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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Chemical Compound Review

Compound 32     N-(3-bromophenyl)-6,7- dimethoxy-quinazolin...

Synonyms: Tocris-1037, WHI-P 79, SureCN9423, PubChem22449, CHEMBL29197, ...
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Disease relevance of Tocris-1037

  • Here, we report a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hypoxia, which contrasts with their proapoptotic effects under normoxia [1].
  • PD153035, a specific inhibitor of the EGFR, and an EGFR-specific antibody that blocks ligand binding completely abrogated basal MAPK activation by endogenous ligands in laryngeal papilloma cells [2].
  • Treatment of our in vitro glioma model with the EGFR kinase inhibitors ZD1839 (Iressa) or PD153035, synthetic anilinoquinazolines with high specificity for EGFR, resulted in significant suppression of EGFR autophosphorylation even with very low levels of drug [3].
  • Of particular interest, the combination of PD153035 and Rp-cAMPs also caused a more substantial apoptotic/necrotic death of these prostatic cancer cells as compared to drugs alone [4].
  • CONCLUSIONS: Epidermal growth factor receptor tyrosine kinase inhibitor PD153035 significantly inhibited motility and invasion in malignant pleural mesothelioma cells in vitro, regardless of their epidermal growth factor receptor expression levels [5].

High impact information on Tocris-1037


Chemical compound and disease context of Tocris-1037


Biological context of Tocris-1037

  • We demonstrated that potent inhibitors of the EGFR, PD153035 and AG1478, blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs), AP-1 activity, and cell transformation [11].
  • Treatment of AGS cells with the epidermal growth factor receptor (EGFR) kinase inhibitors PD153035 and AG1478 resulted in a reduction in H pylori mediated Egr-1 upregulation, demonstrating that EGFR transactivation plays a role in this early cellular process [12].
  • PD153035 caused a dose-dependent growth inhibition of EGF receptor-overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested [13].
  • The novel molecules were synthesized by combining the structural features of the EGFR inhibitor PD153035 (1) and lipoic acid, which among other therapeutic effects triggers apoptosis in human cancer cells [14].
  • Extensive DNase I footprinting experiments performed with a large range of DNA substrates show that EBE-A22, but not PD153035, interacts preferentially with GC-rich sequences and discriminates against homooligomeric runs of A and T which are often cut more readily by the enzyme in the presence of the drug compared to the control [15].

Anatomical context of Tocris-1037

  • In contrast, PD153035 only reduced heregulin-dependent tyrosine phosphorylation in HER2/neu-overexpressing cell lines at significantly higher concentrations (1400-2800 nM) [13].
  • The brominated anilinoquinazoline derivative PD153035 exhibits a very high affinity and selectivity for the epidermal growth factor receptor tyrosine kinase (EGF-R TK) and shows a remarkable cytotoxicity against several types of tumor cell lines [15].
  • PD153035 reduced invasion and fusion of trophoblasts supplemented with hCG-A, but did not diminish the effects provoked by hCG-B [16].
  • Consistent with this notion, this action was blocked by the PTKs inhibitor genistein and the EGFR antagonist PD153035, indicating that contraction was, at least in part, attributable to PTKs phosphorylation that activates VR1, resulting in increased intracellular calcium content in the smooth muscle cells [17].
  • The differences observed in the incubations with rat and human microsomes suggest that in vivo positron emission tomography studies with (11)C-labeled PD153035 in rodents may not be directly predictive for studies in humans [18].

Associations of Tocris-1037 with other chemical compounds


Gene context of Tocris-1037


Analytical, diagnostic and therapeutic context of Tocris-1037


  1. Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Steinbach, J.P., Klumpp, A., Wolburg, H., Weller, M. Cancer Res. (2004) [Pubmed]
  2. Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas. Johnston, D., Hall, H., DiLorenzo, T.P., Steinberg, B.M. Cancer Res. (1999) [Pubmed]
  3. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Li, B., Chang, C.M., Yuan, M., McKenna, W.G., Shu, H.K. Cancer Res. (2003) [Pubmed]
  4. Synergistic antiproliferative and apoptotic effects induced by epidermal growth factor receptor and protein kinase a inhibitors in human prostatic cancer cell lines. Mimeault, M., Pommery, N., Hénichart, J.P. Int. J. Cancer (2003) [Pubmed]
  5. The selective epidermal growth factor receptor tyrosine kinase inhibitor PD153035 suppresses expression of prometastasis phenotypes in malignant pleural mesothelioma cells in vitro. Cole, G.W., Alleva, A.M., Reddy, R.M., Maxhimer, J.B., Zuo, J., Schrump, D.S., Nguyen, D.M. J. Thorac. Cardiovasc. Surg. (2005) [Pubmed]
  6. Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. Alper O, n.u.l.l., Bergmann-Leitner, E.S., Bennett, T.A., Hacker, N.F., Stromberg, K., Stetler-Stevenson, W.G. J. Natl. Cancer Inst. (2001) [Pubmed]
  7. Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation In skin organ culture. Stoll, S., Garner, W., Elder, J. J. Clin. Invest. (1997) [Pubmed]
  8. Epidermal growth factor receptor signaling is partially responsible for the increased matrix metalloproteinase-1 expression in ocular epithelial cells after UVB radiation. Di Girolamo, N., Coroneo, M., Wakefield, D. Am. J. Pathol. (2005) [Pubmed]
  9. Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. Gardner, O.S., Dewar, B.J., Earp, H.S., Samet, J.M., Graves, L.M. J. Biol. Chem. (2003) [Pubmed]
  10. Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines. Li, L., Shaw, P.E. J. Biol. Chem. (2002) [Pubmed]
  11. Transactivation of the epidermal growth factor receptor is involved in 12-O-tetradecanoylphorbol-13-acetate-induced signal transduction. Chen, N., Ma, W.Y., She, Q.B., Wu, E., Liu, G., Bode, A.M., Dong, Z. J. Biol. Chem. (2001) [Pubmed]
  12. Transactivation of the epidermal growth factor receptor by cag+ Helicobacter pylori induces upregulation of the early growth response gene Egr-1 in gastric epithelial cells. Keates, S., Keates, A.C., Nath, S., Peek, R.M., Kelly, C.P. Gut (2005) [Pubmed]
  13. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Bos, M., Mendelsohn, J., Kim, Y.M., Albanell, J., Fry, D.W., Baselga, J. Clin. Cancer Res. (1997) [Pubmed]
  14. Multitarget-directed drug design strategy: a novel molecule designed to block epidermal growth factor receptor (EGFR) and to exert proapoptotic effects. Antonello, A., Tarozzi, A., Morroni, F., Cavalli, A., Rosini, M., Hrelia, P., Bolognesi, M.L., Melchiorre, C. J. Med. Chem. (2006) [Pubmed]
  15. DNA interaction of the tyrosine protein kinase inhibitor PD153035 and its N-methyl analogue. Goossens, J.F., Bouey-Bencteux, E., Houssin, R., Hénichart, J.P., Colson, P., Houssier, C., Laine, W., Baldeyrou, B., Bailly, C. Biochemistry (2001) [Pubmed]
  16. Effects of different human chorionic gonadotrophin preparations on trophoblast differentiation. Saleh, L., Prast, J., Haslinger, P., Husslein, P., Helmer, H., Kn??fler, M. Placenta (2007) [Pubmed]
  17. 1,2-Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea. Kikuno, S., Taguchi, K., Iwamoto, N., Yamano, S., Cho, A.K., Froines, J.R., Kumagai, Y. Toxicol. Appl. Pharmacol. (2006) [Pubmed]
  18. The tyrosine kinase inhibitor PD153035: implication of labeling position on radiometabolites formed in vitro. Sam??n, E., Thorell, J.O., Fredriksson, A., Stone-Elander, S. Nucl. Med. Biol. (2006) [Pubmed]
  19. Role of PPARgamma and EGFR signalling in the urothelial terminal differentiation programme. Varley, C.L., Stahlschmidt, J., Lee, W.C., Holder, J., Diggle, C., Selby, P.J., Trejdosiewicz, L.K., Southgate, J. J. Cell. Sci. (2004) [Pubmed]
  20. Heparin-binding epidermal growth factor-like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3'-kinase and mitogen-activated protein kinase. Jin, K., Mao, X.O., Del Rio Guerra, G., Jin, L., Greenberg, D.A. J. Neurosci. Res. (2005) [Pubmed]
  21. TPA-induced signal transduction: a link between PKC and EGFR signaling modulates the assembly of intercellular junctions in Caco-2 cells. Barbosa, L.A., Goto-Silva, L., Redondo, P.A., Oliveira, S., Montesano, G., De Souza, W., Morgado-Díaz, J.A. Cell Tissue Res. (2003) [Pubmed]
  22. Induction of COX-2 protein expression by vanadate in A549 human lung carcinoma cell line through EGF receptor and p38 MAPK-mediated pathway. Chien, P.S., Mak, O.T., Huang, H.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  23. Mechanisms of Zn(2+)-induced signal initiation through the epidermal growth factor receptor. Samet, J.M., Dewar, B.J., Wu, W., Graves, L.M. Toxicol. Appl. Pharmacol. (2003) [Pubmed]
  24. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Bancroft, C.C., Chen, Z., Yeh, J., Sunwoo, J.B., Yeh, N.T., Jackson, S., Jackson, C., Van Waes, C. Int. J. Cancer (2002) [Pubmed]
  25. Regulation of heparin-binding EGF-like growth factor expression in Ha-ras transformed human mammary epithelial cells. Martínez-Lacaci, I., De Santis, M., Kannan, S., Bianco, C., Kim, N., Wallace-Jones, B., Wechselberger, C., Ebert, A.D., Salomon, D.S. J. Cell. Physiol. (2001) [Pubmed]
  26. Mechanism of novel vitamin K analog induced growth inhibition in human hepatoma cell line. Osada, S., Carr, B.I. J. Hepatol. (2001) [Pubmed]
  27. EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes. Wan, Y.S., Wang, Z.Q., Voorhees, J., Fisher, G. Cell. Signal. (2001) [Pubmed]
  28. Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA's effect on cell death and migration in human ovarian cancer cells. Zhou, C., Qiu, L., Sun, Y., Healey, S., Wanebo, H., Kouttab, N., Di, W., Yan, B., Wan, Y. Int. J. Oncol. (2006) [Pubmed]
  29. EGF stimulates transcription of CaN19 (S100A2) in HaCaT keratinocytes. Stoll, S.W., Zhao, X., Elder, J.T. J. Invest. Dermatol. (1998) [Pubmed]
  30. An EGF receptor inhibitor induces RAR-beta expression in breast and ovarian cancer cells. Grunt, T.W., Puckmair, K., Tomek, K., Kainz, B., Gaiger, A. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  31. Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Woodworth, C.D., Michael, E., Marker, D., Allen, S., Smith, L., Nees, M. Mol. Cancer Ther. (2005) [Pubmed]
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