Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

• MeSH
• erbB receptory antagonisté a inhibitory   chemie   genetika   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• mutace MeSH
• racionální návrh léčiv metody   MeSH
• rozhodování MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• Giotrif,
• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• afatinib MeSH
• chinazoliny * aplikace a dávkování   škodlivé účinky   MeSH
• erbB receptory * antagonisté a inhibitory   chemie   MeSH
• exantém chemicky indukované   MeSH
• indukce remise MeSH
• lidé MeSH
• nádory plic * farmakoterapie   genetika   MeSH
• průjem chemicky indukované   MeSH
• senioři nad 80 let MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations. Samples from xenopatients that responded to cetuximab, an anti-EGFR agent, with disease stabilization displayed high levels of EGFR family ligands and receptors, indicating high EGFR pathway activity. Five of 21 SD models (23.8%) characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small-molecule inhibitor. In addition, a subset of cases in which enhanced EGFR inhibition was unproductive (6 of 16, 37.5%) exhibited marked overexpression of insulin-like growth factor 2 (IGF2). Enrichment of IGF2 overexpressors among cases with SD was demonstrated in the entire xenopatient collection and was confirmed in patients by mining clinical gene expression data sets. In functional studies, IGF2 overproduction attenuated the efficacy of cetuximab. Conversely, interception of IGF2-dependent signaling in IGF2-overexpressing xenopatients potentiated the effects of cetuximab. The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.

• MeSH
• cetuximab MeSH
• chemorezistence MeSH
• erbB receptory chemie   MeSH
• exony MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• imunohistochemie MeSH
• insulinu podobný růstový faktor II chemie   MeSH
• klinické zkoušky jako téma MeSH
• kolorektální nádory farmakoterapie   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• mutace MeSH
• myši MeSH
• nádorové biomarkery metabolismus   MeSH
• protinádorové látky terapeutické užití   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A small molecule EGFR inhibitor, 4-(2-(3-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)ureido)vinyl)-1,2-phenylene diacetate (CIU1) was designed in silico by using caffeic scaffold as core structure. The designed compound showed anti-proliferative action against different solid tumor cell lines, particularly metastatic breast cancer cells. CIU1 inhibited the growth of EGFR-overexpressing MDA-MB-468 triple-negative breast cancer cells and wild-type non-small-cell lung cancer H460 cells with IC50 values of 8.96 μM and 12.98 μM, respectively, these anti-proliferative effects of CIU1 were comparable to gefitinib (a specific EGFR inhibitor) or lapatinib (a dual EGFR and HER2 tyrosine kinase inhibitor). Interestingly CIU1 effectively inhibited the invasive hormone-dependent MCF-7 cancer cells with an IC50 2.34 μM. The immunoblot analyses revealed that CIU1 induced programmed cell death and suppressed EGFR expression in EGFR-overexpressing breast cancer (MDA-MB468) and lung cancer (PC-9) cells. The findings substantiated our design strategy and demonstrated the potential of CIU1 as new lead for further optimization in the development of anticancer drugs against advanced solid tumors.

• MeSH
• erbB receptory antagonisté a inhibitory   chemie   MeSH
• kyseliny kávové chemie   MeSH
• metastázy nádorů MeSH
• molekulární modely MeSH
• molekulární sondy - techniky MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• proliferace buněk MeSH
• triple-negativní karcinom prsu farmakoterapie   MeSH
• Publikační typ
• hodnotící studie MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Competitive binding assays can be used to decipher not only the binding kinetics of studied ligands but also the binding site preference. Such assays are an essential step in the characterization of radioligands. However, the currently used competition assays require high concentrations of usually expensive ligands and still provide only binding site preference. By employing the time-resolved competition assay presented in this paper, binding characteristics including binding site preference can be obtained using less ligand. METHODS: To demonstrate the appropriateness of the time-resolved competition assay, we developed an assay in which the ligand binding was interrupted with a competitor. Experiments were performed on human carcinoma cell lines expressing epidermal growth factor receptor (EGFR). The targeting of the receptor was performed with radio-iodinated epidermal growth factor (EGF). The employed competitors involved either natural ligand transforming growth factor alpha (TGF-α) or anti-EGFR antibodies cetuximab and panitumumab targeting the same EGFR domain. RESULTS: Radio-iodinated EGF bound to EGFR was displaced with either low concentrations of cetuximab or high concentrations of panitumumab. In the case of TGF-α, we observed no competitive displacement of bound EGF at either high or low concentrations. When comparing the time-resolved competition assay with a manual competition assay, the resulting data of measured inhibition constants were in agreement. DISCUSSION: The results summarised in this study confirm the appropriateness of the time-resolved competition assay for assessing ligand binding properties. The assay has the potential to complement or replace conventional competition assays for determining binding site preference in the future.

• MeSH
• časové faktory MeSH
• epidermální růstový faktor chemie   metabolismus   MeSH
• erbB receptory antagonisté a inhibitory   chemie   metabolismus   MeSH
• humanizované monoklonální protilátky chemie   farmakologie   MeSH
• kompetitivní vazba účinky léků   MeSH
• lidé MeSH
• ligandy MeSH
• monoklonální protilátky chemie   farmakologie   MeSH
• nádorové buňky kultivované MeSH
• substrátová specifita MeSH
• transformující růstový faktor alfa chemie   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The presence of activating mutations within the tyrosine kinase domain of the epidermal growth factor receptor gene has been attributed to a positive response to biological therapy of lung cancer by small-molecular tyrosine kinase inhibitors, gefitinib and erlotinib. Among the two most significant mutation types are deletions in exon 19 and a single point substitution in exon 21 (termed L858R). The exon 19 deletions can readily be examined by fragment analysis, due to the characteristic length difference between the normal and mutated PCR product. Analysis of the L858R point mutation, however, presents a greater challenge. The current paper is aimed at developing a sensitive, yet simple, low-cost mutation detection assay directed at the L858R mutation using a method based on CE of heteroduplexes under partial denaturing conditions. We perform optimization of separation conditions on different commercial instruments including ones equipped with 8, 16 and 96 capillaries. We present normalized migration reproducibility in the range from 1 (8 and 16) to 5% (96) RSD. A reliable distinction of the R836R silent polymorphism from a potential presence of the L858R mutation is also demonstrated. In its implementation, the presented assay is just another application running on a conventional CE platform without the need of dedicated instrumentation.

• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• automatizace MeSH
• bodová mutace genetika   MeSH
• chinazoliny farmakologie   MeSH
• denaturace nukleových kyselin MeSH
• elektroforéza kapilární přístrojové vybavení   metody   MeSH
• erbB receptory antagonisté a inhibitory   chemie   genetika   MeSH
• exony genetika   MeSH
• farmakogenetika MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• mutační analýza DNA přístrojové vybavení   MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• výsledek terapie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Receptory pro epidermální růstové faktory (c-erbB/HER) zahrnují receptor pro epidermální růstový faktor (c-erbB-1/EGFR/HER-1) a tři další homologa; c-erbB-2-4/HER-2-4. Tento receptorový systém hraje zásadní roli v regulaci apoptózy, migrace, invazivity a metastázování, proliferace, adhezivity a diferenciace buněk. Změny exprese těchto receptorů jsou spojeny se špatnou prognózou četných nádorů. Z důvodu pochopení jejich významu v nádorové biologii a pro využití těchto receptorů jako míst cíleného terapeutického zásahu probíhá v současné době jejich intenzivní výzkum. V klinické praxi se začíná využívat řada specifických i nespecifických inhibitorů.

The epidermal growth factor receptor (c-erbB/HER) system comprises the epidermal growth factor receptor (c-erbB-1/EGFR/HER-1) and three other homologues c-erbB-2-4/HER-2-4. This receptor system plays a critical role in apoptosis, migration, cell invasivity and metastasis, proliferation, adhezivity and differentiation of the cells. Changes of statut this receptors has been associated with poor prognosis in cancer of numerous tumors. Recently, these receptors have been intensely studied to understand is their importance in cancer biology and as therapeutic targets, and many specific and non-specific c-erbB inhibitors are developed for use.

• MeSH
• erbB receptory analýza   genetika   chemie   MeSH
• finanční podpora výzkumu jako téma MeSH
• interakce mezi receptory a ligandy imunologie   účinky léků   MeSH
• invazivní růst nádoru genetika   imunologie   patofyziologie   MeSH
• lidé MeSH
• metastázy nádorů genetika   imunologie   patofyziologie   MeSH
• monoklonální protilátky aplikace a dávkování   imunologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Biologická léčba při ovlivňování přirozených regulačních mechanismů řídících metabolismus, proliferaci a migraci nádorových buněk využívá nízkomolekulární preparáty, makromolekuly i buněčné efektory imunitního typu. V současnosti je nejvíce mformaci o ovlivnění receptoru pro epidermální růstový faktor (epidermal growth factor receptor = EGFR). Velmi intenzivně je zkoumána možnost inhibice intracelulární domény EGF receptoru s tyrozinkinázovou aktivitou. Jedna se o terapeutický přístup na subcelulární úrovni. Tato onkologická léčba je cílená (tzv. „targeted") na nitrobuněčné mechanismy přenosu signálu, který vyvolává změny proliferační aktivity nádorových buněk. Ve svém sdělení se autorky zabývají různými možnostmi ovlivnění EGFR a uplatněním v klinické praxi.

To influence natural regulatory mechanisms, which control the metabolism, proliferation and migration of tumour cells, biological therapy resorts to low-molecular preparations, macromolecules and cellular immune-type effectors. Today we have primarily information on the influencing of the epidermal growth factor receptor - EGFR. Research concentrates abcbove all on the possibility of inhibiting the intracelular domains of the EGF receptor that has a tyrosinekinase activity. This oncological treatment targets intracellular mechanisms of the transfer of the signal that calls forth changes in the proliferation activity of tumour cells. In their paper the authors discuss various possibilities of influencing EGFR and their application in clinical practice.

• Klíčová slova
• ZD 1839, OSI-774,
• MeSH
• bronchogenní karcinom farmakoterapie   MeSH
• cetuximab MeSH
• erbB receptory antagonisté a inhibitory   chemie   MeSH
• lidé MeSH
• monoklonální protilátky farmakologie   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• signální transdukce MeSH
• trastuzumab MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH