Phosphorylation/Dephosphorylation: Protein Kinase C (PKC) Inhibitors
 | | | Table 1: Isozyme Specificities | Table 2: PK Inhibitors
Inhibitors | Related Products
Protein kinase C (PKC), a ubiquitous, phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, differentiation, and apoptosis. At least eleven closely related PKC isozymes have been reported that differ in their structure, biochemical properties, tissue distribution, subcellular localization, and substrate specificity. They are classified as conventional (a, b1, b2, g), novel (d, e, h, θ, m), and atypical (z, l) isozymes. Conventional PKC isozymes are Ca2+-dependent, while novel and atypical isozymes do not require Ca2+ for their activation. All PKC isozymes, with the exception of z and l, are activated by diacylglycerol (DAG). PKC isozymes negatively or positively regulate critical cell cycle transitions, including cell cycle entry and exit and the G1 and G2 checkpoints.
All PKC isoforms show different distribution among various cells. The a, d, and z isoforms are found in all cells. The g isoform is found only in neuronal cells. The b, e, and l isoforms are found in various tissues, whereas h and t isoforms are predominantly found in epithelial and immune cells.
In its unstimulated state, most of the PKC resides in the cytosol. In this state, the pseudosubstrate sequence of the regulatory domain of PKC interacts with the catalytic domain and prevents access of the substrate to the catalytic site. Binding of a hormone or other effector molecule to the membrane receptor results in activation of phospholipase C (PLC) or phospholipase A2 (PLA2) via a G-protein-dependent phenomenon. The activated PLC hydrolyzes phosphatidylinositol-4, 5-bisphosphate (PIP2) to produce DAG and inositol- 1,4,5-trisphosphate (IP3). The IP3 causes the release of endogenous Ca2+ that binds to the cytosolic PKC and exposes the phospholipidbinding site. The binding of Ca2+ translocates PKC to the membrane, where it interacts with DAG and is transformed into a fully active enzyme.
Altered PKC activity has been linked with various types of malignancies. Higher levels of PKC and differential activation of various PKC isozymes have been reported in breast tumors, adenomatous pituitaries, thyroid cancer tissue, leukemic cells, and lung cancer cells. Downregulation of PKCa is reported in the majority of colon adenocarcinomas and in the early stages of intestinal carcinogenesis. Thus, PKC inhibitors have become important tools in the treatment of cancers. The involvement of PKC in the regulation of apoptosis adds another dimension to the effort to develop drugs that will specifically target PKC. | | | | | | | | | Isozyme-Specific Protein Kinase C Inhibitors (IC50 values are in mM) | | Product | Cat. No. | PKCa | PKCb | PKCbI | PKCbII | PKCg | PKCd | PKCe | PKCx | PKCh | PKCm | Ref. | | Bisindolylmaleimide I | | 0.008 | - | 0.018 | - | - | 0.21 | 0.132 | 5.8 | - | - | 1 | | CGP41251 | N/A | 0.024 | - | 0.017 | 0.032 | 0.018 | 0.360 | 4.50 | >1000 | 0.060 | - | 2 | | Gö 6976 | | 0.0023 | - | 0.006 | - | - | - | - | - | - | 0.02 | 1 | | Gö 6983 | | 0.007 | 0.007 | - | - | 0.006 | 0.01 | - | 0.06 | - | 20 | 3 | | LY333531 | N/A | 0.360 | - | 0.0047 | 0.0059 | 0.400 | 0.250 | 0.600 | >105 | 0.052 | - | 4 | | PKCb Inhibitor | | 0.331 | - | 0.021 | 0.005 | >1.0 | - | 2.8 | - | - | - | 8 | | Ro-31-7549 | | 0.053 | - | 0.195 | 0.163 | 0.213 | - | 0.175 | - | - | - | 5 | | Ro-31-8220 | | 0.005 | - | 0.024 | 0.014 | 0.027 | - | 0.024 | - | - | - | 5 | | Ro-31-8425 | | 0.008 | - | 0.008 | 0.014 | 0.013 | - | 0.039 | - | - | - | 5 | | Ro-32-0432 | | 0.009 | - | 0.028 | 0.031 | 0.037 | - | 0.108 | - | - | - | 5 | | Rottlerin | | 30 | 42 | - | - | 40 | 3 - 6 | 100 | 100 | - | - | 6 | | Staurosporine | | 0.028 | - | 0.013 | 0.011 | 0.032 | 0.028 | 0.025 | >1.5 | - | - | 5 | | UCN01 | N/A | 0.029 | - | 0.034 | - | 0.030 | 0.590 | 0.530 | - | - | - | 7 |
| | | | | | | Table 2: Selected Protein Kinase Inhibitors | | Product | Cat. No. | CKI | CKII | MLCK | PKA | PKC | PKG | | A3, Hydrochloride | | 80 | 5.1 | 7.4 | 4.3 | 47.0 | 3.8 | Adenosine 3',5'-cyclic Monophosphorothioate,
Rp-Isomer, Triethylammonium Salt
| | - | - | - | 11.0 | - | - | Adenosine 3',5'-cyclic Monophophorothioate,
8-Bromo-2'-Monobutyryl-, Rp-Isomer, Sodium Salt | | | | | | | | Adenosine 3',5'-cyclic Monophophorothioate,
8-Chloro-, Rp-Isomer, Sodium Salt | | - | - | - | 50
(type I PKA) | - | - |
|  | | | | | | Inhibitors: Protein Kinase C (PKC) |
|
|
|
|
| Bisindolylmaleimide I |
203290 |
| Bisindolylmaleimide I, Hydrochloride |
203291 |
| InSolution™ Bisindolylmaleimide I |
203293 |
| Bisindolylmaleimide II |
203292 |
| Bisindolylmaleimide III, Hydrochloride |
203294 |
| Bisindolylmaleimide IV |
203297 |
| Bisindolylmaleimide V |
203303 |
| Calphostin C, Cladosporium cladosporioides |
208725 |
| Cardiotoxin, Naja nigricollis |
217504 |
| Chelerythrine Chloride |
220285 |
| Dequalinium Chloride |
263225 |
| Ellagic Acid, Dihydrate |
324683 |
| Gö 6976 |
365250 |
| InSolution™ Gö 6976 |
365253 |
| Gö 6983 |
365251 |
| Gö 7874, Hydrochloride |
365252 |
| H-7, Dihydrochloride |
371955 |
| Iso-H-7, Dihydrochloride |
371956 |
| HBDDE |
372770 |
| Hispidin |
377980 |
| Hypericin |
400076 |
| K-252a, Nocardiopsis sp. |
420298 |
| InSolution™ K-252a, Nocardiopsis sp. |
420297 |
| K-252b, Nocardiopsis sp. |
420319 |
| K-252c |
420305 |
| Melittin |
444605 |
| NGIC-I |
481500 |
| Phloretin |
524488 |
| Piceatannol |
527948 |
| PKC 20-28, Cell-Permeable, Myristoylated |
476480 |
| PKC Inhibitor Peptide 19-31 |
05-23-4904 |
| PKC Inhibitor Peptide 19-36 |
539560 |
| PKCh Pseudosubstrate Inhibitor, Myristoylated |
539604 |
| PKC Inhibitor, EGF-R Fragment 651-658, Myristoylated |
476475 |
| PKCb Inhibitor |
539654 |
| PKCbII/EGFR Inhibitor |
539652 |
| PKCe Translocation Inhibitor Peptide |
539522 |
| PKCe Translocation Inhibitor Peptide, Negative Control |
539542 |
| PKCq Pseudosubstrate Inhibitor |
539634 |
| PKCq Pseudosubstrate Inhibitor, Myristoylated |
539636 |
| PKCz Pseudosubstrate Inhibitor, Myristoylated |
539624 |
| PKCz/i Pseudosubstrate Inhibitor |
539610 |
| Polymyxin B Sulfate |
5291 |
| Ro 31-7549, Immobilized |
557509 |
| Ro-31-7549 |
557508 |
| Ro-31-8220 |
557520 |
| InSolution™ Ro-31-8220 |
557521 |
| Ro-31-8425 |
557514 |
| Ro-32-0432 |
557525 |
| Rottlerin |
557370 |
| Safingol |
559300 |
| Sangivamycin |
559307 |
| Scytonemin, Lyngbya sp. |
565715 |
| D-erythro-Sphingosine, Dihydro- |
300230 |
| D-erythro-Sphingosine, Free Base, High Purity |
567726 |
| D-erythro-Sphingosine, N,N-Dimethyl- |
310500 |
| Staurosporine, N-Benzoyl |
539648 |
| Staurosporine, Streptomyces sp. |
569397 |
| Tamoxifen Citrate |
579000 |
| Tamoxifen, 4-Hydroxy-, (Z)- |
579002 |
| TER14687 |
581800 |
| UCN-01 |
539644 |
| UCN-02 |
539645 |
| Vitamin E Succinate |
679130 |
|
| | | | Other Related Products | Product | Cat. No. | Comments | | Bisindolylmaleimide Inhibitor Set | | Each set contains 250 mg of : - Bisindolylmaleimide I, Hydrochloride (Cat. No. 203291)
- Bisindolylmaleimide II (Cat. No.203292)
- Bisindolylmaleimide III, HCl (Cat. No. 203294)
- Bisindolylmaleimide IV (Cat. No. 203297)
- Bisindolylmaleimide V (Cat. No. 203303)
- RIM-1 (Cat. No. 557325)
| | Protein Kinase C Inhibitor Set | | A set of 6 vials. Each set contains: - 250 mg of Bisindolylmaleimide I (Cat. No. 203290)
- 50 mg of Calphostin C, Cladosporium cladosporioides (Cat. No. 208725)
- 5 mg of Chelerythrine Chloride (Cat. No. 220285)
- 500 mg of Gö 6976 (Cat. No. 365250)
- 500 mg of Myristoylated PKC Inhibitor 20-28, Cell-Permeable
(Cat. No. 476480) - 500 mg of Ro-32-0432 (Cat. No. 557525)
| | Serine/Threonine Kinase Inhibitor Set | | A set of 6 vials. Each set contains: - 250 mg of PKC inhibitor, Bisindolylmaleimide I (Cat. No. 203290)
- 1 mg of PKA inhibitor, H-89, Dihydrochloride (Cat. No. 371963)
- 1 mg of PKG Inhibitor (Cat. No. 370654)
- 1 mg of MLCK inhibitor, ML-7 (Cat. No. 475880)
- 1 mg of CaM kinase II inhibitor, KN-93 (Cat. No. 422708)
- 100 mg of the broad range Serine/Threonine Kinase inhibitor, Staurosporine (Cat. No. 569397)
Not available for sale in Japan. |
| | | | | |
 |
 |
|
