C-erbB-2-kinase

Tauroacidins A (194) and B (195) from an Okinawan sponge Hymeniacidon sp. exhibit inhibitory activity against EGF receptor kinase and c-erbB-2 kinase (IC50 20 pg/ml each) [155]. 

Spongiacidins A (197) and B (198), azepine-type bromopyrrole alkaloids from Hymeniacidon which are geometrical isomers of hymenialdisine (171), inhibit c-erbB-2 kinase (IC50 9.0 and 8.5 pg/ml) and cyclin dependent kinase 4 (IC50 32 and 12 pg/ml) [157],... 

C-terminal to the c-erbB-2 kinase domain is a region of about 40 amino acids not shared with the EGF receptor. This sequence is equivalent in position to the pro-teolytically sensitive region of the EGF receptor and it may be that it is also rather exposed in the c-erbB-2 protein, perhaps looped out from between the kinase domain and the autophosphorylation site domain. If the c-erbB-2 protein does indeed possess a ligand which can stimulate its kinase activity, this region is a candidate for being involved in influencing the molecule s substrate specificity. 

Taurospongin A (78) exhibited potent inhibitory activity against DNA polymerase 3 and HIV reverse transcriptase with IC50 values of 7.0 and 6.5 pM (Ki values of 1.7 and 1.3 pM), respectively. This inhibitory activity has been frequently associated with Ae sulfonic acid function. Furthermore, 78 showed weak inhibitory activity against c-erbB-2 kinase (IC50 28 pg/mL), while there was no cytotoxicity (IC50 >10 pg/mL)... 

Wan, Y. et al.. Synthesis and target identification of hymeiualdisine analogs, Chem. Biol., 11, 247, 2004. Kobayashi, J., Madono, T., and Shigemori, H., Nakijiquinones C and D, new sesquiterpenoid quinones with a hydroxy amino acid residue from a marine sponge inhibiting c-erbB-2 kinase. Tetrahedron, 51, 10867, 1995. 

Rhopaladins A-D are bis-indolic alkaloids containing an imidazohnone they were isolated from Rhopalaea sp. of Japanese origin with yields ranging between 1 and 3.5 X 10 Rhopahdin B is an inhibitor of c-erbB-2 kinase, with an IC50 of 7.4(xgml (Sato et al, 1998). 

It is not known whether c-erbB-2 is a GFR since no ligand for it has yet been identified, but it may possess protein tyrosine kinase activity [21,22]. The sequence of the cytoplasmic domain encodes a tyrosine kinase-like domain very homologous to that of the EGF receptor. This homology (82%) is much higher than that seen between most of the members of the sre gene family (25-40%) and emphasizes the... 

Quinazoline urea derivatives, (I), prepared by Kath (3) were effective as tyrosine kinase inhibitors such as c-erbB-2, c-met, tie-2, PDGFr, FGFr, and VEGFR and used in the treatment of proliferative disorders. 

Akiyama T, Sudo C, Ogawara H, et al. The product of the human c-erbB-2 gene A l85-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986 232 1644-1646. 

Human epidermal growth factor receptor-2 (HER-2 neu) is a member of the type 1 receptor tyrosine kinase family with domains on the cell surface, functioning as growth factor receptors. The type 1 receptor tyrosine kinase family includes the receptors HER-1 (EGFRorc-erbBl), HER-2 (c-erbB-2), HER-3 (c-erbB-3) and HER-4 (c-erbB-4). 

Lonardo, F., E. Di Marco, C. R. King, J. H. Pierce, O. Segatto, S. A. Aaronson, and P. P. Di Fiore. The normal erbB-2 product is an atypical receptor-like tyrosine kinase with constitutive activity in the absence of ligand. New Biol. 2 992-1003.1990. 

Mimnaugh, E. G., C. Chavany, and L. Neckers. Polyubiquitination andproteasomal degradation of the pl85c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem. 271 22796-22801.1996. 

Viloria-Petit AM, Rak J, Hung M-C, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and In vivo. Am J Pathol 1997 151 1523-1530. 

Iressa (gefitinib, 2) is a reversible inhibitor, thus mechanistically it is possible to excert less toxicity in comparison to similar irreversible inhibitors, which bond to the protein covalently. Gefitinib (2) is also quite selective. It is at least 100-fold selective against other tyrosine kinases such as erbB-2, KDR, c-flt or serine/threonine kinases such as PKC, MEK-1, and ERK-2. 

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