The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Yuji Iizawa - One of the best experts on this subject based on the ideXlab platform.
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Combination of Imipenem and TAK-242, a Toll-Like Receptor 4 Signal Transduction Inhibitor, Improves Survival in a Murine Model of Polymicrobial Sepsis
Shock (Augusta Ga.), 2011Co-Authors: Takukyu Sha, Yuji Iizawa, MasayukiAbstract:Sepsis is characterized by an excessive host response to infection. Toll-like receptors (TLRs) are essential for triggering this type of host immune response. Toll-like receptor 4 mediates recognition of LPS from gram-negative bacteria and is an important initiator of sepsis. In the present study, we evaluated the efficacy of TAK-242, a novel TLR4 Signal Transduction Inhibitor, in a murine cecal ligation and puncture (CLP) model. Treatment with TAK-242 (10 mg/kg i.v.) in combination with imipenem (1 mg/kg s.c.) 1 h after CLP significantly increased the survival rates of mice from 17% to 50% (P ≤ 0.01) and suppressed CLP-induced increases in serum levels of IL-1[beta], IL-6, IL-10, and macrophage inflammatory protein 2 by 64%, 73%, 79%, and 81%, respectively (P ≤ 0.025). Additionally, coadministration of TAK-242 with imipenem after CLP significantly inhibited CLP-induced decreases in blood platelet counts by 37% (P ≤ 0.025) and increases in serum levels of alanine aminotransferase by 32% (P ≤ 0.025) and blood urea nitrogen by 43% (P ≤ 0.025). TAK-242 at a dose of 10 mg/kg had no effect on bacterial counts in blood, suggesting that it does not affect blood bacteria spread. These results indicate that TAK-242 shows therapeutic effects in murine polymicrobial sepsis, and it may be a potential therapeutic agent for the treatment of sepsis.
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analysis of binding site for the novel small molecule tlr4 Signal Transduction Inhibitor tak 242 and its therapeutic effect on mouse sepsis model
British Journal of Pharmacology, 2009Co-Authors: Katsunori Takashima, Naoko Matsunaga, M Yoshimatsu, Kaoru Hazeki, Tsuneyasu Kaisho, M Uekata, Osamu Hazeki, Shizuo Akira, Yuji IizawaAbstract:Background and purpose: TAK-242, a novel synthetic small-molecule, suppresses production of multiple cytokines by inhibiting Toll-like receptor (TLR) 4 Signalling. In this study, we investigated the target molecule of TAK-242 and examined its therapeutic effect in a mouse sepsis model. Experimental approach: Binding assay with [3H]-TAK-242 and nuclear factor-κB reporter assay were used to identify the target molecule and binding site of TAK-242. Bacillus calmette guerin (BCG)-primed mouse sepsis model using live Escherichia coli was used to estimate the efficacy of TAK-242 in sepsis. Key results: TAK-242 strongly bound to TLR4, but binding to TLR2, 3, 5, 9, TLR-related adaptor molecules and MD-2 was either not observed or marginal. Mutational analysis using TLR4 mutants indicated that TAK-242 inhibits TLR4 Signalling by binding to Cys747 in the intracellular domain of TLR4. TAK-242 inhibited MyD88-independent pathway as well as MyD88-dependent pathway and its Inhibitory effect was largely unaffected by lipopolysaccharide (LPS) concentration and types of TLR4 ligands. TAK-242 had no effect on the LPS-induced conformational change of TLR4-MD-2 and TLR4 homodimerization. In mouse sepsis model, although TAK-242 alone did not affect bacterial counts in blood, if co-administered with ceftazidime it inhibited the increases in serum cytokine levels and improved survival of mice. Conclusions and implications: TAK-242 suppressed TLR4 Signalling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. When co-administered with antibiotics, TAK-242 showed potent therapeutic effects in an E. coli-induced sepsis model using BCG-primed mice. Thus, TAK-242 may be a promising therapeutic agent for sepsis.
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therapeutic effects of tak 242 a novel selective toll like receptor 4 Signal Transduction Inhibitor in mouse endotoxin shock model
European Journal of Pharmacology, 2007Co-Authors: Takukyu Sha, Mie Sunamoto, Tomoyuki Kitazaki, Jun Sato, Yuji IizawaAbstract:Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated Signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage Inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
Sreenath V Sharma - One of the best experts on this subject based on the ideXlab platform.
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UCS15A, a novel small molecule, SH3 domain-mediated protein–protein interaction blocking drug
Oncogene, 2002Co-Authors: Chitose Oneyama, Hirofumi Nakano, Sreenath V SharmaAbstract:Protein–protein interactions play critical regulatory roles in mediating Signal Transduction. Previous studies have identified an unconventional, small-molecule, Src Signal Transduction Inhibitor, UCS15A. UCS15A differed from conventional Src-Inhibitors in that it did not alter the levels or the tyrosine kinase activity of Src. Our studies suggested that UCS15A exerted its Src-Inhibitory effects by a novel mechanism that involved the disruption of protein–protein interactions mediated by Src. In the present study we have examined the ability of UCS15A to disrupt the interaction of Src–SH3 with Sam68, both in vivo and in vitro . This ability of UCS15A was not restricted to Src–SH3 mediated protein–protein interactions, since the drug was capable of disrupting the in vivo interactions of Sam68 with other SH3 domain containing proteins such as Grb2 and PLCγ. In addition, UCS15A was capable of disrupting other typical SH3-mediated protein–protein interactions such as Grb2–Sos1, cortactin–ZO1, as well as atypical SH3-mediated protein–protein interactions such as Grb2–Gab1. However, UCS15A was unable to disrupt the non-SH3-mediated protein–protein interactions of β-catenin, with E-cadherin and α-catenin. In addition, UCS15A had no effect on the SH2-mediated interaction between Grb2 and activated Epidermal Growth Factor receptor. Thus, the ability of UCS15A, to disrupt protein–protein interactions appeared to be restricted to SH3-mediated protein–protein interactions. In this regard, UCS15A represents the first example of a non-peptide, small molecule agent capable of disrupting SH3-mediated protein–protein interactions. In vitro analyses suggested that UCS15A did not bind to the SH3 domain itself but rather may interact directly with the target proline-rich domains.
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UCS15A, a non-kinase Inhibitor of Src Signal Transduction
Oncogene, 2001Co-Authors: Sreenath V Sharma, Chitose Oneyama, Yoshinori Yamashita, Hirofumi Nakano, Katsura Sugawara, Masako Hamada, Nobuo Kosaka, Tatsuya TamaokiAbstract:Src tyrosine kinase plays key roles in Signal Transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-Signal Transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule Inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-Signal Transduction Inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-Inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-Inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro . These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src Signal Transduction pathway.
Darryl L. Hadsell - One of the best experts on this subject based on the ideXlab platform.
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New Mechanisms of Signal Transduction Inhibitor Action
Clinical Cancer Research, 2003Co-Authors: Adrian V. Lee, Rachel Schiff, Xiaojiang Cui, Deepali Sachdev, Douglas Yee, Andrew P. Gilmore, Charles H. Streuli, Steffi Oesterreich, Darryl L. HadsellAbstract:The explosion of Signal Transduction research over the last 10 years has provided a unique insight into the complexity of these intricate pathways. Whereas intermediates of multiple Signaling pathways have been identified, understanding their function and, in particular, the interactions between them has become a daunting task. The increasing evidence that many of these pathways can cross-talk with each other via Signal transactivation inevitably raises the question of how cells determine specificity in Signaling. Despite the mind-numbing complexity of these pathways, progress has been made in developing highly specific and potent Signal Transduction Inhibitors (STIs). STIs show promise in the treatment of cancer in preclinical studies and are currently in a number of clinical trials. Whereas many of these agents were “rationally designed,” we barely understand their mechanisms of action. This review will highlight how recent studies using these STIs have elucidated novel mechanisms of STI action that may be used in the development of new therapeutic strategies for the treatment of cancer.
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New mechanisms of Signal Transduction Inhibitor action: receptor tyrosine kinase down-regulation and blockade of Signal transactivation.
Clinical Cancer Research, 2003Co-Authors: Adrian V. Lee, Rachel Schiff, Xiaojiang Cui, Deepali Sachdev, Douglas Yee, Andrew P. Gilmore, Charles H. Streuli, Steffi Oesterreich, Darryl L. HadsellAbstract:The explosion of Signal Transduction research over the last 10 years has provided a unique insight into the complexity of these intricate pathways. Whereas intermediates of multiple Signaling pathways have been identified, understanding their function and, in particular, the interactions between them has become a daunting task. The increasing evidence that many of these pathways can cross-talk with each other via Signal transactivation inevitably raises the question of how cells determine specificity in Signaling. Despite the mind-numbing complexity of these pathways, progress has been made in developing highly specific and potent Signal Transduction Inhibitors (STIs). STIs show promise in the treatment of cancer in preclinical studies and are currently in a number of clinical trials. Whereas many of these agents were “rationally designed,” we barely understand their mechanisms of action. This review will highlight how recent studies using these STIs have elucidated novel mechanisms of STI action that may be used in the development of new therapeutic strategies for the treatment of cancer.
Tatsuya Tamaoki - One of the best experts on this subject based on the ideXlab platform.
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UCS15A, a non-kinase Inhibitor of Src Signal Transduction
Oncogene, 2001Co-Authors: Sreenath V Sharma, Chitose Oneyama, Yoshinori Yamashita, Hirofumi Nakano, Katsura Sugawara, Masako Hamada, Nobuo Kosaka, Tatsuya TamaokiAbstract:Src tyrosine kinase plays key roles in Signal Transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-Signal Transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule Inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-Signal Transduction Inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-Inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-Inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro . These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src Signal Transduction pathway.
Chitose Oneyama - One of the best experts on this subject based on the ideXlab platform.
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UCS15A, a novel small molecule, SH3 domain-mediated protein–protein interaction blocking drug
Oncogene, 2002Co-Authors: Chitose Oneyama, Hirofumi Nakano, Sreenath V SharmaAbstract:Protein–protein interactions play critical regulatory roles in mediating Signal Transduction. Previous studies have identified an unconventional, small-molecule, Src Signal Transduction Inhibitor, UCS15A. UCS15A differed from conventional Src-Inhibitors in that it did not alter the levels or the tyrosine kinase activity of Src. Our studies suggested that UCS15A exerted its Src-Inhibitory effects by a novel mechanism that involved the disruption of protein–protein interactions mediated by Src. In the present study we have examined the ability of UCS15A to disrupt the interaction of Src–SH3 with Sam68, both in vivo and in vitro . This ability of UCS15A was not restricted to Src–SH3 mediated protein–protein interactions, since the drug was capable of disrupting the in vivo interactions of Sam68 with other SH3 domain containing proteins such as Grb2 and PLCγ. In addition, UCS15A was capable of disrupting other typical SH3-mediated protein–protein interactions such as Grb2–Sos1, cortactin–ZO1, as well as atypical SH3-mediated protein–protein interactions such as Grb2–Gab1. However, UCS15A was unable to disrupt the non-SH3-mediated protein–protein interactions of β-catenin, with E-cadherin and α-catenin. In addition, UCS15A had no effect on the SH2-mediated interaction between Grb2 and activated Epidermal Growth Factor receptor. Thus, the ability of UCS15A, to disrupt protein–protein interactions appeared to be restricted to SH3-mediated protein–protein interactions. In this regard, UCS15A represents the first example of a non-peptide, small molecule agent capable of disrupting SH3-mediated protein–protein interactions. In vitro analyses suggested that UCS15A did not bind to the SH3 domain itself but rather may interact directly with the target proline-rich domains.
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UCS15A, a non-kinase Inhibitor of Src Signal Transduction
Oncogene, 2001Co-Authors: Sreenath V Sharma, Chitose Oneyama, Yoshinori Yamashita, Hirofumi Nakano, Katsura Sugawara, Masako Hamada, Nobuo Kosaka, Tatsuya TamaokiAbstract:Src tyrosine kinase plays key roles in Signal Transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-Signal Transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule Inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-Signal Transduction Inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-Inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-Inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro . These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src Signal Transduction pathway.