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ABSTRACT: Abnormally elevated EGFR kinase activity can lead to various pathological states, including proliferative diseases such as cancer. The development of selective protein kinase inhibitors has become an important area of drug discovery for the potential treatment of a variety of solid tumors such as breast, ovarian and colorectal cancers, NSCLC, and carcinoma of the head and neck. There are three small molecule EGFR kinase inhibitor drugs in clinical use (gefitinib, erlotinib and lapatinib), and several others are currently undergoing clinical development. This review summarizes the development of EGFR kinase inhibitors, and includes descriptions of the binding modes, the importance of a multiple-targets strategy, the effects of sensitizing and resistance mutations in the EGFR, and molecular diagnostic approaches. In addition, the use of target fishing for selectivity profiling, off-target identification and quantitative structure-activity relationship modeling for the prediction of EGFR inhibition is discussed.
Current opinion in molecular therapeutics 07/2009; 11(3):308-21. · 3.68 Impact Factor
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Eszter Herczenik,
Zoltán Varga, Dániel Eros,
Veronika Makó,
Melinda Oroszlán,
Szabolcs Rugonfalvi-Kiss,
László Romics,
George Füst,
György Kéri,
László Orfi,
László Cervenak
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ABSTRACT: Protein kinase inhibitors (PKIs) as potent signal transduction therapeutic compounds represent a very rapidly expanding group of anticancer drugs. These agents may be toxic for endothelial cells, however, very few experimental data exist on the cytotoxicity of PKIs. The aim of this study was to set up an appropriate test system for endothelial cells and to assess the structure-related cytotoxic effects of a selected library of PKIs. The inhibitor library contains several lead molecules with different basic structures and a set of modified derivatives of the lead compounds. The toxicity of PKIs did not correlate directly with the structural features of the molecules. However, we successfully built up a model based on 15 calculated molecular descriptors, which is capable of predicting cytotoxicity with acceptable probability. Our results show that the cytotoxic effects of PKIs should be taken into account for optimal drug development to overcome endothelial cell-related side effects.
Journal of Receptor and Signal Transduction Research 02/2009; 29(2):75-83. · 1.59 Impact Factor
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ABSTRACT: Ligand-supported homology models of the human histamine H4 receptor (hH4R) were developed based on the crystal structure of bovine rhodopsin and different known H4 ligands (histamine, OUP-16, JNJ7777120). Enrichment tests were performed to analyze whether our hH4R models can select known actives from random decoys. The impact of receptor conformation and the effect of different sets of random decoys, docking methods (FlexX, FlexX-Pharm) and scoring functions (FlexX-Score, D-Score, PMF-Score, G-Score, ChemScore) were investigated. We found that two agonists (histamine and OUP-16) form complementary interactions with Asp94 (3.32), Glu182 (5.46) and Thr323 (6.55), whereas JNJ7777120 interacts with Asp94 (3.32) and Glu182 (5.46) only. These results suggest a role of Thr323 (6.55) in ligand binding and presumably also in receptor activation. The models optimized in the presence of an agonist (histamine) and an antagonist (JNJ7777120) were compared in more detail. We conclude that the ligand used in the model building process can significantly influence the efficacy of virtual screening.
European Journal of Medicinal Chemistry 06/2008; 43(5):1059-70. · 3.35 Impact Factor
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ABSTRACT: The uptake of L-arginine into mouse peritoneal macrophages can be inhibited by numerous amino acids and derivatives. Kinetic studies showed an almost entirely competitive inhibition for both cationic and neutral amino acids and derivatives suggesting that the comparison of their binding specificity by using a quantitative structure-activity relationship (QSAR) study is reasonable. The properties of the most efficient inhibitors were the following: the length of the aliphatic side chain, a general structural similarity to L-arginine (>0.79), cationic character, L-configuration, the presence of an alpha-amino group (with a mean pK(a) of 9.41), the van der Waals volume (mean 225 A(3)) and a low logP value (mean: -2.99). The significance of four other descriptors (neutral character, presence and the pK(a) of an alpha-carboxyl group, and the presence of a modified guanidino group) is much lower. Similar results were obtained for the hCAT-1 cell line, but the significance of the descriptors was slightly different. The L-configuration, van der Waals volume, the low logP value and the length of aliphatic side chain were the most significant, while the pK(a) value of the side chain (mean pK(a)=11.6) was found to be more important than that of the alpha-amino group. In addition, the general similarity to L-arginine, the presence of an amino group in the terminal position of the side chain (Orn, Lys) and the basic character were significant descriptors, while the significance of the acidity is negligibly low. As a final conclusion, the following descriptors were found to be important generally for the cationic transporters: the van der Waals volume, hydrophobicity (log P); L-configuration; the size of the side chain; the general similarity to L-arginine; the presence of an alpha-amino group; the general basicity of the molecule; the pK(a) values of the alpha-amino group (in macrophages) or that of the side chain (in CAT-1 cells). These descriptors can be regarded as the general structurally important binding characteristics of the cationic amino transporters.
Amino Acids 05/2008; 36(3):483-92. · 3.25 Impact Factor
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Rita Székely,
Frigyes Wáczek,
István Szabadkai,
Gábor Németh,
Bálint Hegymegi-Barakonyi, Dániel Eros,
Bálint Szokol,
János Pató,
Doris Hafenbradl,
Jacqueline Satchell,
Brigitte Saint-Joanis,
Stewart T Cole,
László Orfi,
Bert M Klebl,
György Kéri
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ABSTRACT: The Mycobacterium tuberculosis genome encodes for eleven eukaryotic-like Ser/Thr protein kinases. At least three of these (PknA, PknB and PknG) are essential for bacterial growth and survival. PknG is secreted by pathogenic mycobacteria, in macrophages to intervene with host cell signalling pathways and to block the fusion of the lysosomes with the phagosome by a still unknown mechanism. Based on our previously published results, we have initiated a drug discovery program, aiming to improve the potency against PknG and the physiochemical properties of the initially identified hit compound, AX20017, from the class of the tetrahydrobenzothiophenes. We have established a radioactive biochemical PknG kinase assay to test the novel analogues around AX20017. We have developed lead molecules with IC50 values in nanomolar range, and demonstrated their antituberculotic effects on human macrophages. Selected leads might ultimately serve the purpose of inducing phagosomal-lysosomal fusion and therefore destroy the residence of the intracellular mycobacteria. It is unclear at this time if these "homeless" mycobacteria are getting killed by the host, but they will be at least vulnerable to the activity of antimycobacterial agents. Released mycobacteria rely on the essential function of PknB for survival, which is our second molecular kinase target. PknB is a transmembrane protein, responsible for the cell growth and morphology. We have screened our library and synthesized novel compounds for the inhibition of PknB. A pharmacophore model was built and 70,000 molecules from our synthesizable virtual library have been screened to identify novel inhibitor scaffolds for the generation of templated compound libraries. Currently, we are using a radioactive kinase assay employing GarA as the putative, physiological substrate of PknB kinase. We have identified hits and generated optimised hit compounds with IC50 values for the inhibition of PknB in the nanomolar range. Yet those promising hits are not potent enough to yield meaningful "minimum inhibitory concentrations" in mycobacterial growth assays. In the course of our future work, we will increase the potency of the next generation of PknB inhibitors in order to improve their antibacterial activity.
Immunology Letters 04/2008; 116(2):225-31. · 2.53 Impact Factor
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ABSTRACT: The pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), is currently enjoying a renewed interest owing to its recently revealed functions. Among these its enzymatic tautomerase activity remains the most perplexing. There is a notion that some aspects of MIF signaling might involve its catalytic action. Though a true in vivo substrate for MIF has not been identified yet small molecule inhibitors of MIF are sought currently as potential anti-inflammatory agents. We have reported earlier that ketone bodies and some plant phenols feature acidic CH groups that appear to be good markers of their inhibitor potency toward MIF phenylpyruvate tautomerase. These molecules, like phenylpyruvate itself, belong to the keto-carboxylic acids or to the alpha,beta-unsaturated ketones. Some ketones of similar structure have earlier been reported to have anti-inflammatory effect. In this paper we report tautomerase inhibition by certain synthetic alpha,beta-unsaturated cyclic ketones, a novel class of small molecule MIF inhibitors.
International Immunopharmacology 01/2008; 7(13):1741-6. · 2.38 Impact Factor
