PKC inhibitors and activators

Choose the optimal PKC inhibitor and activator based on potency, activity and function for your experiment.


Inhibitors


Target

Small molecule compound

Description



PKC (α, β, γ, δ)



Gö 6983

IC50 of 7 nM (PKCα), 7 nM (PKCβ), 6 nM (PKCγ), 10 nM (PKCδ), 60 nM (PKCζ) and 20000 nM (PKCμ)1.

Broad spectrum PKC inhibitor. Shows cardioprotective and anti-ischemic effects in vivo2.



PKC (α, β, γ, ε)


Enzastaurin

IC50 of 50 nM (PKCβ)3.

Highly selective for PKCβ over other PKCs. Facilitates secretion of growth factors and platelet aggregation3.


PKC (α, γ, η)


Staurosporine

IC50 of 2 nM (PKCα)4, 5 nM (PKCγ) and 4 nM (PKCη)5.

Less potent to other PKC isozymes.


PKC (α, βI, βII, γ)


GF 109203X
(Bisindolylmaleimide I)

IC50 of 5-70 nM6.

Competitive inhibitor with high selectivity for PKC over other kinases6.


PKC (α, β1)


Go6976

IC50 of 2.3 nM (PKCα) and 6.2 nM (PKCβ1)7.

Selectively inhibits Ca2+-dependent PKC isoforms over Ca2+-independent8.

PKCζ

ZIP
(atypical PKC inhibitor)

PKCζ regulatory domain associating myristoylated peptide9. ZIP inhibits PKC subcellular targeting10.



PKCβ


LY 333531 hydrochloride
(Ruboxistaurin)

IC50 of 4.7 nM (PKCβ1) and PKC 5.9 nM (PKCβ1)11.

Competitive and reversible PKCβ selective inhibitor12,13.



PKC (α, β1, βII, γ, ε)


Ro 31-8220 mesylate

IC50 of 22 nM PKC, 28 nM (PKCα), 13 nM (PKCβ1), 11 nM (PKCβII), 32 nM (PKCγ), 25 nM (PKCε)14.

Staurosporine analog, cell-permeable, competitive PKC inhibitor15.



PKC (α, β1, βII, γ, ε)


Ro 32-0432 hydrochloride

IC50 of 21 nM (PKC), 9 nM (PKCα), 28 nM (PKCβ1), 31 nM (PKCβ2), 37 nM (PKCγ), 108 nM (PKCε)14.

Selective cell-permeable PKC inhibitor that prevents T-cell activation16.



PKC (α, β1, δ, η, θ)


Sotrastaurin
(AEB071)

Ki of 0.95 nM (PKCα), 0.64 nM (PKCβ1), 2.1 nM (PKCδ), 1.8 nM (PKCη) and 0.22 nM (PKCθ)17.

Potent PKC inhibitor with immunosuppressant properties, particularly towards T-cells17,18.



PKC (α, β, γ, δ, ε, η, ζ)


Rottlerin

IC50 of 3-6 μM (δ), 30-42 μM (α, β, γ), 80-100 μM (ε, η, ζ)19.

Cell permeable reversible inhibitor exhibiting an effect within 5 min20.


PKCμ


K252a

IC50 of 7 nM (PKCμ)21 and 25 nM (PKC)22.

Staurosporine analog ATP competitive inhibitor of PKC23.












PKC

Baicalein
Quercetin
Luteolin

Inhibits PKC translocation and activity24. Induces apoptosis via ROS induction25.

Bisindolylmaleimide II

Inhibits PKC translocation and activity24. Induces apoptosis via ROS induction25.


Calphostin C

IC50 of 50 nM26.

Photodynamic PKC inhibitor inhibiting malignant cell proliferation26.

Chelerythrine chloride
(CTC, chelerythrine)

IC50 of 660 nM27.

Selective inhibitor of PKC isoforms group A and B28.

L-threo
Dihydrosphingosine

(Safingol)

IC50 of 40 μM29.

Lysosphingolipid PKC inhibitor. Enhances activity of vinca alkaloids and anthracyclines29.


Melittin

IC50 of 3 μM30 and 0.8 μM31.

Binds PKC at its catalytic active site. MgATP can disrupt Melittin-PKC interaction30.


PKC412 (Midostaurin)

Suppresses tumorigenesis via its effects on PKC32. Antiproliferative IC50 of 10 nM. Applications in FLT3-mutated AML and advanced systemic mastocytosis33.



PKC Activators


Small molecule compound

Description


Bryostatin 1

Potent agonist that exhibits nanomolar PKC binding affinities. Demonstrates binding affinities to classical and novel PKC isozyme subgroups34.

Ingenol-3-angelate
(I3A, PEP005)

Broad PKC activator. Exhibits proapoptotic and immunostimulatory effects35,36.

Phorbol-12,13-dibutyrate
(PDBu)

Increases kinase phosphorylation and induces contraction of vascular smooth muscle37,38.

Phorbol 12-myristate
13-acetate

Reversible PKC activator that activates Ca2+-ATPase39. More potent than DAG for PKC activation40.

Prostratin

PKC and NF-κB activator41. Synergizes with calcium/calcineurin signaling42.

SC-9, SC-10

PKC activator that induces PKC phosphorylation. PKC inhibition can be restored with SC-1043,44.


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References

1.           Chung, Y. W., Kim, H. K., Kim, I. Y., Yim, M. B. & Chock, P. B. Dual Function of Protein Kinase C (PKC) in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced Manganese Superoxide Dismutase (MnSOD) Expression: Activation of CREB and FOXO3a by PKC-phosphorylation and by PKC-mediated inactivation of Akt, respectively. J. Biol. Chem. 286, 29681–29690 (2011).

2.           Young, L. H., Balin, B. J. & Weis, M. T. Gö 6983: a fast acting protein kinase C inhibitor that attenuates myocardial ischemia/reperfusion injury. Cardiovasc. Drug Rev. 23, 255–72 (2005).

3.           Lesyk, G., Fong, T., Ruvolo, P. P. & Jurasz, P. The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer cell survival. J. Thromb. Haemost. 13, 1514–1520 (2015).

4.           McIlroy, B. K., Walters, J. D. & Johnson, J. D. A continuous fluorescence assay for protein kinase C. Anal. Biochem. 195, 148–52 (1991).

5.           Meggio, F. et al. Different Susceptibility of Protein Kinases to Staurosporine Inhibition. Kinetic Studies and Molecular Bases for the Resistance of Protein Kinase CK2. Eur. J. Biochem. 234, 317–322 (1995).

6.           Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–81 (1991).

7.           Amako, Y., Syed, G. H. & Siddiqui, A. Protein Kinase D Negatively Regulates Hepatitis C Virus Secretion through Phosphorylation of Oxysterol-binding Protein and Ceramide Transfer Protein. J. Biol. Chem. 286, 11265–11274 (2011).

8.           Zhang, N., Hodge, D., Rogers, T. J. & Oppenheim, J. J. Ca2+-independent Protein Kinase Cs Mediate Heterologous Desensitization of Leukocyte Chemokine Receptors by Opioid Receptors. J. Biol. Chem. 278, 12729–12736 (2003).

9.           Puls, A., Schmidt, S., Grawe, F. & Stabel, S. Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein. Proc. Natl. Acad. Sci. U. S. A. 94, 6191–6 (1997).

10.        Bogard, A. S. & Tavalin, S. J. Protein Kinase C (PKC)  Pseudosubstrate Inhibitor Peptide Promiscuously Binds PKC Family Isoforms and Disrupts Conventional PKC Targeting and Translocation. Mol. Pharmacol. 88, 728–735 (2015).

11.        Michael R. Jirousek, *,† et al. (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno- 1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues:  Isozyme Selective Inhibitors of Protein Kinase Cβ. (1996). doi:10.1021/JM950588Y

12.        Kunt, T. et al. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J. Diabetes Sci. Technol. 1, 929–35 (2007).

13.        Burkey, J. L., Campanale, K. M., O’Bannon, D. D., Cramer, J. W. & Farid, N. A. Disposition of LY333531, a selective protein kinase C β inhibitor, in the Fischer 344 rat and beagle dog. Xenobiotica 32, 1045–1052 (2002).

14.        Wilkinson, S. E., Parker, P. J. & Nixon, J. S. Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem. J 294, 335–337 (1993).

15.        Han, Z., Pantazis, P., Lange, T. S., Wyche, J. H. & Hendrickson, E. A. The staurosporine analog, Ro-31-8220, induces apoptosis independently of its ability to inhibit protein kinase C. Cell Death Differ. 7, 521–530 (2000).

16.        Birchall, A. M. et al. Ro 32-0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation. J. Pharmacol. Exp. Ther. 268, 922–9 (1994).

17.        Evenou, J.-P. et al. The Potent Protein Kinase C-Selective Inhibitor AEB071 (Sotrastaurin) Represents a New Class of Immunosuppressive Agents Affecting Early T-Cell Activation. J. Pharmacol. Exp. Ther. 330, 792–801 (2009).

18.        Manicassamy, S. Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis. Curr. Opin. Investig. Drugs 10, 1225–35 (2009).

19.        Gschwendt, M. et al. Rottlerin, a Novel Protein Kinase Inhibitor. Biochem. Biophys. Res. Commun. 199, 93–98 (1994).

20.        Susarla, B. T. S. & Robinson, M. B. Rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta), inhibits astrocytic glutamate transport activity and reduces GLAST immunoreactivity by a mechanism that appears to be PKCdelta-independent. J. Neurochem. 86, 635–45 (2003).

21.        Gschwendt, M. et al. Inhibition of protein kinase C μ by various inhibitors. Inhibition from protein kinase c isoenzymes. FEBS Lett. 392, 77–80 (1996).

22.        Kase, H. et al. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem. Biophys. Res. Commun. 142, 436–40 (1987).

23.        Mizuno, K., Saido, T. C., Ohno, S., Tamaoki, T. & Suzuki, K. Staurosporine-related compounds, K252a and UCN-01, inhibit both cPKC and nPKC. FEBS Lett. 330, 114–116 (1993).

24.        Kimata, M. et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin. Exp. Allergy 30, 501–8 (2000).

25.        Lu, H.-F. et al. ROS mediates baicalin-induced apoptosis in human promyelocytic leukemia HL-60 cells through the expression of the Gadd153 and mitochondrial-dependent pathway. Anticancer Res. 27, 117–25

26.        Pollack, I. F. & Kawecki, S. The effect of calphostin C, a potent photodependent protein kinase C inhibitor, on the proliferation of glioma cells in vitro. J. Neurooncol. 31, 255–66 (1997).

27.        Huang, S. The role of atypical PKC in the plasticity of the circadian clock in the rat suprachiasmatic nucleus. (2008).

28.        Chmura, S. J. et al. In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. Clin. Cancer Res. 6, 737–42 (2000).

29.        Sachs, C. W., Safa, A. R., Harrison, S. D. & Fine, R. L. Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C. J. Biol. Chem. 270, 26639–48 (1995).

30.        O’Brian, C. A. & Ward, N. E. ATP-sensitive binding of melittin to the catalytic domain of protein kinase C. Mol. Pharmacol. 36, 355–9 (1989).

31.        Katoh, N. Inhibition by Melittin of Phosphorylation by Protein Kinase C of Annexin I from Cow Mammary Gland. J. Vet. Med. Sci 64, 779–783 (2002).

32.        Fabbro, D. et al. PKC412--a protein kinase inhibitor with a broad therapeutic potential. Anticancer. Drug Des. 15, 17–28 (2000).

33.        Gallogly, M. M. & Lazarus, H. M. Midostaurin: an emerging treatment for acute myeloid leukemia patients. J. Blood Med. 7, 73–83 (2016).

34.        Sun, M.-K. & Alkon, D. L. Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug. CNS Drug Rev. 12, 1–8 (2006).

35.        Ersvaer, E. et al. The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity. Toxins (Basel). 2, 174–194 (2010).

36.        Lee, W.-Y. et al. Novel antileukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating protein kinase Ctheta. J. Biol. Chem. 285, 23889–98 (2010).

37.        Basu, A., Sridharan, S. & Persaud, S. Regulation of protein kinase Cδ downregulation by protein kinase Cε and mammalian target of rapamycin complex 2. Cell. Signal. 21, 1680–1685 (2009).

38.        Wagner, B., Schächtele, C. & Marmé, D. Phorbol 12,13-dibutyrate-induced contraction of isolated rabbit vascular smooth muscle. Eur. J. Pharmacol. 140, 227–32 (1987).

39.        Tao, J., Johansson, J. S. & Haynes, D. H. Protein kinase C stimulates dense tubular Ca2+ uptake in the intact human platelet by increasing the Vm of the Ca(2+)-ATPase pump: stimulation by phorbol ester, inhibition by calphostin C. Biochim. Biophys. Acta 1107, 213–22 (1992).

40.        Mosior, M. & Newton, A. C. Calcium-Independent Binding to Interfacial Phorbol Esters Causes Protein Kinase C To Associate with Membranes in the Absence of Acidic Lipids . Biochemistry 35, 1612–1623 (1996).

41.        Mehla, R. et al. Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner. PLoS One 5, e11160 (2010).

42.        Chan, J. K., Bhattacharyya, D., Lassen, K. G., Ruelas, D. & Greene, W. C. Calcium/calcineurin synergizes with prostratin to promote NF-κB dependent activation of latent HIV. PLoS One 8, e77749 (2013).

43.        Watson, P. H. W., Mortimer, S. T., Tanguay, K. E. & Hanley, D. A. Activation and inhibition of protein kinase c in cultured bovine parathyroid cells: Effect on the release of c-terminal fragments of parathyroid hormone. J. Bone Miner. Res. 7, 667–674 (2009).

44.        Chang, J. T. et al. hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells. Br. J. Cancer 94, 870–878 (2006).



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