9h-purine-9-propanamine--6-amino-8-((6-iodo-1-3-benzodioxol-5-yl)thio)-n-(1-methylethyl)- has been researched along with Neoplasms* in 10 studies
1 review(s) available for 9h-purine-9-propanamine--6-amino-8-((6-iodo-1-3-benzodioxol-5-yl)thio)-n-(1-methylethyl)- 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 |
1 trial(s) available for 9h-purine-9-propanamine--6-amino-8-((6-iodo-1-3-benzodioxol-5-yl)thio)-n-(1-methylethyl)- and Neoplasms
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First-in-Human Trial of Epichaperome-Targeted PET in Patients with Cancer.
Adult patients with cancer (. Our first-in-human results demonstrate the safety and feasibility of noninvasive Topics: Adult; Aged; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Female; HSP90 Heat-Shock Proteins; Humans; Iodine Radioisotopes; Male; Middle Aged; Neoplasms; Positron Emission Tomography Computed Tomography; Purines; Tissue Distribution | 2020 |
8 other study(ies) available for 9h-purine-9-propanamine--6-amino-8-((6-iodo-1-3-benzodioxol-5-yl)thio)-n-(1-methylethyl)- and Neoplasms
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Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug.
The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90 and is overexpressed in many cancer cells. The orthosteric ATP-binding site of TRAP1 has been considered the primary inhibitor binding location, but TRAP1 allosteric modulators have not yet been investigated. Here, we generated and characterized the Hsp90 inhibitor PU-H71, conjugated to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with a C Topics: Allosteric Site; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Molecular Docking Simulation; Neoplasms; Protein Conformation; Purines | 2020 |
Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors.
Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor. Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Crystallography, X-Ray; HeLa Cells; HSP90 Heat-Shock Proteins; Humans; Mice, Nude; Mitochondria; Molecular Docking Simulation; Neoplasms; Pyrazoles; Pyrimidines | 2017 |
Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells.
Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies. Topics: A549 Cells; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Benzoquinones; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Amplification; Genetic Predisposition to Disease; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mutation; Mutation, Missense; Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Purines; RNA Interference; Transfection; Triazoles | 2017 |
PU-H71, a novel Hsp90 inhibitor, as a potential cancer-specific sensitizer to carbon-ion beam therapy.
PU-H71, a heat shock protein 90 (Hsp90) inhibitor, has yielded therapeutic efficacy in many preclinical models and is currently in clinical trials. Carbon-ion radiotherapy (CIRT) has provided successful tumor control; however, there is still room for improvement, particularly in terms of tumor-specific radiosensitization. The Hsp90 inhibitor PU-H71 has been shown to sensitize tumor cells to X-ray radiation. A murine osteosarcoma cell line (LM8) and a normal human fibroblast cell line (AG01522) were treated with PU-H71 before X-ray, 14- or 50-keV/µm carbon-ion beam (C-ion) irradiation. Cell survival and protein expression were evaluated with colony formation and western blot, respectively. Treatment with PU-H71 alone was shown to be non-toxic to both cell lines; however, PU-H71 was shown to significantly sensitize LM8 cells to not only X-ray, but also to C-ion irradiation, while only a minimal sensitizing effect was observed in AG01522 cells. PU-H71 treatment was found to suppress the protein expression levels of Rad51 and Ku70, which are associated with the homologous recombination pathway and the non-homologous end-joining pathway of double-strand break repair. The findings reported here suggest that PU-H71 could be a promising radiosensitizer for CIRT. Topics: Animals; Benzodioxoles; Cell Death; Cell Line, Tumor; DNA Breaks, Double-Stranded; Fibroblasts; Heavy Ion Radiotherapy; HSP90 Heat-Shock Proteins; Humans; Mice; Neoplasms; Purines; Radiation Tolerance; Radiation-Sensitizing Agents; X-Rays | 2016 |
Hsp90 inhibition by PU-H71 induces apoptosis through endoplasmic reticulum stress and mitochondrial pathway in cancer cells and overcomes the resistance conferred by Bcl-2.
Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because of its role in stabilizing the active form of a wide range of client oncoproteins. This study investigated the mechanism of apoptosis induced by the purine-scaffold Hsp90 inhibitor PU-H71 in different human cancer cell lines and examined the role of Bcl-2 and Bax in this process. We demonstrated that Hsp90 inhibition by PU-H71 generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of Grp94, Grp78, ATF4 and CHOP. In response to PU-H71-induced ER stress, apoptosis was triggered in melanoma, cervix, colon, liver and lung cancer cells, but not in normal human fibroblasts. Apoptosis was executed through the mitochondrial pathway as shown by down-regulation of Bcl-2, up-regulation and activation of Bax, permeabilization of mitochondrial membranes, release of cytochrome c and activation of caspases. We also found that, in contrast to the ER stressor thapsigargin, PU-H71 induced apoptosis in cells overexpressing Bcl-2 and thus overcame the resistance conferred by this anti-apoptotic protein. In addition, although Bax deficiency rendered cells resistant to PU-H71, combined treatment with the anticancer drugs cisplatin or melphalan greatly sensitized these cells to PU-H71. Taken together, these data suggest that inhibition of Hsp90 by PU-H71 is a promising strategy for cancer treatment, particularly in the case of tumors resistant to conventional chemotherapy. Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Benzodioxoles; Blotting, Western; Caspases; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Flow Cytometry; Fluorescent Antibody Technique; HSP90 Heat-Shock Proteins; Humans; Melphalan; Mitochondria; Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Purines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thapsigargin; Tumor Cells, Cultured; Unfolded Protein Response | 2013 |
Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies.
PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-κB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-κB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKγ, NF-κB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies. Topics: Animals; Apoptosis; Autophagy; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Gammaherpesvirinae; Herpesviridae Infections; HSP90 Heat-Shock Proteins; Humans; Mice; Neoplasm Transplantation; Neoplasms; NF-kappa B; Proteome; Proteomics; Purines; Signal Transduction; Viral Proteins | 2013 |
Naughty chaperone as a target for viral cancer.
Topics: Animals; Benzodioxoles; Herpesviridae Infections; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Purines; Viral Proteins | 2013 |
Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.
Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition. Topics: Animals; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Computational Biology; Drug Discovery; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Proteomics; Purines; Signal Transduction | 2011 |