Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a systematic effort to design potent inhibitors of the anti-apoptotic tyrosine kinase BTK (Bruton's tyrosine kinase) as anti-leukemic agents with apoptosis-promoting and chemosensitizing properties, we have constructed a three-dimensional homology model of the BTK kinase domain. Our modeling studies revealed a distinct rectangular binding pocket near the hinge region of the BTK kinase domain with Leu460, Tyr476, Arg525, and Asp539 residues occupying the corners of the rectangle. The dimensions of this rectangle are approximately 18 x 8 x 9 x 17 A, and the thickness of the pocket is approximately 7 A. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domain of BTK. The lead compound LFM-A13, for which we calculated a Ki value of 1.4 microM, inhibited human BTK in vitro with an IC50 value of 17.2 +/- 0.8 microM. Similarly, LFM-A13 inhibited recombinant BTK expressed in a baculovirus expression vector system with an IC50 value of 2.5 microM. The energetically favorable position of LFM-A13 in the binding pocket is such that its aromatic ring is close to Tyr476, and its substituent group is sandwiched between residues Arg525 and Asp539. In addition, LFM-A13 is capable of favorable hydrogen bonding interactions with BTK via Asp539 and Arg525 residues. Besides its remarkable potency in BTK kinase assays, LFM-A13 was also discovered to be a highly specific inhibitor of BTK. Even at concentrations as high as 100 micrograms/ml (approximately 278 microM), this novel inhibitor did not affect the enzymatic activity of other protein tyrosine kinases, including JAK1, JAK3, HCK, epidermal growth factor receptor kinase, and insulin receptor kinase. In accordance with the anti-apoptotic function of BTK, treatment of BTK+ B-lineage leukemic cells with LFM-A13 enhanced their sensitivity to ceramide- or vincristine-induced apoptosis. To our knowledge, LFM-A13 is the first BTK-specific tyrosine kinase inhibitor and the first anti-leukemic agent targeting BTK.
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PMID:Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. 1009 45

The Hic-5 protein is encoded by a transforming growth factor-beta1- and hydrogen peroxide-inducible gene, hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains. Like paxillin, Hic-5 is localized in focal adhesion plaques in association with focal adhesion kinase in cultured fibroblasts. We carried out yeast two-hybrid screening to identify cellular factors that form a complex with Hic-5 using its LIM domains as a bait, and we identified a cytoplasmic tyrosine phosphatase (PTP-PEST) as one of the partners of Hic-5. These two proteins are associated in mammalian cells. From in vitro binding experiments using deletion and point mutations, it was demonstrated that the essential domain in Hic-5 for the binding was LIM 3. As for PTP-PEST, one of the five proline-rich sequences found on PTP-PEST, Pro-2, was identified as the binding site for Hic-5 in in vitro binding assays. Paxillin also binds to the Pro-2 domain of PTP-PEST. In conclusion, Hic-5 may participate in the regulation of signaling cascade through its interaction with distinct tyrosine kinases and phosphatases.
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PMID:Hic-5, a paxillin homologue, binds to the protein-tyrosine phosphatase PEST (PTP-PEST) through its LIM 3 domain. 1009 76

Protein phosphorylation in a human glioblastoma cell line, T98G, was examined after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of focal adhesion kinase (FAK) and serine phosphorylation of Akt at 1 h after stimulation. Concommitantly, the association of FAK with phosphatidylinositide 3'-OH-kinase (PI 3-kinase) was also observed by the hydrogen peroxide stimulation. When T98G cells were incubated with wortmannin, a PI 3-kinase inhibitor, both PI 3-kinase activity and phosphorylation of Akt were inhibited, whereas apoptosis by oxidative stress was accelerated. Concomitant with apoptosis, elevated level of CPP32 protease activity (caspase-3) was observed, with decreases in Bcl-2 protein and increases in Bax protein. These results suggested that in the signal transduction pathway from FAK to PI 3-kinase, Akt promotes survival. Thus, it became apparent that FAK is the upstream signal protein of the PI 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis in T98G cells.
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PMID:FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. 1018 51

Intense flashes of light were observed in sodium bicarbonate and hydrogen peroxide solutions when they were exposed to pulsed microwave radiation, and the response was greatly enhanced by a microwave-absorbing, biosynthesized polymer, diazoluminomelanin. A FPS-7B radar transmitter, operating at 1.25 GHz provided pulses of 5.73 +/- 0.09 micros in duration at 10.00 +/- 0.03 pulses/s with 2.07 +/- 0.08 MW forward power (mean +/- standard deviation), induced the effect but only when the appropriate chemical interaction was present. This phenomenon involves acoustic wave generation, bubble formation, pulsed luminescence, ionized gas ejection, and electrical discharge. The use of pulsed microwave radiation to generate highly focused energy deposition opens up the possibility of a variety of biomedical applications, including targeting killing of microbes or eukaryotic cells. The full range of microwave intensities and frequencies that induce these effects has yet to be explored and, therefore, the health and safety implications of generating the phenomena in living tissues remain an open question.
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PMID:Pulsed microwave induced light, sound, and electrical discharge enhanced by a biopolymer. 1023 Sep 35

Reactive oxygen species (ROS) are implicated in the pathophysiology of several vascular disorders including atherosclerosis. Although the mechanism(s) of ROS-induced vascular damage remains unclear, there is increasing evidence for ROS-mediated modulation of signal transduction pathways. Exposure of bovine pulmonary artery endothelial cells to hydrogen peroxide (H(2)O(2)) enhanced tyrosine phosphorylation of 60- to 80- and 110- to 130-kDa cellular proteins, which were determined by immunoprecipitation with specific antibodies focal adhesion kinase (p125(FAK)) and paxillin (p68). Brief exposure of cells to a relatively high concentration of H(2)O(2) (1 mM) resulted in a time- and dose-dependent tyrosine phosphorylation of FAK, which reached maximum levels within 10 min (290% of basal levels). Cytoskeletal reorganization as evidenced by the appearance of actin stress fibers preceded H(2)O(2)-induced tyrosine phosphorylation of FAK, and the microfilament disruptor cytochalasin D also attenuated the tyrosine phosphorylation of FAK. Treatment of BPAECs with 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-AM attenuated H(2)O(2)-induced increases in intracellular Ca(2+) but did not show any consistent effect on H(2)O(2)-induced tyrosine phosphorylation of FAK. Several tyrosine kinase inhibitors, including genistein, herbimycin, and tyrphostin, had no detectable effect on tyrosine phosphorylation of FAK but attenuated the H(2)O(2)-induction of mitogen-activated protein kinase activity. We conclude that H(2)O(2)-induced increases in FAK tyrosine phosphorylation may be important in H(2)O(2)-mediated endothelial cell activation.
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PMID:Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in vascular endothelial cells. 1040 42

The title compound, C11H8Br2N2O2 (LFM-A13), is the first reported BTK-specific tyrosine kinase inhibitor and the first antileukemic agent targeting BTK (Bruton's tyrosine kinase). The crystal structure showed that the molecule adopts an approximately planar conformation aided by an intramolecular hydrogen bond formed between the hydroxyl group and the amide carbonyl group. The dihedral angle between the phenyl ring and the plane defined by the N-C-C=C-CH3 group is 8.2 (6) degrees. The crystal packing shows an additional weak intermolecular hydrogen bond between the hydroxyl group and the amide carbonyl-O atom of the centrosymmetrically related molecule.
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PMID:Alpha-cyano-N-(2,5-dibromophenyl)-beta-hydroxybut-2-enamide. 1048 6

The signaling pathways critical for cell survival are mediated in part by the composition and integrity of the extracellular matrix and the action of its components on specific cell adhesion receptors. Withdrawal of anchorage-dependent epithelial cells from their association with ECM results in apoptotic cell death. Consistently, the matrix metalloproteinases (MMPs) or their inhibitors (TIMPs) have been suggested to regulate apoptosis. In this report, we investigated whether bcl-2 inhibition of apoptosis involves regulation of TIMP expression. We have found that bcl-2 overexpression induces TIMP-1 expression in breast epithelial cell lines (MCF10A, MCF10AneoT.TG3B, and MCF-7), whereas it has no effect on TIMP-2 expression. We demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin, or X-ray irradiation. In addition, TIMP-1 overexpression inhibits apoptosis after the loss of cell adhesion (anoikis) in MCF10A cells, suggesting that the antiapoptotic activity of TIMP-1 does not depend on its ability to stabilize cell-matrix interactions. We also showed that TIMP-1 overexpression is associated with constitutive activation of focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.
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PMID:Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. 1062 22

The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells. It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and MO7e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571. Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases). To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H(2)O(2)) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H(2)O(2) substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H(2)O(2) or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of MO7e cells with H(2)O(2) or pervanadate increased the tyrosine kinase activity of c-ABL. Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation.
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PMID:The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. 1083 15

The title compounds, 1-cyano-2-hydroxy-N-[4-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI492, 1-cyano-2-hydroxy-N-[3-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI493, and N-[3-bromo-4-(trifluoromethoxy)phenyl]-1-cyano-2-hydroxybut-2-e namide , C(12)H(8)BrF(3)N(2)O(3), PHI495, are potent inhibitors of Bruton's tyrosine kinase (BTK). The molecular structures of these compounds are similar and they display similar hydrogen-bonding networks and crystal packing. Examination of the crystal-packing interaction in the three compounds reveals an alternating direction of adjacent molecules in the crystalline lattice due to intermolecular cyano-amide hydrogen bonding. PHI492, a positional isomer of PHI493, does not form intermolecular O-H.O hydrogen bonds between molecules and crystallizes in a space group different from that of PHI493 and PHI495. The aromatic ring and the amide group of each molecule form a conjugated pi-system which ensures planarity, with further stabilization gained from intramolecular O-H.O hydrogen bonds.
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PMID:Three leflunomide metabolite analogs. 1102 16

The crystal structure of the title compound, C(16)H(16)N(3)O(3)(+). Cl(-).CH(4)O (WHI-P131, an inhibitor of Janus kinase 3), contains four hydrogen bonds. There are two hydrogen bonds within the asymmetric unit, i.e. interactions between WHI-P131 OH and Cl(-), and between methanol and Cl(-). There is a third interaction between WHI-P131 NH and Cl(-) (related by a 2(1) screw) and a fourth between WHI-P131 NH and methanol (related by an n-glide). The hydrogen-bond pattern for these interactions can be described by the first-level hydrogen-bond graph-set notation D(1)(1)(2)D(1)(1)(2)D(1)(1)(2)D(1)(1)(2). The second-level graph-set notation (for combinations of two hydrogen bonds) was determined to be D(1)(2)(3)D(1)(2)(3)D(2)(2)(4)D(2)(2)(9)D(2)(2)(14)C(1)(2)(9).
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PMID:An inhibitor of Janus kinase 3:4-(4-hydroxyphenylamino)-6, 7-dimethoxyquinazolin-1-ium chloride methanol solvate. 1102 27


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