Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and c-erbB-2

Cockerill, Stuart; Stubberfield, Colin R.; Stables, Jeremy N.; Carter, Malcolm; Guntrip, Stephen B.; Smith, Kathryn J.; McKeown, Steve C.; Shaw, R. J.; Topley, Peter; Thomsen, Lindy L.; Affleck, Karen; Jowett, Amanda; Hayes, D. Neil; Willson, Malcolm; Woollard, P.M.; Spalding, David J.

doi:10.1016/s0960-894x(01)00219-0

Cited by 76 publications

(57 citation statements)

References 8 publications

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“…It is therefore tempting to speculate that enhanced signaling through p95 ErbB2 -containing receptor complexes plays a role in metastatic progression. We now show that GW572016, a reversible inhibitor of ErbB2 and EGFR tyrosine kinases (Cockerill et al, 2001), blocks p95 ErbB2 phosphorylation in breast cancer cell lines and tumor xenografts, whereas trastuzumab has no effect. In contrast to the full-length receptor, p95 ErbB2 almost exclusively associates with ErbB3 compared with EGFR, providing an explanation for the activation of p95 ErbB2 and ErbB3 by HRG.…”

Section: Introductionmentioning

confidence: 71%

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Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

et al. 2004

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The expression of the NH 2 terminally truncated ErbB2 receptor (p95 ErbB2 ) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185 ErbB2 . We now show that heregulin (HRG), but not EGF, stimulates p95 ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phosphop95 ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185 ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95 ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95 ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95 ErbB2 , p185 ErbB2 , and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95 ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95 ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95 ErbB2 -expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95 ErbB2 -ErbB3 heterodimers. Thus, p95 ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.

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Section: Introductionmentioning

confidence: 71%

“…Alexa Fluor680 goat anti-rabbit IgG was obtained from Molecular Probes (Eugene, OR, USA). GW572016, N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}-methyl)-2-furyl]-4-quinazolinamine, was synthesized as previously described (Cockerill et al, 2001). GW572016 for cell culture work was dissolved in DMSO.…”

Section: Methodsmentioning

confidence: 99%

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

et al. 2004

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“…Unlike lapatinib, which is a reversible inhibitor that competes with ATP at the binding sites (13), most pan-HER inhibitors bind to the kinases in a covalent and irreversible form (14,15). It is hypothesized that the prolonged suppression of multiple targets within the HER receptor family may overcome the problems with adaptability and redundancy in signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and Lapatinib

Kalous

Conklin

Desai

et al. 2012

Molecular Cancer Therapeutics

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The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC 50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G 0 -G 1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978-87. Ó2012 AACR.

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“…[27][28][29][30][31] Some compounds are reported to have an anti-inflammatory activity mainly due to interfering with inflammatory enzymes. Therefore, further experiments concerning the effects of TAS-3-124 on the activity of inflammatory enzymes will be necessary in the future.…”

Section: Discussionmentioning

confidence: 99%

The Effect of a Newly Synthesized Indazole Compound, TAS-3-124, on Experimental Autoimmune Disease

Akabane

Miyagawa

Nii

et al. 2004

Biological & Pharmaceutical Bulletin

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Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and c-erbB-2

Cited by 76 publications

References 8 publications

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and Lapatinib

The Effect of a Newly Synthesized Indazole Compound, TAS-3-124, on Experimental Autoimmune Disease

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