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Concentration: 1 mM Heat Map
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A multi-kinase inhibitor used generally as a PKC inhibitor in the literature, and less commonly as an inhibitor of p70S6K and GSK-3. In an extended cell-free assay of 110 kinases, the top 10 inhibited kinases in decreasing order of predicted potency were (IC50
, nM): GSK-3β (2), PKCα (6), SLK (10), RSK isoforms (15-23), PKN2 (16), PIM1 (18), CLK1 (19), MSK1 (23), p70S6K (40) and CDK2 (44). In cells, it is a cell-permeable and competitive inhibitor of PKC (IC50
= 10 nM) over CaMKII (IC50
= 17 μM) and PKA (IC50
= 900 nM). It inhibits GSK-3 in primary adipocytes (IC50
= 6.8 nM) and GSK-3β in immunoprecipitates (IC50
= 2.8 nM). It inhibits EGF-induced activation of p70S6K in mouse fibroblasts (IC50
= 600 nM), but not in adult rat ventricular myocytes up to 1 μM. Other known PKC-independent effects include: (1) preventing growth factor induced expression of MAP kinase phosphatase-1 (MKP1/CL100) and the transcription factor c-Fos in rat fibroblasts, (2) JNK1 activation even after PKC down-regulation, possibly a secondary result of reduced MKP1 (a negative regulator of JNK), and (3) inhibition of the phosphorylation of Raf-1 and induction of apoptosis, independent of its effects on PKC, in HL-60 cells.
Roberts NA, Marber MS, Avkiran M. (2004) Specificity of action of bisindolylmaleimide PKC inhibitors: do they inhibit the 70kDa ribosomal S6 kinase (p70S6K) in cardiac myocytes? Biochem Pharmacol. 68(10):1923-8; Marmy-Conus N, Hannan KM, Pearson RB. (2002) Ro 31-6045, the inactive analogue of the protein kinase C inhibitor Ro 31-8220, blocks in vivo activation of p70(s6k)/p85(s6k): implications for the analysis of S6K signalling. FEBS Lett. 519(1-3):135-40; Powell, D.J., et al. 2003. Mol. cell Biol. 23, 7794. Han, Z., et al. 2000. Cell Death Differ. 7, 521. Hers, I., et al. 1999. FEBS Lett. 460, 433. Alessi, D.R., 1997. The protein kinase C inhibitors Ro 318220 and GF 109203X are equally potent inhibitors of MAPKAP kinase-1beta (Rsk-2) and p70 S6 kinase. FEBS Lett. 402(2-3):121; Beltman, J., et al. 1996. J. Biol. Chem. 271, 27018. Keller, H.U., and Niggli, V. 1993. Biochem. Biophys. Res. Commun. 194, 1111. McKenna, J.P., and Hanson, P.J. 1993. Biochem. Pharmacol. 46, 583. Davis, P.D., et al. 1992. J. Med. Chem. 35, 994.