Inhibitor SourceBook™ Second Edition

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Phosphorylation/Dephosphorylation Protein Kinase C (PKC) Inhibitors Protein kinase C (PKC), a ubiquitous, phospholipiddependent 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 Ca 2+ -dependent, while novel and atypical isozymes do not require Ca 2+ 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 G 1 and G 2 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 A 2 (PLA 2 ) via a G-protein-dependent phenomenon. The activated PLC hydrolyzes phosphatidylinositol-4, 5-bisphosphate (PIP 2 ) to produce DAG and inositol- 1,4,5-trisphosphate (IP 3 ). The IP 3 causes the release of endogenous Ca 2+ that binds to the cytosolic PKC and exposes the phospholipidbinding site. The binding of Ca 2+ 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 PKC a 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. References: Oka, M., and Kikkawa, U. 2005. Cancer Metastasis Rev. 24, 287. Mailoi, E., and Fortino, V. 2004. Endocr. Relat. Cancer 11, 6 . Black, J.D. 2000. Front. Biosci. 5, 406. Cooper, D.R., et al. 999. Arch. Biochem. Biophys. 372, 69. Yamamoto, M., et al. 998. Exp. Cell Res. 240, 349. Rasmussen, H., et al. 995. Endocr. Rev. 16, 649. Taylor, S.S., et al. 995. FASEB J. 9, 255. Nishizuka, Y. 995. FASEB. J. 9, 484. Newton, A.C. 995. J. Biol. Chem. 270, 28495. Hanks, S., and Hunter, T. 995. FASEB J. 9, 576. Blobe, G.C., et al. 994. Cancer Metastasis Rev. 13, 4 . Basu, A. 993. Pharmacol. Ther. 59, 257. More online... www.calbiochem.com/inhibitors/PKC 36 Orders Phone 800 854 34 7 Calbiochem • Inhibitor SourceBook Fax 800 776 0999 Web www.emdbiosciences.com/calbiochem
Isozyme Specificities of Selected Protein Kinase C Inhibitors (IC 50 values are in µM) Calbiochem • Inhibitor SourceBook Phosphorylation/Dephosphorylation Product Cat. No. PKC a PKC b PKC bI PKC bII PKC g PKC d PKC e PKC z PKC m PKC h Ref. Bisindolylmaleimide I (Gö 6850) 203290 0.008 — 0.0 8 — — 0.2 0. 32 5.8 — — CGP4 25 — 0.024 — 0.0 7 0.032 0.0 8 0.360 4.50 > 000 — 0.060 2 Gö 6976 365250 0.0023 — 0.006 — — — — — 0.02 — Gö 6983 365251 0.007 0.007 — — 0.006 0.0 — 0.06 20 — 3 LY33353 — 0.360 — 0.0047 0.0059 0.400 0.250 0.600 > 0 5 — 0.052 4 PKCb Inhibitor 539654 0.33 — 0.02 0.005 > .0 — 2.8 — — — 5 Ro-3 -7549 557508 0.053 0. 95 0. 63 0.2 3 — 0. 75 — — — 6 Ro-3 -8220 557520 0.005 — 0.024 0.0 4 0.027 — 0.024 — — — 6 Ro-3 -8425 557514 0.008 — 0.008 0.0 4 0.0 3 — 0.039 — — — 6 Ro-32-0432 557525 0.009 — 0.028 0.03 0.037 — 0. 08 — — — 6 Rottlerin 557370 30 42 — — 40 3 - 6 00 00 — — 7 Staurosporine 569397 0.028 — 0.0 3 0.0 0.032 0.028 0.025 > .5 — — 6 UCN0 — 0.029 — 0.034 — 0.030 0.590 0.530 — — — 8 References: . Martiny-Baron, G.M. et al. 993. J. Biol. Chem. 268, 9 94. 2. Marte, B.M., et al. 994. Cell Growth Differ. 5, 239. 3. Gschwendt, M., et al. 996. FEBS Lett. 392, 77. Protein Kinase C (PKC) Inhibitors Product Cat. No. Comments Size Price Bisindolylmaleimide I 203290 {2-[1-(3-Dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide; Gö 6850; GF 109203X} InSolution Bisindolylmaleimide I Bisindolylmaleimide I, Hydrochloride A highly selective cell-permeable PKC inhibitor (K i = 0 nM) that is structurally similar to staurosporine. Acts as a competitive inhibitor for the ATP-binding site of PKC. Shows high selectivity for the a, bII, g, and e isozymes of PKC. May inhibit protein kinase A at a much higher concentration (K i = 2 mM). 203293 {2-[1-(3-Dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide; Gö 6850} A mg/ml solution of Bisindolylmaleimide I (Cat. No. 203290) in anhydrous DMSO. 203291 {2-[1-(3-Dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, HCl} An inhibitor of PKC (K i = 0 nM). Inhibits PKA at much higher concentrations (K i = 2 mM). An enhanced water-soluble form of Bisindolylmaleimide I (Cat. No. 203290). Bisindolylmaleimide II 203292 {2-[1-[2-(1-Methylpyrrolidino)ethyl]-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide} A potent and selective inhibitor of PKC (IC 50 = 3 nM). Also inhibits PKA at much higher concentrations (IC 50 = 2 mM). Bisindolylmaleimide III, Hydrochloride 203294 {2-[1-(3-Aminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, HCl} A potent and selective inhibitor of PKC (IC 50 = 26 nM). It also inhibits PKA at much higher concentrations (IC 50 = 500 nM). Bisindolylmaleimide IV 203297 [Arcyriarubin A; 2,3-bis(1H-Indol-3-yl)maleimide] A potent and selective inhibitor of PKC (IC 50 = 87 nM) and PKA (IC 50 = 2.7 mM). Bisindolylmaleimide V 203303 [2,3-bis(1H-Indol-3-yl)-N-methylmaleimide; Ro 31-6045] Useful as a negative control compound for PKC inhibition studies (IC 50 > 00 mM). Blocks the activation of p70 s6k /p85 s6k in vivo (IC 50 = 8 mM). Calphostin C, Cladosporium cladosporioides Cardiotoxin, Naja nigricollis 4. Jirousek, M.R., et al. 996. J. Med. Chem. 39, 2664. 5. Tanaka, M., et al. 2004. Bioorg. Med. Chem. Lett. 14, 5 7 . 6. Wilkinson, S.E., at al. 993. Biochem. J. 294, 335. 7. Gschwendt, M., et al. 994. Biochem. Biophys. Res. Commun. 199, 93. 8. Seynaeve, C.M., et al. 994. Mol. Pharmacol. 45, 207. 208725 (UCN-1028c) Cell-permeable, highly specific inhibitor of PKC (IC 50 = 50 nM) that interacts with the protein’s regulatory domain by competing at the binding site of diacylglycerol and phorbol esters. At higher concentrations inhibits MLCK (IC 50 > 5 mM), PKA (IC 50 > 50 mM), PKG (IC 50 >25 mM), and p60 v-src protein tyrosine kinase (IC 50 > 50 mM). Does not compete with Ca 2+ or phospholipids. 217504 A cytolytic toxin that causes depolarization of skeletal muscle fibers in vitro. Stimulates Ca 2+ transport and ATP hydrolysis by sarcolemmal Ca 2+ /Mg 2+ -ATPase. Its action is strongly potentiated by phospholipase A 2 . Inhibits PKC (IC 50 = .8 mM). Not available for sale outside of the United States. 250 mg mg 250 mg mg 250 mg mg 250 mg mg 250 mg mg $35 $ 03 ml $ 07 $35 $ 03 mg $ 45 50 mg 00 mg $52 $ 42 $49 $ 4 $44 $ 4 $8 $ 48 mg $ 63 Technical Support Phone 800 628 8470 E-mail calbiochem@emdbiosciences.com 37
Page 1 and 2: Inhibitor SourceBook Second Editio
Page 3 and 4: Calbiochem • Inhibitor SourceBook
Page 7 and 8: Akt (Protein Kinase B) Inhibitors,
Page 9 and 10: Calmodulin-Dependent Protein Kinase
Page 11 and 12: Casein Kinase (CK) Inhibitors Casei
Page 13 and 14: Checkpoint Kinase Inhibitors Eukary
Page 15 and 16: Cyclin-Dependent Kinase (Cdk) Inhib
Page 21 and 22: Glycogen Synthase Kinase-3 (GSK-3)
Page 23 and 24: Glycogen Synthase Kinase Inhibitors
Page 25 and 26: c-Jun N-Terminal Kinase (JNK/SAP Ki
Page 27 and 28: Mitogen-Activated Protein (MAP) Kin
Page 29 and 30: MAP Kinase Inhibitors, continued Ca
Page 31 and 32: Myosin Light Chain Kinase (MLCK) In
Page 33 and 34: Phosphatidylinositol 3-Kinase (PI 3
Page 37: Protein Kinase A (PKA; cAMP-Depende
Page 41 and 42: Protein Kinase C (PKC) Inhibitors,
Page 47 and 48: Protein Tyrosine Kinase (PTK) Inhib
Page 57 and 58: Raf Kinase Inhibitors Raf kinases a
Page 59 and 60: Rho Kinase (ROCK) Inhibitors, conti
Page 61 and 62: Protein Phosphatase Inhibitors Calb
Page 63 and 64: Protein Phosphatase Inhibitors, con
Page 65 and 66: Apoptosis Caspase Inhibitors Activa
Page 67 and 68: Caspase Inhibitors, continued Produ
Page 69 and 70: Other Selected Inhibitors of Apopto
Page 73 and 74: DNA Methyltransferase Inhibitors DN
Page 75 and 76: Histone Acetylase and Deacetylase I
Page 77 and 78: Related Products Histone Deacetylas
Page 79 and 80: Nuclear Import/Export Inhibitors, c
Page 83 and 84: Telomerase Inhibitors, continued Ca
Page 85 and 86: Topoisomerase Related Inhibitors, c
Page 87 and 88: Lipid Signaling Acetyl-CoA Carboxyl
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Cyclooxygenase (COX) Inhibitors, co
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HMG-CoA (3-Hydroxy-3-Methylglutaryl
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Lipoxygenase (LOX) Inhibitors Lipox
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Phospholipase Inhibitors Several si
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Sphingomyelinase Inhibitors Ceramid
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Amyloidogenesis Inhibitors Calbioch
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Secretase Inhibitors Deposition of
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Secretase Inhibitors Calbiochem •
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Calbiochem • Inhibitor SourceBook
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Glutathione S-Transferase (GST) Inh
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Guanylate Cyclase Inhibitors, conti
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Characteristics of various forms of
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Nitric Oxide Synthase (NOS) Inhibit
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Proteases Anthrax Lethal Factor (LF
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the ratio of active (76 kDa) to ina
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Collagenase Inhibitors (Also see Ma
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Matrix Metalloproteinase (MMP) Inhi
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Matrix Metalloproteinase Inhibitors
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Tissue Inhibitors of Matrix Metallo
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Protease Inhibitors The proper func
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Protease Inhibitors, continued Calb
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Protease Inhibitors, continued Calb
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Protease Inhibitors, continued Sele
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Protease Inhibitor Cocktails, conti
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N Animal-Free Protease Inhibitor Co
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Proteasome and Ubiquitination Pathw
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Transmembrane receptors of various
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Angiotensin-Converting Enzyme (ACE)
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ATPase Inhibitors, continued Calbio
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Calbiochem • Inhibitor SourceBook
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Inhibitors of Glycoprotein Processi
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Heat Shock Protein Inhibitors Heat
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Inhibitors of Mitochondrial Functio
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NF-kB Activation Inhibitors NF-kB,
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NF-kB Activation Inhibitors, contin
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Phosphodiesterase (PDE) Inhibitors
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Plasminogen Activator Inhibitors Ti
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Protein Synthesis Inhibitors, conti
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Sonic Hedgehog Signaling Inhibitors
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Why can’t I make serial dilutions
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Calpastatin, Human, Recombinant, Do
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InSolution Microcystin-LR, Microcys
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RNA Polymerase III Inhibitor ......
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324875 ............................
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Trademarks CALBIOCHEM®
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