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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate signaling pathways critical to the molecular economy of many types of tumors, including oncogene signaling, cyclin-dependent kinase activation, steroid hormone receptors, and mediators of invasion and metastasis. Thus, Hsp90-directed agents could affect molecules upon which tumors depend for their proliferation and survival. Initial clinical studies have therefore sought to incorporate assessment of these endpoints into initial clinical evaluations. Three schedules of administration have been supported for initial evaluation in Phase I studies sponsored by the National Cancer Institute (NCI) or supported by NCI and sponsored by Cancer Research UK. In the daily times five schedule, a recommended Phase II dose (RPTD) of 40 mg/m(2) has been reached, while once weekly or three of four weekly schedules are defining RPTDs of 295 and 308 mg/m(2). Toxicity is tolerable and appears dominated by hepatic, gastrointestinal, and constitutional symptoms. Concentrations of drug at peak of ~1700-3000 nM are concordant with concentrations predictive of useful outcomes in pre-clinical model systems. Evidence of modulation of Hsp90 partner molecules has been obtained in both surrogate and some tumor compartments. These very early results encourage additional clinical evaluations of 17AAG and related molecules.
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PMID:Clinical development of 17-allylamino, 17-demethoxygeldanamycin. 1452 89

CMV423 (2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new antiviral agent with potent and selective in vitro activity against the beta-herpesvirus human cytomegalovirus (HCMV), but not against alpha- or gamma-herpesviruses. Here we report that its activity also extends to human herpesvirus 6 (HHV-6) and 7 (HHV-7). When compared in vitro to ganciclovir and foscarnet (the standard drugs recommended for treatment of HHV-6 infections), CMV423 showed a superior selectivity, due to its high activity (antiviral IC(50): 53nM) and low cytotoxicity (CC(50): 144microM), both in continuous cell lines and in CBLCs infected with HHV-6. From mechanistic experiments at the level of viral mRNA and protein expression, we learned that CMV423 targets an event following viral entry but preceding viral DNA replication. Its antiviral action was dependent on the cell line used, implying involvement of a cellular component. When compared to a panel of known protein kinase inhibitors, CMV423 was found to share anti-HHV-6 characteristics with herbimycin A, which affects tyrosine kinase activity through heat shock protein 90 (Hsp90) inhibition. We demonstrated that high concentrations of CMV423 have an inhibitory effect on the total cellular protein tyrosine kinase activity, and that CMV423 and herbimycin A, when combined, act synergistically against HHV-6. The activities of cyclin-dependent kinases, protein kinases A and C, and the HHV-6-encoded pU69 kinase were not affected. We, therefore, conclude that CMV423 exerts its activity against HHV-6 through inhibition of a cellular process that is critical at early stages of viral replication and that may affect protein tyrosine kinase activity.
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PMID:Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early stage of viral replication by the non-nucleoside compound CMV423. 1469 45

To find novel pharmacological tools useful for analyzing the molecular mechanism of apoptosis from natural resources, in the present study, we examined the activity of IC101, a cyclic depsipeptide isolated from Streptomyces sp. MJ202-72F3, to induce apoptosis in the L1210 cell line. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IC101 caused a concentration-dependent cell death with a 50% effective concentration value of 20 nM. Cell shrinkage, chromatin condensation, a typical DNA ladder pattern, and up-regulation of cleaved caspase-3 expression, which were biochemical characteristics of apoptosis, were induced by IC101. It also was observed that IC101 caused a concentration-dependent dephosphorylation of Akt and Bad without affecting phosphatidylinositol-3 kinase, an upstream molecule of Akt. IC101 dephosphorylated the 90-kDa protein, as assayed by immunblotting of the cell extract by using anti-phosphotyrosine antibody. To identify the 90-kDa protein, immunoprecipitation and direct nano-flow liquid chromatography-tandem mass spectrometry (LC-MS) were performed to demonstrate that this protein was heat shock protein 90 (HSP90). Consistently, it was observed that IC101 induced the HSP90 tyrosine dephosphorylation by immunoblot analysis of immunoprecipitates with anti-HSP90 antibody using anti-phosphotyrosine antibody. IC101 caused the degradation of Raf-1, which formed a complex with HSP90. The HSP90-ATP binding also was inhibited by IC101 in a noncompetitive manner. An interaction of HSP90 with Akt was shown to be inhibited by IC101 in a concentration-dependent manner. These results suggest that IC101 dephosphorylates Akt through an inhibition of HSP90 functions, resulting in the interaction with Akt to induce apoptotic cell death of L1210 cells.
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PMID:IC101 induces apoptosis by Akt dephosphorylation via an inhibition of heat shock protein 90-ATP binding activity accompanied by preventing the interaction with Akt in L1210 cells. 1516 34

Recent advances in the use of natural products and compounds derivedfrom natural products as agents for the treatment of cancer and other diseases are reviewed. The antitumor agents discussed include tubulin interactive agents, inhibitors of topoisomerases I and II, caspase activators, proteasome inhibitors, histone deacetylase inhibitors, heat shock protein 90 inhibitors, protein kinase inhibitors, and inhibitors of hypoxia inducible factor 1. It can be concluded that, despite a perceived lack of popularity in recent years, the use of natural product scaffolds in searching for drug leads is still being practiced.
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PMID:The search for novel drug leads for predominately antitumor therapies by utilizing mother nature's pharmacophoric libraries. 1578 45

Until now, there has not been enough information on how androgens or androgen deprivation may influence the response of cancer cells to radiation. In this study, the effect of dihydrotestosterone (DHT) on cellular proliferative activity and radiosensitivity was examined in a hormone-sensitive human prostate cancer cell line, LNCaP. In addition, the study also examined how a heat shock protein 90 (Hsp90) chaperone complex inhibitor modified the effect of DHT on the radiosensitivity of the cells, because binding of the androgen receptor (AR) to Hsp90 is required to maintain the stability and functioning of AR. The hormone-sensitive human prostate cancer cell line, LNCaP, was used. Radicicol was used as one of the known Hsp90 chaperone complex inhibitors, and the cells were incubated in the presence of this compound at a concentration of 500 nM. Cellular radiosensitivity was determined by the clonogenic assay; the changes in the protein expression were examined by Western blotting or immunofluorescence. DHT at a concentration of 1 nM caused enhancement of the proliferative activity and reduction of the radiosensitivity of the cells. Radicicol at a concentration of 500 nM abolished the DHT-induced decrease in cellular radiosensitivity and potentiated the radiation-induced cell killing synergistically. Consistent with the changes in the cellular radiosensitivity, radicicol degraded AR, Raf-1 and HER2/neu via reduced binding of AR to Hsp90, although selective degradation of HER2/neu caused by Herceptin, a monoclonal antibody against HER2, did not affect the cellular radiosensitivity. The results suggest that the Hsp9O chaperone complex may be a potential molecular target for potentiation of radiation-induced cell killing in a hormone-sensitive prostate cancer cell line.
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PMID:Heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor. 1596 64

Nuclear autoantigenic sperm protein (NASP) is a linker histone binding protein that is cell-cycle regulated. Synchronized HeLa cells are delayed in progression through the G1/S border when transiently transfected to overexpress full-length NASP, but not the histone-binding site (HBS) deletion mutant (NASP-DeltaHBS). The purpose of the current study was to identify possible NASP-associated proteins in HeLa cell nuclei that could elucidate NASP's influence on the cell cycle and chromatin remodeling. For this purpose, we employed a new approach: mass spectrometry identification of initially cross-linked proteins after their separation in a second dimension by reducing SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Of the twelve proteins identified, three appear to be relevant to NASP's function: heat shock protein 90 (HSP90), DNA-activated protein kinase, and ATP-dependent DNA helicase II (70-kDa subunit). Individual protein-protein interactions were tested by immunoprecipitation techniques. This new method can be used for expedited identification of binding partners of different proteins in enriched fractions and as a complementary or alternative strategy to the yeast two-hybrid system and immunoprecipitation methods.
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PMID:Mass spectrometry identification of NASP binding partners in HeLa cells. 1608 Jan 55

Checkpoint kinase 1 (Chk1), a serine/threonine kinase that regulates DNA damage checkpoints, is destabilized when heat shock protein 90 (Hsp90) is inhibited, suggesting that Chk1 is an Hsp90 client. In the present work we examined the interplay between Chk1 and Hsp90 in intact cells, identified a source of unchaperoned Chk1, and report the in vitro chaperoning of Chk1 in reticulocyte lysates and with purified chaperones and co-chaperones. We find that bacterially expressed Chk1 is post-translationally chaperoned to an active kinase. This reaction minimally requires Hsp90, Hsp70, Hsp40, Cdc37, and the protein kinase CK2. The co-chaperone Hop, although not essential for the activation of Chk1 in vitro, enhanced the chaperoning process, whereas the co-chaperone p23 did not stimulate the chaperoning reaction. Additionally, we found that the C-terminal regulatory domain of Chk1 affects the association of Chk1 with Hsp90. Collectively these results provide new insights into Hsp90-dependent chaperoning of a client kinase and identify a novel, biochemically tractable model system that will be useful to further dissect the Hsp90-dependent chaperoning of this important and ubiquitous class of Hsp90 clients.
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PMID:Chaperoning checkpoint kinase 1 (Chk1), an Hsp90 client, with purified chaperones. 1633 May 44

Endothelial NO synthase (eNOS) via the production of NO in the endothelium plays a key role in cardiovascular biology and is tightly regulated by co- and posttranslational mechanisms, phosphorylation, and protein-protein interactions. The cell division cycle 37 homolog (Cdc37) is a key heat shock protein 90 (Hsp90) cochaperone for protein kinase clients, and Akt/Hsp90 interaction is dependent on Cdc37. Because both Hsp90 and Akt are key eNOS regulatory proteins, we hypothesized that Cdc37 interacts with eNOS as part of the regulatory complex. In the present study, we demonstrate by coimmunoprecipitation and affinity purification in bovine aortic endothelial cells (BAECs) that Cdc37 is complexed with eNOS, Hsp90, and Akt. In addition, cell fractionation data indicate that Cdc37 is found in caveolae with eNOS. Further analysis by in vitro binding assays reveals a direct interaction between purified Cdc37 and eNOS. Incubation of purified Cdc37 with purified wild-type eNOS decreases eNOS activity in vitro. Overexpression of wild-type Cdc37 in BAECs inhibits eNOS activity and NO release, whereas overexpression of S13A-Cdc37 mutant in BAECs increases eNOS activity and NO release. Taken together, these data suggest that Cdc37 has a direct regulatory interaction with eNOS and may play an important role in mediating the eNOS protein complex formation as well as subsequent eNOS phosphorylation and activation.
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PMID:Direct interaction of the cell division cycle 37 homolog inhibits endothelial nitric oxide synthase activity. 1641 Apr 63

Inhibition of heat shock protein 90 (Hsp90) has emerged as a novel intervention for the treatment of solid tumors and leukemias. Here, we report that F(1)F(0)-ATP synthase, the enzyme responsible for the mitochondrial production of ATP, is a co-chaperone of Hsp90. F(1)F(0)-ATP synthase co-immunoprecipitates with Hsp90 and Hsp90-client proteins in cell lysates of MCF-7, T47D, MDA-MB-453, and HT-29 cancer cells. Inhibition of F(1)F(0)-ATP synthase by efrapeptins results in the disruption of the Hsp90 complexing with its substrate proteins and, in most cases, in the degradation of the latter. Hsp90-client proteins affected by the inhibition of F(1)F(0)-ATP synthase included ERalpha, mutated p53 (m.p53), Hsp70, Hsp27, and caspase-3 but not Raf-1. This is the first report identifying caspase-3 as a substrate protein of Hsp90. Unlike typical Hsp90 inhibitors, efrapeptin treatment triggers Hsp70 downregulation in parallel with depletion of Hsp90. This suggests that suppression of Hsp90 chaperone function through inhibition of F(1)F(0)-ATP synthase does not result in activation of transcription factor HSF-1, a generally unfavorable consequence of anti-cancer treatments based on Hsp90 inhibition.
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PMID:F1F0-ATP synthase functions as a co-chaperone of Hsp90-substrate protein complexes. 1668 2

The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive. We have identified two new biomarkers [insulin-like growth factor binding protein-2 (IGFBP2) and HER-2 extracellular domain] that can be readily detected in patient sera by ELISA. Both secreted proteins are derived from or regulated by Hsp90 client proteins, raising hopes that they might be sensitive serum markers of HSP90 inhibitor activity. Several structurally unrelated HSP90 inhibitors dose-dependently decreased secretion of both IGFBP-2 and HER-2 extracellular domain into culture medium, and both proteins were more sensitive to HSP90 inhibitors than previously identified biomarkers. In sera from BT474 tumor-bearing mice, both IGFBP-2 and HER-2 extracellular domain were down-regulated by 17-AAG in a time-dependent and dose-dependent manner, coincident with the degradation of HER-2 and attenuation of AKT activity in the tumors. Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response. In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors.
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PMID:Identification of new biomarkers for clinical trials of Hsp90 inhibitors. 1673 58


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