monorden has been researched along with Neoplasms* in 18 studies
11 review(s) available for monorden and Neoplasms
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Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions.
Hsp90 is one of the most important chaperones involved in regulating the maturation of more than 300 client proteins, many of which are closely associated with refractory diseases, including cancer, neurodegenerative diseases, and viral infections. Clinical Hsp90 inhibitors bind to the ATP pocket in the N-terminal domain of Hsp90 and subsequently suppress the ATPase activity of Hsp90. Recently, with the increased understanding of the discrepancies in the isoforms of Hsp90 and the modes of Hsp90-co-chaperone-client complex interactions, some new strategies for Hsp90 inhibition have emerged. Novel Hsp90 inhibitors that offer selective suppression of Hsp90 isoforms or specific disruption of Hsp90-co-chaperone protein-protein interactions are expected to show with satisfactory efficacy and safety profiles. This review summarizes the recent progress in Hsp90 inhibitors. Additionally, Hsp90 inhibitory strategies are emphasized in this review. Topics: Animals; Antineoplastic Agents; Autoimmune Diseases; Benzoquinones; Forecasting; HSP90 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Molecular Chaperones; Neoplasms; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary | 2020 |
ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism.
ATP citrate lyase (ACLY) is a cytosolic homotetrameric enzyme that catalyzes the conversion of citrate and coenzyme A (CoA) to acetyl-CoA and oxaloacetate, with the simultaneous hydrolysis of ATP to ADP and phosphate. Interestingly, ACLY is a strategic enzyme linking both the glycolytic and lipidic metabolism. In tumour cells characterized by an altered energetic metabolism, an increased glucose uptake and an accelerated glycolytic flux lead to an intensified production of mitochondrial citrate. Once transported to the cytosol, citrate is here converted by ACLY to acetyl-CoA, an essential biosynthetic precursor for fatty acid synthesis and mevalonate pathway. ACLY expression and activity proved to be aberrantly expressed in many types of tumours, and its pharmacological or genetic inhibition significantly inhibited cancer cell proliferation and induced apoptosis. Increasing evidences highlight the central role of ACLY, conferring a great therapeutic potential to this enzyme as a key target for the treatment of cancer. ACLY inhibitors, previously developed for metabolic disorders, have recently attracted interest as promising anti-cancer agents. After a brief introduction to the structure and the pathophysiological role of ACLY, this review article provides an overview of the main ACLY inhibitors reported in the literature. Topics: Antineoplastic Agents; ATP Citrate (pro-S)-Lyase; Dose-Response Relationship, Drug; Glucose; Humans; Lipid Metabolism; Molecular Structure; Neoplasms; Structure-Activity Relationship | 2018 |
Translational Shift of HSP90 as a Novel Therapeutic Target from Cancer to Neurodegenerative Disorders: An Emerging Trend in the Cure of Alzheimer's and Parkinson's Diseases.
Despite having extensive research, the apparent pathogenic mechanism of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDs) have not yet fully understood. The Heat Shock Protein 90 (HSP90), a ubiquitous molecular chaperone, found to have an important role in averting protein misfolding and aggregation through inhibition of apoptotic activity in neuro-inflammatory diseases. Various researchers have confirmed its role in maintaining aberrant neuronal protein's functional stability to a great capacity. It is also involved in regulating the activity of the heat shock factor-1 (HSF-1), a vital regulator of the heat shock response mechanism that cells employ to protect themselves against stress conditions. This quality makes the HSP90 an ideal candidate for novel inhibitory target for therapeutic modality in NDs.. An extensive literature search was conducted for relevant studies on PubMed, ScienceDirect, Springer- Link etc. The articles were carefully read in their entirety to determine whether they contained information on the topic of interest. Additionally, the reference sections of these articles were searched manually to get more relevant and eligible studies.. We have taken an attempt to reveal how HSP90 play important roles with key neuronal proteins involved in supporting the AD and PD pathology. We have further on structure-function relationship of HSP90 to understand its efficacy as a new target in AD and PD by utilizing new generation of HSP90 inhibitors such as geldanamycin and its derivatives, 17-AAG, 17-DMAG, IPI-504, radicicol and its derivatives. HSP90 inhibition leads to suppress atypical neuronal activity by assisting in improving protein aggregation and its related toxicity. Further, the formation of neuronal aggregates is also influenced by HSP90 inhibitors and provides protection from toxicity of protein through HSF-1 activation and HSP70 induction in AD.. HSP90 inhibition has emerged as a potential target in treating diverse array of diseases especially NDs. In spite of a large amount of research in this direction, the clear cut molecular mechanisms of HSPs associated with neuroprotection are still poorly elucidated and hence more focus is needed toward HSPs and its inhibitory mechanism. The development of HSP90 inhibitors that induce heat-shock response without cytotoxicity for treatment of NDs are still in its early stage. A panel of novel designed research and clinical trial studies are greatly needed to establish the therapeutic reliability and efficacy of HSPs in order to provide best cure for NDs. Topics: Alzheimer Disease; Animals; HSP90 Heat-Shock Proteins; Humans; Macrolides; Neoplasms; Parkinson Disease; Protein Conformation | 2017 |
Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside?
The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the rematuration of denatured proteins. Proteins dependent upon Hsp90 are associated with all six hallmarks of cancer. Upon Hsp90 inhibition, protein substrates are degraded via the ubiquitin-proteasome pathway. Consequentially, inhibition of Hsp90 offers a therapeutic opportunity for the treatment of cancer. Natural product inhibitors of Hsp90 have been identified in vitro, which have served as leads for the development of more efficacious inhibitors and analogs that have entered clinical trials. This review highlights the development of natural product analogs, as well as the development of clinically important inhibitors that arose from natural products. Topics: Animals; Antineoplastic Agents; Benzoquinones; Biological Products; Drug Design; Drug Discovery; Enzyme Inhibitors; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lactams, Macrocyclic; Macrolides; Molecular Docking Simulation; Neoplasms; Protein Binding; Protein Structure, Tertiary; Purines | 2016 |
Progress in the discovery and development of heat shock protein 90 (Hsp90) inhibitors.
The discovery and clinical development of heat shock protein 90 (Hsp90) inhibitors continue to progress. A number of Hsp90 inhibitors are in clinical trials, and preclinical discoveries of new chemotypes that bind to distinct regions in the protein as well as isoform selective compounds are active areas of research. This review will highlight progress in the field since 2010. Topics: Animals; Antineoplastic Agents; Benzoquinones; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Neoplasms; Neuroprotective Agents; Protein Isoforms; Rats; tau Proteins | 2014 |
[Progress in the study of heat shock protein 90 inhibitors].
Heat shock protein 90 is a new target of antitumor drug, the inhibitor of Hsp90 fight against tumor by destroy and degrade the structure of protein. In recent years, looking for Hsp90 inhibitor is not only via structure modifying of natural products, but also via high throughput screening and computer aided drug design to find and synthesize new kinds of Hsp90 inhibitor. Anyway, Hsp90 inhibitor has considered as an important biology target and to pay more and more attention. This review describes recent developments of small molecule Hsp90 inhibitors. Topics: Adenine; Animals; Anisoles; Antineoplastic Agents; Benzoquinones; Catechin; Cell Line, Tumor; Crystallization; Heterocyclic Compounds, 2-Ring; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Macrolides; Molecular Structure; Neoplasms; Pyrazoles; Structure-Activity Relationship | 2010 |
Using natural product inhibitors to validate Hsp90 as a molecular target in cancer.
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include telomerase, mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), mutated B-Raf, mutated EGF receptor, and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause inactivation, destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in various preclinical tumor models. One Hsp90 inhibitor, 17-AAG, is currently in Phase II clinical trial and other inhibitors will shortly be entering the clinic. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Identification of benzoquinone ansamycins as the first Hsp90 inhibitors allowed investigators to determine the biologic effects, at first in vitro and then in vivo, of pharmacologic inhibition of Hsp90. These studies rapidly enhanced our understanding of Hsp90 function and led to the identification of radicicol as a structurally distinct Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development. Topics: Animals; Antibiotics, Antineoplastic; Biological Products; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Macrolides; Molecular Structure; Neoplasms; Novobiocin | 2006 |
Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site.
Natural products have continued to drive the development of new chemotherapeutics and elucidation of new biological targets for the treatment of disease. Since Whitesell and Neckers' original discovery that geldanamycin does not directly inhibit v-Src, but instead manifests its biological activity through inhibition of the Hsp90 molecular chaperone, additional natural products and natural product derivatives have been identified and developed to inhibit the Hsp90 protein folding machinery. 17-AAG, a geldanamycin analogue, is currently in clinical trials for the treatment of several types of cancer. Recent work has produced improved radicicol analogues that show promising Hsp90 inhibitory activity in vitro. In addition, chimeric molecules of these two natural products are active in vitro and represent a novel class of Hsp90 inhibitors for cancer treatment. In addition to their chemotherapeutic uses, natural product inhibitors and their derivatives have been utilized to probe the biological mechanisms by which Hsp90 inhibition regulates tumor cell growth. As a consequence of these studies, the molecular chaperones have emerged as an exciting new class of therapeutic targets. This review will highlight the utility of the natural products, geldanamycin and radicicol, as well as improved analogues and the activities exhibited by these compounds against various cancer cell lines. Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Benzoquinones; Binding Sites; Drug Design; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Macrolides; Models, Molecular; Molecular Structure; Neoplasms; Structure-Activity Relationship | 2006 |
Altered states: selectively drugging the Hsp90 cancer chaperone.
The molecular chaperone Hsp90 is an exciting cancer drug target. The first Hsp90 inhibitor to enter clinical trials--the geldanamycin derivative 17AAG--has recently demonstrated proof-of-concept for successful target modulation, with sighs of therapeutic benefit. An important property of Hsp90 inhibitors is their ability to cause simultaneous, combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. However, the reason for therapeutic selectivity in cancer cells versus normal cells is unclear. New research now shows that Hsp90 exists in cancer cells in a heightened, activated state that is highly susceptible to inhibition by 17AAG. Topics: Antibiotics, Antineoplastic; Benzoquinones; Drug Design; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lactones; Macrolides; Neoplasms; Oncogene Proteins; Protein Binding; Quinones; Rifabutin | 2004 |
Development of radicicol analogues.
Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, and thus inhibit the signal transduction pathway. In addition, direct binding of radicicol to the N-terminal ATP/ADP binding site of Hsp90 was shown, and thus radicicol has been recognized as a structurally unique antibiotic that binds and inhibits the molecular chaperone Hsp90. Although radicicol itself has little or no activity in animals because of instability in animals, its oxime derivatives showed potent antitumor activities against human tumor xenograft models. Hsp90 client proteins were depleted and apoptosis was induced in the tumor specimen treated with radicicol oxime derivatives. Taken together, these results suggest that the antitumor activity of radicicol oxime derivatives is mediated by binding to Hsp90 and destabilization of Hsp90 client proteins in the tumor. Among Hsp90 clients, we focused on ErbB2 and Bcr-Abl as examples of important targets of Hsp90 inhibitors. Radicicol oxime showed potent antitumor activity against ER negative/ErbB2 overexpressing breast cancer and Bcr-Abl expressing CML. Putative mechanisms of action and future directions of radicicol oxime against these kinds of tumor are discussed. Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Genes, erbB-2; HSP90 Heat-Shock Proteins; Humans; Lactones; Macrolides; Molecular Chaperones; Neoplasms | 2003 |
[Morphological reversion of tumor cells by histone deacetylase inhibitors and radicicol].
Trichostatins and trapoxins, structurally unrelated microbial metabolites, are specific inhibitors of histone deacetylases. Radicicol inhibits Src family protein-tyrosine kinases. Recently, these agents were found to induce morphological reversion and enhanced expression of gelsolin, an actin regulatory protein, in a variety of transformed cells. Microinjection of an anti-gelsolin antibody that neutralizes the gelsolin function caused inhibition of the morphological change, suggesting that gelsolin expression is associated with the suppression of transformation. Topics: Animals; Cell Transformation, Neoplastic; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Lactones; Macrolides; Mice; Neoplasms; Neoplasms, Experimental; Protein-Tyrosine Kinases; Tumor Cells, Cultured | 1997 |
7 other study(ies) available for monorden and Neoplasms
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Radicicol induces intracellular accumulation of glycan-deficient clusterin variant.
Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the mechanistic basis, this variant proved to be a product disposed from the stressed ER. During this process, inhibitory effect of radicicol on protein degradation results in cytosolic accumulation of glycan-deficient clusterin variant that signals cell death. These results provide a therapeutic insight into the targeted proteostasis perturbation of clusterin as an anti-cancer strategy. Topics: Cell Line, Tumor; Clusterin; Endoplasmic Reticulum Stress; Glycosylation; HSP90 Heat-Shock Proteins; Humans; Macrolides; Neoplasms; Protein Isoforms; Protein Synthesis Inhibitors; Proteolysis | 2015 |
The lipogenesis pathway as a cancer target.
Topics: Acetyl-CoA Carboxylase; Animals; Antineoplastic Agents; ATP Citrate (pro-S)-Lyase; Biosynthetic Pathways; Fatty Acid Synthases; Fatty Acids; Humans; Lipogenesis; Models, Chemical; Molecular Structure; Neoplasms | 2011 |
Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors.
A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors. Topics: Animals; Antineoplastic Agents; Ascomycota; Benzopyrans; Cell Line, Tumor; Cell Proliferation; Female; HSP90 Heat-Shock Proteins; Humans; Mice; Mice, Nude; Neoplasms; Pigments, Biological | 2010 |
Targeting the Hsp90 chaperone: synthesis of novel resorcylic acid macrolactone inhibitors of Hsp90.
A series of benzo-macrolactones has been prepared by chemical synthesis, and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. A new synthesis of these resorcylic acid macrolactone analogues of the natural product radicicol is described in which the key steps are the acylation and ring opening of a homophthalic anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the macrocycle. The methodology has been extended to a novel series of macrolactones incorporating a 1,2,3-triazole ring. Topics: Antineoplastic Agents; Binding Sites; Crystallography, X-Ray; HSP90 Heat-Shock Proteins; Humans; Macrolides; Neoplasms; Protein Binding; Triazoles | 2010 |
Dipalmitoylation of radicicol results in improved efficacy against tumor growth and angiogenesis in vivo.
Tumor-related angiogenesis is likely to be a potential target for the treatment of cancer. One key to develop this angiostatic strategy would be to find useful angiogenesis inhibitors. Here we report the effects of radicicol, a microbial angiogenesis inhibitor that we previously identified using the chorioallantoic membrane assay, and its novel analog, 14,16-dipalmitoyl-radicicol, on tumor angiogenesis and growth. As expected for agents containing a penolic hydroxyl group, systemic administration of radicicol had little or no effect on neovascularization triggered by a M5076 mouse tumor cell line or a RMT-1 rat mammary carcinoma cell line established from autochthonous rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene in a mouse dorsal air sac assay system. The agent did not show growth-inhibitory activity against either transplantable M5076 tumors or autochthonous 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. In contrast, 14,16-dipalmitoyl-radicicol potently suppressed tumor angiogenesis and growth in these experimental models. Furthermore, the analog significantly prolonged the survival rate of M5076-implanted mice. Although not stronger than radicicol, it dose-dependently inhibited embryonic angiogenesis in the chorioallantoic membrane assay, the dose required for half-maximal inhibition (ID(50)) value being 23 microg (27 nmol) per egg, and showed concentration-dependent antiproliferative activity against microvascular endothelial cells in vitro. These data suggest that 14,16-dipalmitoyl-radicicol is a promising antitumor agent with antiangiogenic activity. Topics: Air Sacs; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chorioallantoic Membrane; Fatty Acids, Monounsaturated; Female; Macrolides; Mice; Molecular Structure; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Rats; Survival Rate | 2007 |
The topoisomerase II-Hsp90 complex: a new chemotherapeutic target?
The modulation of DNA topology by topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and has thus become a highly attractive target for chemotherapeutic drugs. However, these drugs are highly toxic, and so new approaches are required. One such strategy is to target topoisomerase II-interacting proteins. Here we report the identification of potential topoisomerase II-associated proteins using immunoprecipitation, followed by 1-D and 2-D gel electrophoresis and MALDI-TOF mass spectrometry. A total of 23 proteins were identified and, of these, 17 were further validated as topoisomerase IIalpha-associated proteins by coimmunoprecipitation and Western blot. Six of the interacting proteins were cellular chaperones, including 3 members of the heat shock protein-90 (Hsp90) family, and so the effect of Hsp90 modulation on the antitumor activity of topoisomerase II drugs was tested using the sulforhodamine B assay, clonogenic assays and a xenograft model. The Hsp90 inhibitors geldanamycin, 17-AAG (17-allylamino-17-demethoxygeldanamycin) and radicicol significantly enhanced the activity of the topoisomerase II poisons etoposide and mitoxantrone in vitro and in vivo. Thus, our method of identifying topoisomerase II-interacting proteins appears to be effective, and at least 1 novel topoisomerase IIalpha-associated protein, Hsp90, may represent a valid drug target in the context of topoisomerase II-directed chemotherapy. Topics: Adenocarcinoma; Animals; Benzoquinones; Breast Neoplasms; Carcinoma, Adenosquamous; Colonic Neoplasms; DNA Topoisomerases, Type II; Electrophoresis, Gel, Two-Dimensional; Enzyme Inhibitors; Female; HSP90 Heat-Shock Proteins; Humans; Immunoprecipitation; Lactams, Macrocyclic; Lactones; Macrolides; Mice; Mice, Nude; Molecular Chaperones; Neoplasms; Protein Binding; Quinones; Rifabutin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transplantation, Heterologous; Tumor Cells, Cultured | 2006 |
Inhibitors of anchorage-independent growth affect the growth of transformed cells on poly(2-hydroxyethyl methacrylate)-coated surfaces.
We have described a microplate colorimetric assay to quantitate anchorage-independent cell growth, using plates coated with an anti-adhesive polymer poly (2-hydroxyethyl methacrylate) (polyHEMA).We investigated whether this method could be applied to human cancer cells of epithelial origin. HAG-1, a non-tumorigenic human gall-bladder carcinoma cell line, and its pSVneo and c-H-ras transfectants, which are also non-tumorigenic, did not grow on a polyHEMA-surface. In contrast, the v-src transformant which produced tumors in nude mice and formed colonies in soft agar, was able to proliferate on the coated surface, suggesting that tumorigenicity of human cancer cells correlates with the ability to grow on a polyHEMA-coated surface. We report on the feasibility of this method as a screening system for inhibitors of oncogenic transformation. Herbimycin A and radicicol, which have been reported to block Src function, suppressed the growth of v-src-transformed NRK and HAG-1 cells on the non-adhesive polyHEMA-surface at concentrations significantly lower than on plastic. Differences in the inhibitory concentrations were not observed with KB cells, and cytotoxic agents such as adriamycin did not show any selectivity between the 2 surfaces. Growth of ras-transformed cells on the coated surface was selectively blocked by L-739,749, a farnesyltransferase inhibitor. The results demonstrate that compounds causing reversion of transformed cells to normal, hence, selectively inhibiting cell growth in anchorage-independent conditions, can be screened using this microtiter plate assay. Topics: Adenocarcinoma; Animals; Benzoquinones; Cell Adhesion; Cell Division; Cell Line, Transformed; Drug Screening Assays, Antitumor; Humans; Lactams, Macrocyclic; Lactones; Macrolides; Methacrylates; Mice; Neoplasms; Oligopeptides; Protein-Tyrosine Kinases; Quinones; Rifabutin; Tumor Cells, Cultured; Urinary Bladder Neoplasms | 1996 |