Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.
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PMID:Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. 1219 40

The syntheses and biological evaluations of 4-anilinoquinoline-3-carbonitrile analogues of the three clinical lead 4-anilinoquinazolines Iressa, Tarceva, and CI-1033 are described. The EGFR and HER-2 kinase inhibitory activities and the cell growth inhibition of the two series are compared with each other and with the clinical lead EKB-569. Similar activities are observed between these two series.
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PMID:Syntheses and EGFR and HER-2 kinase inhibitory activities of 4-anilinoquinoline-3-carbonitriles: analogues of three important 4-anilinoquinazolines currently undergoing clinical evaluation as therapeutic antitumor agents. 1227 Jan 71

Erlotinib HCl (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, highly selective, reversible inhibitor of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase. Inhibition of tyrosine kinase activity prevents HER1/EGFR phosphorylation, the associated downstream signaling events, and may block tumorigenesis mediated by inappropriate HER1/EGFR signaling. In vitro and in vivo studies show that erlotinib has activity against human colorectal, head and neck, non-small cell lung, and pancreatic tumor cells. Recent preclinical studies suggest that erlotinib may also have activity against tumors that are dependent on HER2 activation for growth and/or survival. Preclinical studies have addressed the feasibility of using erlotinib in combination with various chemotherapeutic agents, radiotherapy, and targeted agents. Combining agents that have different mechanisms of action has the potential to improve efficacy and inhibit the development of resistance. For example, in preclinical studies, combining erlotinib with cisplatin, doxorubicin, gemcitabine, or low-dose paclitaxel has an additive effect on antitumor activity with no increase in toxicity. Preclinical data provide a strong rationale for investigating erlotinib in the clinical setting. However, additional studies are required to gain further insights into the processes that regulate or influence the antitumor activity of erlotinib.
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PMID:Preclinical studies with Erlotinib (Tarceva). 1284 Jul 97

Pharmacokinetic and pharmacodynamic studies have an important role in the optimization of targeted agents. Phase I pharmacokinetic studies show that treatment with erlotinib HCl (Tarceva; Genentech Inc, South San Francisco, CA), an orally available epidermal growth factor receptor (HER1/EGFR)-tyrosine kinase inhibitor, on a daily, uninterrupted schedule is feasible. Also, plasma drug concentrations, likely to be clinically effective based on preclinical studies, are consistently achieved at the recommended phase II dose of 150 mg/day, the maximum tolerated dose. Pharmacodynamic studies are in progress to assess the activation of HER1/EGFR and associated downstream signaling pathways in tissue samples from patients treated with erlotinib. Expression of p27 is identified as a potential surrogate marker of erlotinib activity, and is a focus of ongoing and future studies. Also, studies indicate that skin may be a useful surrogate tissue for evaluating the pharmacodynamic effects of therapy. These studies will hopefully enable us to accurately assess the extent of target inhibition in patients treated with erlotinib and help optimize its clinical use.
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PMID:Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of Erlotinib (Tarceva). 1284 Jul 98

Erlotinib HCI (Tarceva; Genentech, Inc, South San Francisco, CA) is an orally available, quinazoline-based agent that competes with adenosine triphosphate for binding with the intracellular catalytic domain of epidermal growth factor receptor (HER1/EGFR) tyrosine kinase, inhibiting phosphorylation. This action blocks downstream signal transduction and inhibits the tumorigenic effects associated with ligand-dependent and ligand-independent HER1/EGFR activation. In preclinical studies, erlotinib has substantial antitumor activity against various human tumor xenografts alone and in combination with chemotherapeutic drugs. Phase I data showed that erlotinib was well tolerated, with encouraging antitumor activity in patients with various types of solid tumors. Furthermore, phase II monotherapy trials in patients with advanced non-small cell lung cancer, ovarian cancer, and head and neck squamous cell cancer, respectively, show favorable activity compared with single-agent chemotherapy in similar patient populations. Phase III trials with erlotinib in non-small cell lung cancer and pancreatic cancer are in progress, as are a range of studies in various indications designed to optimize the use of erlotinib alone and in combination with chemotherapy, radiotherapy, and other targeted agents.
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PMID:Erlotinib (Tarceva): an update on the clinical trial program. 1284 Jul 99

The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new targets and prognostic indices that can direct the most appropriate choice of treatment for advanced disease. Many human tumors express high levels of growth factors and their receptors that can be used as potential therapeutical targets. Tyrosine-kinase receptors, including many growth factor receptors such the receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and Her2/neu, have been found overexpressed in urothelial tumors. For many of these growth factor receptors, the degree of expression has been associated with the progression of cancer and a poor prognosis. Among the best studied growth factor receptors are the two members of EGF receptor familiy EGFr (ErbB-1), and Her2/neu (ErbB-2). Several preclinical studies in bladder cancer models, have confirmed that systemic administration of growth factor inhibitors inhibits the growth and metastasis of human transitional cell carcinoma established in the bladder wall of athymic nude mice. Additional studies indicate that therapy with EGFR inhibitors enhances the activity of conventional cytoreductive chemotherapeutic agents, in part by inhibiting tumor cell proliferation, angiogenesis, and inducing apoptosis. Novel targeted therapy hold promise to improve the current results of bladder cancer treatment. Based on the success seen with anti-HER2 monoclonal antibodies (Herceptin) and the promising results with EGFR targeted agents (IMC-C225 Cetuximab, ZD1389 Iressa, OSI-774 Tarceva, GW 57016) in other tumor types, and based on the results obtained in preclinical models, there is a great interest in assessing these agents in patients with bladder cancer. Several trials are now ongoing testing these new agents alone or in combination with chemotherapy in bladder cancer patients. The integration of these newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression. However, the value of integration of biologically targeted agents into combined modality treatment for patients with bladder cancer has still to be proven.
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PMID:Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family. 1285 May 30

Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
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PMID:Erlotinib: preclinical investigations. 1468 18

Lung cancer is very frequent and associated with a high mortality. In the last 25 years therapeutic progress have been limited and do not allow a 5 year global survival rate exceeding to 13-14%. Tumor biology permits a better comprehension of cancerization mechanisms and offers hope of new treatments with targeted therapies which would be specific of cancer cells and so more efficient and less toxic. Epidermal growth factor (EGF) pathway and its receptor (EGFR) expressed by most lung cancer cells is the most successfully completed example. The bond of EGF with its receptor stimulates tyrosine kinase domain of EGFR and allows transduction of an activating signal. Inhibition of this signaling pathway stops tumor growth. Several agents are in development, from preclinical studies to phase III trials. It is a matter of humanized monoclonal antibodies, such as C225 (cetuximab), targeted against EGFR, or small molecules inhibiting tyrosine kinase activity of EGFR including ZD1839 (Iressa), OS1774 (Tarceva) or CI1033, and last antisense oligonucleotides. Antibodies and small molecules are well tolerated and are responsible for limited amount of side effects, mostly cutaneous toxicity and diarrhoea. Antitumor activity has been observed in monotherapy reaching up to 25% of clinical responses in the best series. EGFR inhibition seems to be also promising in combination with chemotherapy according to the synergy observed in preclinical studies and response rate up to 50% have been reported. But phase III studies have been disappointing and additional studies are warranted before consideration for a current daily practice, mostly that severe secondary effects were reported with pulmonary toxicities. In particular it remains to explain why clinical responses do not appear correlated with EGFR expression.
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PMID:[Therapeutic implications of epidermal growth factor receptor in lung cancer]. 1476 45

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

Inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity have shown promise as novel anticancer agents in a variety of common solid tumors. In preclinical studies and phase I trials, tumor responses to EGFR-TK inhibitors (EGFR-TKIs), such as gefitinib (Iressa, AstraZeneca Pharmaceuticals LP, Wilmington, DE) and erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY, and Genentech, Inc., South San Francisco, CA) were observed in heavily pretreated patients with advanced non-small cell lung cancer (NSCLC), head and neck cancer, breast cancer, colorectal cancer, and other solid tumors. Subsequent phase II studies resulted in tumor responses, disease stabilization, symptom improvement, and improved quality of life in patients with advanced NSCLC who had received prior platinum-based chemotherapy or platinum and docetaxel chemotherapies. Side effects related to treatment with EGFR-TKIs were generally mild, reversible, and noncumulative. Severity and frequency of drug-related adverse events were related directly to dose. The potential role of EGFR-TKIs in treating other solid tumors currently is being studied. Furthermore, research is being conducted to explore the potential use of EGFR-TKIs in novel combinations with chemotherapy, radiation therapy, endocrine therapy, and other molecular targeted therapies.
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PMID:Epidermal growth factor receptor tyrosine kinase inhibitors: evolving role in the treatment of solid tumors. 1510 18


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