HSP90 inhibitors 17-AAG and VER-82576 inhibit porcine deltacoronavirus replication in vitro

2021 ◽  
pp. 109316
Author(s):  
Yujia Zhao ◽  
Dai Xiao ◽  
Luwen Zhang ◽  
Daili Song ◽  
Rui Chen ◽  
...  
Keyword(s):  
Hsp90 Inhibitors

scholarly journals Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism

2010 ◽  
Vol 107 (7) ◽  
pp. 3146-3151 ◽  
Author(s):  
X. Sun ◽  
E. A. Barlow ◽  
S. Ma ◽  
S. R. Hagemeier ◽  
S. J. Duellman ◽  
...  
Keyword(s):  
Malignant Cells ◽  
Hsp90 Inhibitors ◽  
Dependent Mechanism

scholarly journals Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

2021 ◽  
Author(s):  
Evelyn M. Mrozek ◽  
Vineeta Bajaj ◽  
Yanan Guo ◽  
Izabela Malinowska ◽  
Jianming Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Xenograft Model ◽  
Growth Delay ◽  
Hsp90 Inhibitors ◽  
Null Cell ◽  
Standard Dosage

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored.  Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

Drug Design, Synthesis and In Vitro Evaluation of Substituted Benzofurans as Hsp90 Inhibitors

2018 ◽  
Vol 14 (1) ◽  
Author(s):  
Sundeep Kadasi ◽  
Thadeu E.M.M. Costa ◽  
Neha Arukala ◽  
Mallika Toshakani ◽  
Chaitanya Duggineti ◽  
...  
Keyword(s):  
Drug Design ◽  
Hsp90 Inhibitors ◽  
Design Synthesis ◽  
In Vitro Evaluation

scholarly journals HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma

Blood ◽  
2016 ◽  
Vol 128 (21) ◽  
pp. 2517-2526 ◽  
Author(s):  
Caron Jacobson ◽  
Nadja Kopp ◽  
Jacob V. Layer ◽  
Robert A. Redd ◽  
Sebastian Tschuri ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Key Points ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Key Points Inhibition of HSP90 targets multiple dependences in mantle cell lymphoma. Clinically available HSP90 inhibitors overcome ibrutinib resistance in vitro and in vivo.

Preclinical Evaluation of A Potent 2nd Generation Small-Molecule Hsp90 Inhibitor STA-9090 In Hematological Cell Lines

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2899-2899
Author(s):  
Weiwen Ying ◽  
David Proia ◽  
Suqin He ◽  
Jim Sang ◽  
Kevin Foley ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Small Molecule ◽  
First Generation ◽  
Cell Lymphoma ◽  
Hsp90 Inhibitor ◽  
Phase 2 ◽  
Hsp90 Inhibitors

Abstract Abstract 2899 STA-9090 is a potent, second generation, small-molecule Hsp90 inhibitor, with a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors. In preclinical in vitro and in vivo studies, STA-9090 has shown potency up to 100 times greater than the first-generation Hsp90 inhibitors against a wide range of solid and hematological cancer types including those resistant to imatinib, sunitinib, erlotinib, and dasatinib. STA-9090 is currently being evaluated two Phase 1 and four Phase 2 trials (non-small cell lung, GIST, colon, and gastric) in solid tumor cancers; and two trials in hematologic cancers. Additional Phase 2 trials in several other indications are planned for 2H 2010. Inhibition of Hsp90 by STA-9090 results in the destabilization of a broad range of oncogenic kinases often overexpressed or mutated in hematological cancers. For example, the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in the anaplastic large cell lymphoma (ALCL) cell line Karpas 299, is degraded rapidly in the presence of STA-9090 in vitro, resulting in the loss of viability. Similar results were shown in other NPM-ALK driven ALCL cells including SU-DHL-1 and SR-786 with IC50 less than 20 nM. Stability of other kinases common to hematological malignancies, such as Bcr-Abl, FLT3 and c-Kit, were also shown to be highly sensitive to STA-9090, resulting in potent cell death of cell lines addicted to signaling by these kinases. In vivo, STA-9090 was highly effective in a subcutaneous xenograft model of diffuse large B-cell lymphoma SU-DHL-4 with resulting %T/C values of 26, 4, -90 and -93 when dosed at 25, 50, 75 and 100 mg twice per week, respectively. Importantly, 75 and 100 mg/kg STA-9090 dosed 2 times per week for a total of 3 weeks (150 and 200 mg/kg weekly) resulted in 25% and 50% of the animals in each group being free of tumors by the end of the study, respectively. MV4-11, an AML (FLT3ITD) cell line, turned out to be one of the most sensitive xenograft models to STA-9090 treatment. STA-9090 at 100 mg/kg or125mg/kg once weekly was highly efficacious with 37.5% of mice achieving tumor free with acceptable toxicity at the end of the 3-week treatment period. In conclusion, STA-9090 exhibits preferable biological profiles both in vitro and in vivo in treating hematological malignances. Clinical studies for using STA-9090 both once weekly and twice weekly are ongoing. Disclosures: Ying: Synta Pharmaceuticals: Employment. Proia:Synta Pharmaceuticals: Employment. He:Synta Pharmaceur: Employment. Sang:Synta Pharmaceuticals: Employment. Foley:Synta Pharmaceuticals: former employee. Du:Synta Pharmaceuticals: former employee. Blackman:Synta Pharmaceuticals: Employment. Wada:Synta Pharmaceuticals: Employment. Sun:Synta Pharmaceuticals: Employment. Koya:Synta Pharmaceuticals: Employment.

In vitro and in vivo Evaluation of 17-phenylpropylamine/phenoxyethylamine- 17-demethoxygeldanamycins as Potent Hsp90 Inhibitors

2015 ◽  
Vol 11 (5) ◽  
pp. 482-488 ◽  
Author(s):  
Zhenyu Li ◽  
Lejiao Jia ◽  
Hongjiao Xu ◽  
Chunhua Lu ◽  
Yuemao Shena
Keyword(s):  
Hsp90 Inhibitors

A Hyperactive Signalosome Results in High Sensitivity to HSP90 Inhibitors in AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2567-2567
Author(s):  
Hongliang Zong ◽  
Tony Taldone ◽  
Gail J. Roboz ◽  
Gabriela Chiosis ◽  
Monica L. Guzman
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
In Vivo Imaging ◽  
Flow Cytometric Analysis ◽  
Leukemia Cell ◽  
Hsp90 Inhibitor ◽  
Hsp90 Inhibitors ◽  
Stat Signaling

Abstract HSP90 is well established in supporting tumorigenesis by stabilizing oncogenic client proteins. Given this crucial role, a number of HSP90 inhibitors have been tested in various types of cancer, including leukemia. However, clinical trials thus far revealed only a subset of AML patients benefited from the treatment. Therefore, precision medicine approaches to define parameters that predict the patients' response to HSP90 inhibitors are needed to select patients who are most likely to benefit. We have previously demonstrated that PU-H71, a novel purine scaffold HSP90 inhibitor with selectivity for a tumor-specific HSP90 and currently translating into Phase 2 clinical evaluation, is capable of ablating malignant blasts, progenitor and stem cells in AML patient samples using in vitro studies. We found that leukemia cell lines (n=18) and primary AML patient samples (n=26) with greater numbers of simultaneously activated signaling networks, including PI3K-AKT and JAK-STAT, were the most sensitive to HSP90 inhibition. Using different genetic models, our studies revealed that diverse oncogenic transformations that converge upon simultaneous hyperactivation of PI3K-AKT and JAK-STAT promote sensitivity to PU-H71. To validate the efficacy of PU-H71 in vivo, we generated AML-GFP-luciferase xenograft models using cell lines with hyperactive signalosome. Xenotransplanted mice were treated with PU-H71 one week post-engraftment. In vivo imaging indicated that MOLM-13 xenografted leukemia was rapidly and significantly reduced by PU-H71 treatment. Six doses of PU-H71 produced robust anti-leukemic activity as indicated by in vivo imaging and flow cytometric analysis of post-treatment bone marrow (no disease detected). In addition, we generated 7 AML patient-derived xenografts (PDX) cohorts with samples that displayed varied levels of activation of PI3K-AKT and JAK-STAT signaling pathways. After initial validation that status of the PI3K-AKT and JAK-STAT signaling pathways were preserved in the PDX, we initiated treatment with PU-H71 and found that, as predicted, the AML-PDX with the most hyperactive signalosome were the most sensitive to in vivo treatment to PU-H71. Importantly, samples with hyperactive PI3K-AKT and JAK-STAT signaling also demonstrated a significant reduction in LSC using secondary transplants. Taken together, we found that a hyperactive signalosome results in increased sensitivity to the HSP90 inhibitor PU-H71 in vitro and in vivo. Our study suggests that evaluation of PI3K-AKT and JAK-STAT signaling pathways may provide a means to select patients who are most likely to benefit from HSP90 inhibitory therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective DNA Gyrase Inhibitors: Multi-Target In Silico Profiling with 3D-Pharmacophores

2021 ◽  
Vol 14 (8) ◽  
pp. 789
Author(s):  
Tihomir Tomašič ◽  
Asta Zubrienė ◽  
Žiga Skok ◽  
Riccardo Martini ◽  
Stane Pajk ◽  
...  
Keyword(s):  
In Silico ◽  
Dna Gyrase ◽  
In Vitro Assays ◽  
Hsp90 Inhibitors ◽  
Activity Profiling ◽  
Binding Domains ◽  
Highly Active ◽  
Target Binding ◽  
Gyrase Inhibitors

(1) Background: DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. (2) Methods: To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. (3) Results: The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. (4) Conclusions: The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

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