Table 3.
PKC Inhibitors
| Class/ Inhibitor |
Chemistry | Site of Action | Isoform Selectivity |
Kd or IC50 | Reference |
|---|---|---|---|---|---|
|
Isoquinolines H-7 |
1-(5-isoquinolinesulfonyl)-2-methylpiperazines | ATP-binding site | PKCβI 3.5
μM PKCζ 6 μM |
(Howcroft and Lindquist, 1991) | |
|
Benzophenones Chelerythrine |
1,2-dimethoxy-12-methyl[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium | ATP-binding site | Pan-PKCs | 0.66 μm | (Ding et al., 2011b) |
| Balanol | 2-{[2,6-dihydroxy-4-({[(3S,4R)-3-[(4-hydroxybenzene)amido]azepan-4-yl]oxy}carbonyl)phenyl]carbonyl}-3-hydroxybenzoic acid | ATP-binding site | Pan-PKCs PKCβII> βI> η> δ> α> ɛ |
4–9 μm | (Pande et al., 2008; Mochly-Rosen et al., 2012) |
|
Indolocarbazoles Gö6976 |
5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile | Catalytic domain | PKCα, β1 | PKCα 2.3, βI 6.2 nM | (Martiny-Baron et al., 1993; Grandage et al., 2006) |
| Gö6983 | 1H-Pyrrole-2,5-dione, 3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)- | ATP-binding site Suppresses PKCμ auto-phosphorylation |
Pan-PKC inhibitor Potent: PKCα,
β, γ, δ Less potent: PKCζ |
PKCα 7, β 7, γ 6, δ 10, ζ 60 nM | (Gschwendt et al., 1996; Peterman et al., 2004) |
| Enzastaurin (LY317615) | 3-(1-methyl-1H-indol-3-yl)-4-(1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione | ATP-binding site | Potent: PKCβ Less potent: PKCα, γ, ɛ |
PKCα 39, β 6, γ 83, ɛ 110 nM | (Graff et al., 2005; Rovedo et al., 2011) |
| LY379196 | ATP-binding site | PKCβ | 3–6 μM | (Slosberg et al., 2000) | |
| Staurosporine (CGP41251) | 9,13-Epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-1-one, 2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-, [9S-(9α,10β,11β,13α)]- | ATP-binding site | Pan-PKCs Potent: PKCα, γ, η Less potent: PKCδ, ɛ |
PKCα 2, γ 5, δ 20, η 4 nM | (Tamaoki et al., 1986; Meggio et al., 1995) |
| CGP53353 | 5,6-bis[(4-Fluorophenyl)amino]-1H-isoindole-1,3(2H)-dione | ATP-binding site | PKCβ | PKCβI 3.8, βII 0.41 μM | (Deng et al., 2012) |
| UCN-01 | 7-hydroxystaurosporine | ATP-binding site | cPKCs | 25–50 nM | (Tamaoki, 1991) |
| Sotrastaurin (AEB071) | 3-(1H-indol-3-yl)-4-(2-(4-methylpiperazin-1-yl)quinazolin-4-yl)-1H-pyrrole-2,5-dione | ATP-binding site | Pan-PKC, especially PKCθ | PKCα 0.95, βI 0.64, δ 2.1, ɛ 3.2, η 1.8, θ 0.22 nM (Ki) | (Evenou et al., 2009; Naylor et al., 2011) |
|
Staurosporine
Analogs Ruboxistaurin (LY333531) |
(9S)-9-[[(Dimethyl-d6)amino]methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-Dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione Hydrochloride | ATP-binding site | PKCβI, βII. | PKCβI 4.7, βII: 5.9 nM | (Aiello et al., 2011) |
| Midostaurin (PKC412, CGP41251) | (9S,10R,11R,13R)-2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiamzonine-1-one | ATP-binding site | Pan-PKCs | 12 nM | (Millward et al., 2006) |
| Bisindolylmaleimide (GF 109203X, Gö 6850) | 3-(1-(3-(Dimethylamino)propyl)-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione | ATP-binding site | Pan-PKC, especially PKCα, βI | PKCα 8.4, βI 18, βII 16, γ 20, δ 210, ɛ 132, ζ 5800 nM | (Toullec et al., 1991; Gekeler et al., 1996) |
| Ro 31-8220 | Carbamimidothioic acid, 3-[3-[2,5-dihydro-4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-1H-pyrrol-3-yl]-1H-indol-1-yl]propyl ester, methanesulfonate | Catalytic domain | Pan-PKC: PKCα, βI, βII, γ, ɛ | PKCα 5, βI 24, βII: 14, γ 27, ɛ 24 nM | (Wilkinson et al., 1993; Davies et al., 2000) |
| SCH47112 | ATP-binding site | (Reynolds et al., 1997) | |||
|
Dicationic, lipophilic
compounds Dequalinium Cl |
Quinolinium, 1,1′-(1,10-decanediyl)bis[4-amino-2-methyl-, chloride (1:2) | Covalently modifies the C2-domain | All PKC | 7 μM-18 μM | (Castle et al., 1993; Manetta et al., 1993; Roffey et al., 2009) |
|
Flavonoid Myricitrin |
4H-1-Benzopyran-4-one, 3-[(6-deoxy-α-L-mannopyranosyl)oxy]-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)- | Prevents PKCα and PKCɛ activation by phorbol esters | PKCα, ɛ | (Meotti et al., 2006) | |
| Quercetin | 4H-1-Benzopyran-4-one, 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy- | Slight PKC inhibitor | (Navarro-Nunez et al., 2010) | ||
|
Benzothiazole Riluzole |
6-(trifluoromethoxy)benzothiazol-2-amine | ATP-binding site | PKCα | (Noh et al., 2000) | |
|
Perylenequinone Calphostin C (UCN-1028C) |
1-[3,10-dihydroxy-12-[2-(4-hydroxyphenoxy)carbonyloxypropyl]-2,6,7,11-tetramethoxy-4,9-dioxoperylen-1-yl]propan-2-yl benzoate | Regulatory domain: Competes at the binding site for DAG and phorbol esters. |
cPKCs, nPKCs | 50 nM | (Ogiwara et al., 1998) |
|
Phenolic ketone Rottlerin (Mallotoxin) |
5,7-dihydroxy-2,2-dimethyl-6-(2,4,6-trihydroxy-3-methyl-5-acetylbenzyl)-8-cinnamoyl-1,2-chromene) | ATP-binding site | PKCδ Other nPKCs |
PKCδ 5 μM Other PKCs 30 μM |
(Gschwendt et al., 1994) |
|
Macrolactone Bryostatin 1 (NSC 339555) |
(1S,3S,5Z,7R,8E,11S,12S,13E,15S,17R,21R,23R,25S)-25-(Acetyloxy)-1,11,21-trihydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate | C1 domain of PKC: competes with phorbol ester and diacylglycerol binding | Twofold selectivity for PKCɛ over PKCα and PKCδ (short term administration activates PKC, long term inhibits) | (Kraft et al., 1986; Roffey et al., 2009; Mochly-Rosen et al., 2012) | |
|
Membrane
lipids Sphingosine (D-erythro-Sphingosine) |
2-Amino-4-octadecene-1,3-diol; trans-4-Sphingenine | Regulatory domain: Competitive inhibitor with phosphatidylserine | 2.8 μM | (Khan et al., 1990) | |
| N,N-Dimethyl-D-erythro-sphingosine | (E,2S,3R)-2-(Dimethylamino)octadec-4-ene-1,3-dio | 12 μM | (Kim and Im, 2008) | ||
|
Taxol Tamoxifen |
2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine | Regulatory domain | cPKCs | (Zarate et al., 2007) | |
|
Purine
nucleoside Sangivamycin |
4-amino-5-carboxamide-7-(D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine | ATP-binding site | 10 μM | (Osada et al., 1989) | |
|
Carbonitrile 5-vinyl-3-pyridinecarbonitriles |
Catalytic domain | PKCθ | PKCθ 4.7 nM | (Tumey et al., 2009) | |
|
Pyrimidine 2,4-Diamino-5-nitropyrimidine |
Catalytic domain | PKCθ | (Cywin et al., 2007) | ||
|
Sterols Spheciosterol sulfate A |
Catalytic domain | PKCζ | PKCζ 1.59 μM | (Whitson et al., 2009) | |
| Spheciosterol sulfate B | Catalytic domain | PKCζ | PKCζ 0.53 μM | ||
| Spheciosterol sulfate C | Catalytic domain | PKCζ | PKCζ 0.11 μM | ||
|
Antisense
oligonucleotides Isis3521 (CGP64128A, Aprinocarsen) |
20-mer phosphorothioate oligodeoxynucleotide | Inhibits PKCα mRNAexpression | PKCα | – | (Lahn et al., 2003) |
| Isis9606 | 19-mer phophorothioate oligodeoxynucleotide | Inhibits PKCα mRNA | PKCα | – | (Levesque et al., 1997) |
|
Short
peptides Myristoylated-pseudosubstrate peptide inhibitor |
Peptide sequence: myr-FARKGALRQ | Substrate-binding site | cPKCs | – | (Eichholtz et al., 1993) |
| αV5-3 | Peptide sequence: QLVIAN | Site: aa 642–647 | PKCα | – | (Kim et al., 2011b) |
| βIV5-3 | Peptide sequence: KLFIMN | Inhibits PKC translocation Site: aa 646–651 |
PKCβI | – | (Ferreira et al., 2011) |
| βIIV5-3 | Peptide sequence: QEVIRN | Inhibits PKC translocation Site: aa 645–650 |
PKCβII | – | (Stebbins and Mochly-Rosen, 2001) |
| βC2-4 | Peptide sequence: SLNPEWNET | Site: aa 218–226 | All cPKCs | – | (Ron et al., 1995) |
| δV1-1 (KAI-9803, Delcasertib) | Peptide sequence: SFNSYELGSL | RACK-binding site Inhibits translocation Site: aa 8–17 |
PKCδ | – | (Chen et al., 2001) |
| ɛV1-2 (KAI-1678) | Peptide sequence: EAVSLKPT | RACK-binding site Inhibits translocation Site: aa 14–21 |
PKCɛ | – | (Gray et al., 1997) |
| KCe-12 and KCe-16 | Substrate-binding site | PKCɛ | – | (Yonezawa et al., 2009) | |
| ZIP | Peptide sequence: SIYRRGARRWRKL | ζ–pseudo substrate | PKCζ and aPKCs | – | (Braun and Mochly-Rosen, 2003) |
| γV5-3 | Peptide sequence: RLVLAS | Site: aa 659–664 | PKCγ | – | (Sweitzer et al., 2004) |
|
Other α-tocopherol, adriamycin, aminoacridine, apigenin, cercosporin, chlorpromazine, dexniguldipine, polymixin B, trifluoperazine, UCN-02 | |||||
aa, amino acid