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PD153035 hydrochloride

Potent EGFR inhibitor CAS# 153436-54-5

PD153035 hydrochloride

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Chemical structure

PD153035 hydrochloride

3D structure

Chemical Properties of PD153035 hydrochloride

Cas No. 153436-54-5 SDF Download SDF
PubChem ID 4705 Appearance Powder
Formula C16H14BrN3O2 M.Wt 360.2
Type of Compound N/A Storage Desiccate at -20°C
Synonyms ZM 252868; Tyrphostin AG 1517; AG 1517; SU 5271
Solubility DMSO : 33.33 mg/mL (92.53 mM; Need ultrasonic)
Chemical Name N-(3-bromophenyl)-6,7-dimethoxyquinazolin-4-amine
SMILES COC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=CC=C3)Br)OC
Standard InChIKey LSPANGZZENHZNJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C16H14BrN3O2/c1-21-14-7-12-13(8-15(14)22-2)18-9-19-16(12)20-11-5-3-4-10(17)6-11/h3-9H,1-2H3,(H,18,19,20)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PD153035 hydrochloride

DescriptionPD153035 is a potent and specific inhibitor of EGFR with Ki and IC50 of 5.2 pM and 29 pM.
TargetsEGFREGFR    
IC505.2 pM (Ki)29 pM    

Protocol

Cell Assay [3]
Different EGF receptor-overexpressing cell lines (A43 1, Difi, MDA-MB-468, MDA-MB-231, DU145, SiHa, C4i, and MEl 80) are treated with PD153035 at increasing concentrations of 0.125-2.5 p.M. Growth inhibitory effect in monolayer cell culture is assessed[3].

Animal Administration [3]
Mice: Mice are injected with PD153035 (80 mg/kg) or vehicle and rumors are excised at 20 minutes and 180 minutes and extracts are prepared. Two mice are used for each time point and the experiment is repeated four times. Within each of the four experiments ANOVA is used to compare the inhibition by PD 153035 of the EGF-stimulation[3].

References:
[1]. Bridges AJ, et al. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem. 1996 Jan 5;39(1):267-76. [2]. Fry DW, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science. 1994 Aug 19;265(5175):1093-5. [3]. Bos M, et al. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptoractivation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106. [4]. Kunkel MW, et al. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs. 1996;13(4):295-302.

PD153035 hydrochloride Dilution Calculator

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PD153035 hydrochloride Molarity Calculator

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Preparing Stock Solutions of PD153035 hydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7762 mL 13.8812 mL 27.7624 mL 55.5247 mL 69.4059 mL
5 mM 0.5552 mL 2.7762 mL 5.5525 mL 11.1049 mL 13.8812 mL
10 mM 0.2776 mL 1.3881 mL 2.7762 mL 5.5525 mL 6.9406 mL
50 mM 0.0555 mL 0.2776 mL 0.5552 mL 1.1105 mL 1.3881 mL
100 mM 0.0278 mL 0.1388 mL 0.2776 mL 0.5552 mL 0.6941 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on PD153035 hydrochloride

PD153035 (4-(3-Bromoanilino)-6,7-dimethoxyquinazoline) is an extremely potent epidermal growth factor receptor (EGFR) inhibitor that competitively binds at the ATP site with the half maximal inhibition concentration IC50 of 0.025 nM resulting in the inhibition of the tyrosine kinase activity of the EGFR [1].

PD153035 has been found to inhibit EGF-dependent EGFR phosphorylation in a variety of human cancer cell lines over-expressing EGFRs, which include A431, Difi, DU145, MDA-MB-468, ME180 and C4i, with IC50 of 0.22 μM, 0.3 μM, 0.4 μM, 0.68 μM, 0.95 μM and 2.5 μM respectively leading to suppression of proliferation and clonogenicity in those cell lines [2].

Besides exerting potent inhibition against EGFRs, PD153035 also inhibits the closely related HER2/neu receptor but to a lesser degree [2].

References:
[1] Bridges AJ, Zhou H, Cody DR, Rewcastle GW, McMichael A, Showalter HD, Fry DW, Kraker AJ, Denny WA. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem. 1996 Jan 5;39(1):267-76.
[2] Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106.

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References on PD153035 hydrochloride

A novel hybrid peptide targeting EGFR-expressing cancers.[Pubmed:21112771]

Eur J Cancer. 2011 Mar;47(5):773-83.

Several potential molecular-targeted anticancer drugs focus on the inhibition of receptor tyrosine kinase and tumour growth, but these tyrosine kinase inhibitors (TKI) have been reported that the mutations of kinase-related signal molecule genes in cancer cells lead to the drug resistance. To overcome this issue, we have designed a novel targeting anticancer 'hybrid-peptide' EGFR-lytic peptide, in which epidermal growth factor receptor (EGFR) binding peptide is conjugated with a newly designed lytic-type peptide containing cationic-rich amino acids that disintegrates the cell membrane to kill cancer cells. In this report, cytotoxic activity of EGFR-lytic peptide was investigated in various human cancer and normal cell lines. It was found that the resulting conformational change in the novel lytic peptide enabled it to bind selectively to the membrane of cancer cells, and due to its acquired synergistic action, hybrid peptide demonstrated selective destruction of cancer cells as swiftly as 10 min after exposure. Treatment with EGFR-lytic peptide exerted a sufficient in vitro cytotoxic activity against TKI-resistant cancer cells with K-ras mutations. Moreover, in vivo analyses revealed that this peptide displayed significant antitumour activity in mouse xenograft models of both human K-ras mutation negative and positive cancers. Thus, hybrid peptide can be a unique and powerful tool for a new cancer-targeted therapy.

Gefitinib, but not erlotinib, is a possible inducer of Fra-1-mediated interstitial lung disease.[Pubmed:23324306]

Keio J Med. 2012;61(4):120-7.

Gefitinib is an anticancer drug developed to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Two structurally-related EGFR tyrosine kinase inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), are used as oral chemotherapy by patients with non-small-cell lung cancer. Immediately after introduction of gefitinib to clinical practice, interstitial lung disease was identified as a life-threatening adverse effect, although this condition can be well managed. It is still unclear whether gefitinib and other EGFR inhibitors induce similar adverse effects in lung. We previously established mouse models of interstitial lung disease in which gefitinib induces expression of Fosl1 (which encodes the AP-1 transcription factor Fra-1) in the presence of exogenous or endogenous Toll-like receptor ligands, leading to abnormal cytokine and chemokine expression. Here, we compared and monitored the effects of EGFR inhibitors gefitinib, erlotinib and AG1517 (PD153035) on the mRNA expression levels of Fosl1, Tnf and Ccl2. Unexpectedly, gefitinib, but not the other tyrosine kinase inhibitors, elicited the Fosl1 expression profile proposed to be predictive of interstitial lung disease, suggesting that gefitinib-induced interstitial lung disease is an off-target effect not elicited by erlotinib.

Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.[Pubmed:22393153]

J Immunol. 2012 Apr 1;188(7):3513-21.

Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. In this study, we show that erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), reduces the severity of established collagen-induced arthritis, a mouse model of RA, and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with collagen-induced arthritis and patients with RA. Taken together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefits in the treatment of RA.

Tyrosine kinase inhibitors influence ABCG2 expression in EGFR-positive MDCK BCRP cells via the PI3K/Akt signaling pathway.[Pubmed:22354538]

ChemMedChem. 2012 Apr;7(4):650-62.

Multidrug resistance observed in cancer chemotherapy is commonly attributed to overexpression of efflux transporter proteins. These proteins act as ATP-dependent drug efflux pumps, actively extruding chemotherapeutic agents from cells and causing a decrease in intracellular drug accumulation. Besides the well-recognized role of P-glycoprotein (P-gp, ABCB1), the breast cancer resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an important role in multidrug resistance. In contrast to P-glycoprotein, only a few inhibitors of ABCG2 are known. According to the literature, tyrosine kinase inhibitors (TKIs) can be considered to be broad-spectrum inhibitors, interacting with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs, gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR inhibitors such as gefitinib and PD158780 reduced both total and surface expression of ABCG2 in EGRF-positive MDCK BCRP cells by interaction with the PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect of XR9577, a well-known ABCG2 modulator, lowering the concentration required for half maximal inhibition. On the other hand, BCR-ABL inhibitors had no influence on ABCG2 expression and modulator activity. Interestingly, a combination of an EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant reduction of ABCG2 expression at low concentrations of the drugs. Based on our results, we assume that EGFR exerts a post-transcriptional enhancing effect on ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression with EGFR inhibitors, combined with the inhibition of ABCG2 with potent modulators might be a promising approach to circumvent MDR in cancer cells.

Description

PD153035 (SU-5271; AG1517; ZM 252868) is a potent EGFR inhibitor with Ki and IC50 of 6 and 25 pM, respectively.

Keywords:

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