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: -