows about 24-fold lower binding to phosphodiesterase1.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: -


Rp-8-Br-cGMPS

[Rp-8-Bromo-Guanosine 3',5'-cyclic monophosphorothioate]

Potency: Ki= 4 µM1.

Membrane permeability: Y / Solubility: H2O / MW: 462.2

Comments: More permeable than the Rp-cGMPS.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: At high concentrations, it can act as an agonist of cyclic-nucleotide-gated channels (CNGC; EC50= 173.5 µM).


8-pCPT-cGMPS

[Rp- 8-(4-Chlorophenylthio)-Guanosine 3',5'-cyclic Monophosphorothioate]

Potency: -

Membrane permeability: Y / Solubility: H2O, DMSO / MW: 605.1

Comments: Metabolically-stable; significantly more lipophilic and membrane-permeable than Rp-cGMPS or Rp-8-Br-cGMPS.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: -



Rp-8-Br-PET-cGMPS

[Rp- beta-Phenyl-1,N2-etheno-8-bromo-Guanosine 3',5'-cyclic Monophosphorothioate]

Potency: Ki = 30 nM.

Membrane permeability: Y / Solubility: H2O / MW: 562.3

Comments: Competitive inhibitor of protein kinase G types 1a and 1b; metabolically-stable and more lipophilic and cell-permeable than Rp-8-pCPT-cGMPS.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: Blocks cGMP-gated retinal type ion channels (IC50 = 25 µM) and the activation of purified PKA type II (Ki = 10 µM).


KT5823

[(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg-3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester]

Potency: Ki= 234 nM (PKC: 4.0µM for PKC, and >10.0 µM for PKA)1

Membrane permeability: Y / Solubility: DMSO / MW: 495.5

Comments: Compound structurally similar to staurosporin, that interferes at the level of the ATP binding site of the catalytic domain of PKG2.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

2Hidaka H, Kobayashi R. Pharmacology of protein kinase inhibitors. Annu Rev Pharmacol Toxicol 1992;32:377

CAUTION: It has not been proved to selectively inhibit PKG in intact cells. At this respect some doubts have rised because of different communications: KT5823 was not able to inhibit PKG-mediated vimentin phosphorylation1, and even potentiated PKG induced VASP phosphorylation in intact patelets1. Recently, it has been described that it did not block PKG-mediated phosphorylation of PDE52.

1Smolenski A, Burkhardt AM, Eigenthaler M, Butt E, Gambaryan S, Lohmann SM, Walter U. Functional analysis of cGMP-dependent protein kinases I and II as mediators of NO/cGMP effects. Naunyn-Schmiedeberg's Arch Pharmacol 1998;358:134

2Rybalkin SD. Regulation of PDE5 activity by cGMP binding and phosphorylation. 1st International Conference on cGMP 2003, 1:op029


PKG Inhibitor

[RKRARKE; H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH]

Potency: Ki = 86 µM (Ki = 550 µM for PKA)

Membrane permeability: - / Solubility: H2O / MW: 943.1

Comments: -

CAUTION: -


Protein kinase G Ialfa inhibitor

[RQIKIWFQNRRMKWKKLRKKKKKH; H-Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Leu-Arg-Lys-Lys-Lys-Lys-Lys-His-OH]

Potency: It inhibits PKG Ia with a Ki= 25 nM; it inhibits NO-induced vasodilation, ED50= 47 µM (Ki = 493 µM for PKA) 1

Membrane permeability: Y / Solubility: DMSO / MW: 3294.1

Comments: It is considered a selective inhibitor of protein kinase G Ia

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: -


H-7

[1-(5-Isoquinolinesulfonyl)-2-methylpiperazine]

Potency: Ki= 870 nM (for PKG); Ki for other kinases: 97 µM MLCK, 3.0 µM PKA, 6 µM PKC1.

Membrane permeability: Y / Solubility: H2O / MW: 364.3

Comments: cAMP and cGMP-dependent protein kinase inhibitor.

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: -


Staurosporin

Potency: Ki= 8.5 nM (for PKG); Ki for other kinases: 20 nM CaMK, 1.3 nM MLCK, 7 nM PKA, 700 pM PKC1.

Membrane permeability: Y / Solubility: DMSO, MeOH / MW: 466.5

Comments: potent and general inhbitor od protein kinases

1Inhibitor SourceBook, Calbiochem, Merck Biosciences

CAUTION: -






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