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

• In some experiments, EGFR kinase activity in parental cells was inhibited by treatment with PD153035 [6].
• Neither PD153035 nor 225 IgG was toxic to keratinocytes, as judged by calcein-AM uptake [7].
• The epidermal growth factor receptor inhibitor PD153035 partially blocked the UVB-mediated induction of MMP-1 and totally abrogated its production after stimulation with either heparin-binding epidermal growth factor-like growth factor or epidermal growth factor [8].
• The selective epidermal growth factor receptor (EGFR) kinase inhibitors, PD153035 and ZD1839 (Iressa), abolished PPARalpha and gamma agonist-dependent Erk activation [9].
• BC cell growth could be inhibited by dominant-negative versions of STAT3 and the JAK inhibitor AG490 but not by PD153035 or PD168393, inhibitors of ErbB1 kinase activity [10].

Chemical compound and disease context of Tocris-1037

• N-oleoylethanolamine (OE), an inhibitor of acidic ceramidase, consistently potentiated the apoptotic effects of PD153035 in all the prostatic cancer cell lines tested [4].

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

• The use of a specific EGFR tyrosine kinase inhibitor, PD153035, correlated with PPARgamma dephosphorylation and translocation to the nucleus, indicating a mechanism for regulating the balance between proliferation and differentiation [19].
• The effect of HB-EGF was also blocked by the EGF receptor (EGFR/ErbB1) inhibitors PD153035 and PD158780, implicating EGFR in HB-EGF-induced cell proliferation [20].
• Potent specific EGFR inhibitors, such as PD153035 and Tyrphostin 25, as well as Calphostin C, an inhibitor of PKC, significantly blocked the effect of TPA on AJs [21].
• Furthermore, the epithelial growth factor (EGF) receptor specific inhibitor (PD153035) reduced vanadate-induced COX-2 expression [22].
• The EGFR kinase inhibitor PD153035 ablated all phosphorylation induced by EGF but none caused by Zn(2+) [23].

Gene context of Tocris-1037

• EGFR antagonist PD153035 and anti-EGFR antibody C225 completely inhibited EGF-induced reporter activity and cytokine expression, but only partially inhibited constitutive activity [24].
• However, the Ha-ras transformed MCF-10A cells were more refractory to inhibition by these agents and only a combination of the 225 MAb and PD153035 was able to significantly abrogate HB-EGF induction by EGF [25].
• However, CPD 5-mediated extracellular signal-regulated kinase (ERK) phosphorylation was not antagonized by inhibition of upstream activation with PD153035 [26].
• In vitro kinase assay using GST-c-Jun as a substrate revealed that pretreatment of PD153035 completely inhibited UV- and IL-1-induced c-Jun kinase activity in cultured keratinocytes [27].
• TSA transiently activated EGFR tyrosine phosphorylation and AKT activation in a time- and dose-dependent manner, which had been inhibited by EGFR inhibitor PD153035 and PI3 kinase inhibitor LY294002 [28].

Analytical, diagnostic and therapeutic context of Tocris-1037

• CaN19 was strongly induced after 24 h of organ culture, and its induction could be blocked by PD153035, a specific inhibitor of EGF receptor tyrosine kinase activity [29].
• Western blotting, colorimetric in vitro cell proliferation assays, and reverse transcription-polymerase chain reaction demonstrated that the EGFR inhibitor PD153035 not only blocked activation of EGFR and inhibited cell growth, but also stimulated RAR-beta expression in MDA-MB-468 breast and OVCAR-3 ovarian carcinoma cells [30].
• We used cDNA microarrays to examine alterations in gene expression after treatment of carcinoma cells with PD153035, a specific and reversible inhibitor of EGFR function [31].

References