macrocyclic lactams

..These results demonstrate that c-Met/HGF pathway is functional in SCLC, and it would be useful to target this pathway toward novel therapy...

..Thus, RACK1 is an essential component of an O(2)/PHD/VHL-independent mechanism for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex...

..A model is presented to relate these findings to previous models and another complex between hsp90, hsp70, and p60 that appears to be an intermediate in PR assembly...

..Thus, benzoquinone ansamycin drugs and their derivatives, such as 17-allyl-aminogeldanamycin, are excellent candidates as small molecule drug inhibitors of HIF-1 overexpression in cancer cells...

..Therefore, Hsp90-directed chaperones are regulators of mitochondrial integrity, and their organelle-specific antagonists may provide a previously undescribed class of potent anticancer agents...

..This article reviews the current status and future prospects for the exploitation of Hsp90 as a new molecular target for cancer treatment...

..These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics...

....

..We suggest that geldanamycin derivatives such as 17-DMAG should be considered for the development of a drug treatment for polyQ disorders and other neurodegenerative diseases involving protein aggregation...

..These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the apoptotic effects of cytotoxic agents. The sequence of drug administration and the RB status significantly influence efficacy...

..Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL...

....

..Furthermore, while the presence of p23 decreases the sensitivity of Hsp90-dependent processes to ansamycin treatment, ansamycin antibiotics disrupt signaling through some mechanism other than altering the Hsp90-p23 interaction...

..This, and the pocket's similarity to substrate-binding sites, suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/refolding reaction...

..Thus, Hsp90 or some of its client proteins may provide novel targets for the chemotherapy of filarial infection...

....

....

..In conclusion, these studies have shown that reduction of 17-AAG by NQO1 generates 17-AAGH2, a relatively stable hydroquinone that exhibits superior Hsp90 inhibition...

..Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target...

....

..Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins...

..Thus, we describe the chaperone complex as being a regulator of PPARalpha and PPARbeta activity and have identified a novel, subtype-specific, inhibitory role for Hsp90...

..These findings provide new insights into the nature of unusual N-terminal nucleotide-binding fold of Hsp90 and suggest that target-related drug resistance is unlikely to emerge in patients receiving GA-like chemotherapeutic agents...

....

....

..We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics...

..Staining with ubiquitin to identify protein aggregates revealed reduced redistribution of ubiquitin, consistent with reduced protein aggregation likely due at least in part to induction of Hsp70 by GA...

....

..These data suggest an important contraindication to the Hsp90 targeted cancer therapy currently undergoing clinical trial...

..To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks...

..These cofactors interact physically and functionally with the conserved AAA(+)-type DNA helicases Rvb1/Rvb2, which are key components of several chromatin remodeling factors, thereby linking Hsp90 to epigenetic gene regulation...

..We recommend this dose for phase II clinical trials...

..These results thus suggest Hsp90 may play a role in stage switch...

..Given the redundancy and complexity of the molecular abnormalities present in most breast cancers, the ability of Hsp90 inhibitors to alter the activity of multiple oncogenic targets may prove of unique therapeutic benefit...

..Radicicol and geldanamycin could both maintain chaperone induction for at least 3 weeks and alter the detergent soluble properties of polyQ aggregates over this time course...

..Together, these results define a dual requirement for Hsp90 as a regulator of NF-kappaB signaling by its general involvement in IKK activation and by its role in IKK homeostasis...

..g. with tumor regressions) to 17-AAG may be associated with modulation of Hsp90 expression. The expression of this target should be followed in clinical studies with 17-AAG...

....

..GA did not, however, appear to restore wild-type transcriptional activating activity to mutant p53 proteins in either A1-5 cells or human breast cancer cell lines...

..We conclude that selective tyrosine phosphorylation of P2X7 receptor-associated HSP90 may act as a negative regulator of P2X7 receptor complex formation and function...

..Our results are consistent with Hsp90 homeostasis serving as cellular thermometer for these primitive eukaryotes, controlling both the heat shock response and morphological differentiation...

....

..Thus, our studies show that a defective stress response can be pharmacologically restored and suggest that the HSF1 deactivation pathway may play an important role in the regulation of Hsp expression...

..Our results indicate that hsp90 facilitates MHC class I antigen processing through epitope production in a complex of the 26 S proteasome...

..It was concluded that telomerase and Hsp90 can promote the proliferation of the cultured RPE cells, while the inhibitor of them can induce apoptosis and inhibit the growth of the RPE cells...

..We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors...

..Signaling through this pathway was inhibited by GA, concomitant with loss of Raf-1 protein, but was restored if Raf-1 was protected from GA-induced degradation by proteasome inhibitors...

..In addition, over-expression of survivin attenuated cytotoxicity induced by the combination of 17-AAG and TRAIL. In summary, survivin is a key regulator of TRAIL-17-AAG mediated cell death in malignant glioma...

..v., i.p., or orally. 17AAG is widely distributed to tissues. These pharmacokinetic data generated have proven relevant to the design of recently initiated clinical trials of 17AAG and could be useful in their interpretation...

..Taken together, Hsp90 is important for maintaining Sp1 stability during mitosis by the JNK-1-mediated phosphorylation of Sp1 to enable division into daughter cells and to regulate the expression of related genes in the interphase...

..We combined these data with codon evolution models in an attempt to identify whether hsp-90 from GA-binding and non-binding species has evolved under different evolutionary constraints...

..These data suggest that Hsp90 uniquely stabilizes ErbB2 via interaction with its kinase domain and that GA stimulates ErbB2 degradation secondary to disruption of ErbB2/Hsp90 association...

..Our results establish Hsp90 as an ATP-dependent chaperone...

..Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors...

..Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects...

..Thus, it was suggested that nicotine induces apoptosis, possibly via Hsp90 alpha expression, in human cells tested...

..The synthesis of a red-shifted cy3B-GM ligand and its evaluation as a fluorescence polarization probe for Hsp90 is presented...

..e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90...

..Thus, it is not surprising that new HSP90 agents are under development against this novel target for cancer therapy and several show promise...

..This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases...

....

..Because of the chemoprotective activity of several proteins that are Hsp90 clients, the combination of an Hsp90 inhibitor with a standard chemotherapeutic agent could dramatically increase the in vivo efficacy of the therapeutic agent...

..Based upon a model for drug-induced degradation of ErbB-2, we propose a general strategy for selective destruction of oncoproteins by targeting their interaction with molecular chaperones...

....

..This is the first report on the AHBA biosynthetic gene cluster in a geldanamycin-producing strain...

..This strategy warrants further attention in Bcr/abl(+) hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors...

....

....

..These studies establish that AEG3482 inhibits JNK activation and apoptosis by a mechanism involving induced expression of HSP proteins...

..Additionally, ZAP-70 expression in CLL cells confers markedly heightened sensitivity to 17-AAG or 17-DMAG, suggesting that these or other Hsp90 inhibitors could be valuable therapeutically in patients with aggressive CLL...

..Taken together, our findings suggest that differential calcium signaling may account for the differential induction of HSP and the action of GA and RA...

..Hepatocellular injury was evident only at high dose exposures. This is believed to be the first use of an in vitro liver tissue model to accurately predict the differential and concentration-dependent toxicities of these compounds...

..In summary, these results suggest that dosage will be a critical factor in the treatment of tumor patients with HSP90 inhibitors...

..These data suggest mutational activation of EGFR is associated with dependence on Hsp90 for stability and that Hsp90 inhibition may represent a novel strategy for the treatment of EGFR-mutant NSCLC...

..Our findings suggest that Hsp90 inhibitors may prove useful either alone or as a component of multi-drug regimens in the treatment of neuroblastoma and osteosarcoma...

..Dog liver slices can thus be used to evaluate species-, compound-, and concentration-dependent differences in toxicity...

....

..Treating cells with Hsp90 inhibitors facilitates Raf degradation, thereby down-regulating the activity of ERK...

..Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of such an activity from that of heat shock protein 90...

..Finally, comparison is made between the use and applicability of this type of immunoassay and other techniques such as western blotting, immunohistochemistry, and flow cytometry analysis...

..This assay was able to measure plasma concentrations of AAG, the lower limit of quantitation being 12.5 nM, at a starting dose of 10 mg/m2 infused intravenously over 1 h in a Phase I clinical trial in adult patients with solid tumors...

..Conversely, HSP90 did not markedly increase in all treatments. Based on the results in this study, we suggest that apoptosis induced by TSA can be prevented by GA-induced increment of heat shock proteins, particularly HSP70...

..These data suggest that erbB2 status in ovarian cancr may contribute to chemosensitivity, in some cases leading to increased sensitivity (as with geldanamycin) but in other cases leading to resistance (as with cisplatin)...

..Although the ERK kinase regulates LPS-induced reduction of apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the feedback regulation of neutrophil apoptosis...

..These data establish a role for HSP90 in the cellular transcriptional response to ER stress and demonstrate that chaperone systems on both sides of the ER membrane serve to integrate this signal transduction cascade...

..Although more research is needed to clarify the precise spectrum of antitumor activity of proteasome inhibitors, this novel approach to targeting human malignancies is highly promising...

....

..We suggest that in the clinic, micromolar concentrations of 17AAG must accumulate in the tumor cells to achieve antitumor effects in patients comparable with ones achieved in tissue culture settings...

..In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinic trials with encouraging results...

..These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias...

..In the context of an inflammatory process, the intracellular signal pathway activated by sFbg may be an early event influencing the functionality of PMN...

..These findings further suggest that therapies targeting tyrosine kinases, including p80, may have clinical utility...

..Activation was associated with increased phosphorylation and higher cytotoxic effector functions...

..These studies demonstrate for the first time the activity of GAs against human gliomas in vitro and in vivo and suggest that destruction of EF-2 kinase may be an important cytotoxic mechanism of this unique class of drug...

..G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug...

..These results indicate that ansamycins can exert potent anti-inflammatory effects on brain glial cells which may provide therapeutic benefit in neuroinflammatory diseases...

....

....

..Furthermore, poly-ubiquitination is not sufficient for efficient proteasomal targeting of Hsp client proteins...

....

..2 but not in HCT116 cells, which we postulate to be the basis for higher survival of p53-deficient cells when treated with combinations of the two drugs...

..This ability is simply unavailable using conventional methodology...

....

..In conclusion, Hsp90- interfering drugs represent a potential novel class of drugs to promote the survival of neurons and open up a promising approach to the treatment of neurodegenerative diseases. ..

..Hits resulted from the FP assay will be tested for Her2 degradation potency in the breast cancer cell line SKBr3. Highest ranking compounds in both screens will be taken for further testing in follow-up research programs. ..

....

..To our knowledge, this has not been accomplished, and we believe that we are uniquely positioned to initiate this goal. ..

..This work may suggest new therapeutic approaches to a variety of inflammatory or neoplastic lung diseases for which current therapy is often unsatisfactory. ..

..This information could hasten the development of new, mechanism-based interventions for lung disorders, including acute lung injury or lung neoplasia. ..

..Upon completion of the award period, Dr. Bagatell will be well prepared to move forward as an independent investigator. ..

..abstract_text> ..

..Since the studies are conducted on freshly isolated CCD, the results will provide information essential for understanding the role of NO in the regulation of Na+ and K+ transport in the CCD. ..

..The proposed studies are expected to provide insights of how checkpoint defects in tumors can be exploited to render them more susceptible to combined treatment with chemotherapy and checkpoint inhibitors such as 17AAG. ..

..These findings may be useful in the rational design of future clinical trials involving HDACi. ..

..The effect of PGE2 has relevance to Bartter's Syndrome where hyperprostaglandinemia is prominent and inhibition of prostaglandin production reverses partially the physiological consequences of impaired TAL function. ..

..In pre- and post-treatment tumor samples, we will determine which HDACs are involved in the cellular effects induced by the HDACi and which HDACs may predict response. ..

..This is an important first step toward a molecular understanding of the unique recognition properties, transport mechanism of Pgp, and will further facilitate the design of new, more potent reversal agents. ..

..Specific Aim 2 To examine whether mono-ubiquitination of ROMK channels is regulated by PKA and PTK. Specific aim 3 To explore the role of CD63 in mediating ROMK1 tyrosine phosphorylation and mono-ubiquitination. ..

..Finally, the utility of the topo II inhibitors could be enhanced if their efficacy could be increased without worsening toxicity, as our preclinical data appears to indicate. ..

....

..In addition, we will attempt to identify the mode by which ATO controls the activity of STAT3 and how this effect alters the gene profile patterns and induces apoptosis. ..

..In the second sub-aim we will assay for chaperone activity of novel co-chaperones that are important for protein kinase folding. Finally, we will distinguish between the role of Cdc37 in Cdk folding and cyclin binding. ..

..The goal of this project is to help us understand why infants develop pulmonary hypertension, determine what happens in the lung blood vessels during disease development, and develop treatments for this disease. ..

..It is the long-term objective of this laboratory to identify these metabolites, develop biochemical and chemical tools to better understand their physiologic roles, and ultimately intervene pharmacologically. ..

..The public health significance of this project is that we aim to protect patients from severe cardiotoxic effects of anti-cancer drugs, which in many cases, limits the use of otherwise effective therapies. ..

..The public health significance of this project is that we aim to protect patients from severe cardiotoxic effects of anti-cancer drugs, which in many cases, limits the use of otherwise effective therapies. ..

..Abstract Not Provided ..

..The public health significance of this project is that we aim to protect patients from severe cardiotoxic effects of anti-cancer drugs, which in many cases, limits the use of otherwise effective therapies. ..

..The proposed clinical investigation has enormous health significance and may shed light on the development and progression of neurological dysfunction in infants and children on prolonged parenteral nutrition. ..

..3) Develop isozyme-specific P450 inhibitors using (i) structure based rational design; (ii) computational/molecular modeling; and (iii) library screening. ..

..It is the long-term objective of this laboratory to identify these metabolites, develop biochemical and chemical tools to better understand their physiologic roles, and ultimately intervene pharmacologically. ..

..abstract_text> ..

..and (e) elucidation of the P450 active site. ..

..In light of the almost universal distribution of cytochrome P-450 in mammalian tissues, this work will have profound implications for our understanding of fatty acid metabolism and its relationship to homeostasis...

....