TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family, participates in proinflammatory cellular signaling pathways by activating JNK/p38 MAPKs and NF-B. To identify drugs that prevent inflammation, we screened inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone of fungal origin, 5Z-7-oxozeaenol, as a highly potent inhibitor of TAK1. This compound did not effectively inhibit the catalytic activities of the MEKK1 or ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1. In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of TAK1, JNK/ p38 MAPK, IB kinases, and NF-B, resulting in inhibition of cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to inhibit picryl chlorideinduced ear swelling. Thus, 5Z-7-oxozeaenol blocks proinflammatory signaling by selectively inhibiting TAK1 MAPKKK.TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) 1 family that phosphorylates and activates MKK3, MKK4, MKK6, and MKK7 MAPKKs, which in turn activate the c-Jun N-terminal kinase (JNK) and p38 MAPKs (1-3). We have recently demonstrated that TAK1 also activates IB kinases (IKKs), ultimately leading to activation of the transcription factor NF-B (4). TAK1 participates in proinflammatory cellular signaling pathways such as the interleukin-1 (IL-1) pathway by activating both JNK/p38 MAPKs and IKKs. Exposure of cells to IL-1 induces the interaction between endogenous TAK1 and TRAF6 (tumor necrosis factor (TNF) receptor-associated factor 6), a molecule essential for IL-1 activation of both JNK/p38 and NF-B. This interaction in turn leads to TAK1 activation. We have previously identified two TAK1-binding proteins, TAB1 and TAB2 (5, 6). When ectopically co-expressed, TAB1 augments the kinase activity of TAK1, indicating that TAB1 functions as an activator of TAK1 (5, 7). TAB2 functions as an adaptor linking TAK1 to TRAF6 by directly binding to both, thereby mediating TAK1 activation in the IL-1 signaling pathway (6,8).Several lines of evidence suggest that TAK1 is a key molecule in proinflammatory signaling pathways. Various proinflammatory cytokines and endotoxins activate the kinase activity of endogenous TAK1 (4, 9, 10). Overexpression of kinase-dead TAK1 inhibits IL-1-and TNF-induced activation of both JNK/p38 and NF-B (4, 10). The Drosophila homolog of TAK1 was recently identified as an essential molecule for host defense signaling in Drosophila (11). Furthermore, the TAK1 gene-silencing study using the small interfering RNA method defined that TAK1 is essential for both IL-1-and TNF-induced NF-B activation in mammalian cells (12). Therefore, it can be expected that inhibition of TAK1 activity may be effective in preventing inflammation and tissue destruction promoted by proinflammatory cytokines.In this study, we screened for compounds that can inhibit TAK1 kinase activity. This strategy resulted in the isolation of one natural compound 5Z-7-oxozeaenol, a resorcylic lactone of fungal ori...
Purpose: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC.Experimental Design: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5-20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria.Results: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P ¼ 0.033).Conclusion: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation.
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