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- | Journal: High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia. (Pubmed Central) - Nov 6, 2023
Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.
- | luminespib (AUY922) / Ligand, TAE-684 / Novartis, Scripps Research Institute
Journal: Transcriptomic clock predicts vascular changes of prodromal diabetic retinopathy. (Pubmed Central) - Aug 14, 2023
We also identified NVP-TAE684, geldanamycin, and NVP-AUY922 as the top three potential drugs which can potentially attenuate the early DR. Although we need more in vivo studies in the future to support our re-purposed drugs, we have provided a data-driven approach to drug discovery.
- | luminespib (AUY922) / Ligand
Journal: Prediction of Prognosis and Chemotherapeutic Sensitivity Based on Cuproptosis-Associated lncRNAs in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma. (Pubmed Central) - Aug 2, 2023
Several drug sensitivities were more sensitive in high-risk patients and showed significant correlations with the risk models, such as Bortezomib_1191, Luminespib_1559, and Rapamycin_1084, suggesting that these drugs may be candidate clinical drugs for patients with a high risk of CESC. In summary, this study further explored the mechanism of CRLs in CESC and provided a more optimized prognostic model and some insights into chemotherapy of CESC.
- | luminespib (AUY922) / Ligand
Journal: Benzo(a)pyrene regulates chaperone-mediated autophagy via heat shock protein 90. (Pubmed Central) - Jul 31, 2023
Our study also revealed that BaP regulates CMA through HSP90. This study fills the gap of the effect of BaP on autophagy and its mechanism, which will lead to a more comprehensive understanding of the action mechanism of BaP.
- || Review, Journal, EGFR exon 20: New therapies in non-small cell lung cancer with EGFR exon 20 insertion mutations. (Pubmed Central) - Jun 19, 2023
However, therapies were assessed in single-arm CTs with low-quality evidence. Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs.
- | luminespib (AUY922) / Ligand
Journal: Hsp90 mutants with distinct defects provide novel insights into cochaperone regulation of the folding cycle. (Pubmed Central) - Jun 9, 2023
Overall, our results indicate that the timing of transition into and out of the closed conformation is tightly regulated by cochaperones. Further analysis will help elucidate additional steps required for progression through the Hsp90 folding cycle and may lead to new strategies for modulating Hsp90 function.
- | Journal: Using ChEMBL to Complement Schistosome Drug Discovery. (Pubmed Central) - May 27, 2023
Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel...Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range...ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development.
- APPLICATIONS OF HIGH-THROUGHPUT DRUG SCREENING AS DRUG REPURPOSING STRATEGY FOR POOR OUTCOME SUBGROUPS OF PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (Poster area) - May 12, 2023 - Abstract #EHA2023EHA_959;
This study has highlighted the emerging benefit of HTP drug screening applications guiding the early design oftherapies for multiple or specific patient subgroups in an approach of repurposing drugs available in the pharmacological landscape. Drug sensitivity, Targeted therapy, B cell acute lymphoblastic leukemia, Down Syndrome
- || luminespib (AUY922) / Ligand
Review, Journal: Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review. (Pubmed Central) - Mar 26, 2023
It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.
- luminespib (AUY922) / Ligand
Anticancer activity of Hsp90 inhibitor AUY922 in nasopharyngeal carcinoma and non-small cell lung cancer cells (Section 14; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_7255;
These findings provide evidence that AUY922 could be useful for the treatment of NPC and NSCLC as a single agent or in combination with cisplatin. Most importantly, our results provide a preclinical proof of concept for the efficacy of AUY922 in cisplatin-resistant NPC and NSCLC treatment.
- Synergistic efficacy of HSP90 and PI3K inhibitors in adrenocortical carcinoma (Section 14; Poster Board #20) - Mar 14, 2023 - Abstract #AACR2023AACR_4906;
Conclusively, combination of HSP90 and PI3K inhibitors demonstrated a promising in vitro synergistic efficacy by inhibiting the key oncogenic targets of ACC. Further validation of in vivo efficacy is warranted.
- | luminespib (AUY922) / Ligand
Journal, Gene Expression Profile: Identification of Novel Anti-ZIKV Drugs from Viral-Infection Temporal Gene Expression Profiles. (Pubmed Central) - Feb 27, 2023
Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future.
- | luminespib (AUY922) / Ligand
Journal, PD(L)-1 Biomarker, IO biomarker: Integrated bioinformatic analysis identified a novel prognostic pan-programmed cell death signature for bladder cancer. (Pubmed Central) - Dec 13, 2022
Docetaxel, staurosporine, and luminespib were identified as potentially effective drugs for high-PPRPS bladder cancer patients. In summary, we developed the Pan-PCD signature to improve the accuracy of bladder cancer prognostic predictions and to provide a novel classification method to guide treatment selection.
- | luminespib (AUY922) / Ligand
Journal: Developing Isoxazole as a Native Photo-Cross-Linker for Photoaffinity Labeling and Chemoproteomics. (Pubmed Central) - Nov 16, 2022
Subsequently, two isoxazole-based drugs, Danazol and Luminespib, were employed in chemoproteomic studies, revealing their potential cellular targets. These results provide valuable strategies for future chemoproteomic study and drug development.
- | luminespib (AUY922) / Ligand
Biomarker, Journal: A novel signature to guide osteosarcoma prognosis and immune microenvironment: Cuproptosis-related lncRNA. (Pubmed Central) - Aug 17, 2022
The mRNA expression level of AL591767.1 was decreased in OS, and that of AL645608.6, CARD8-AS1, AC005041.3, AC098487.1, and UNC5B-AS1 was upregulated in OS. CRLncs that can guide OS prognosis and the immune microenvironment and drugs that may have a potential curative effect on OS obtained in this study provide a theoretical basis for OS survival research and clinical decision-making.
- || Retrospective data, Review, Journal, IO biomarker, EGFR exon 20: Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and pooled analysis of patient outcomes. (Pubmed Central) - Aug 6, 2022
Conventional treatments used in patients with EGFR exon 20 insertion mutation-positive NSCLC have limited efficacy, though chemotherapy appeared to be associated with better response and survival outcomes than non-exon 20 targeting EGFR-TKIs and IO agents. This supports the need to identify EGFR exon 20 insertion mutations as the availability of new targeted treatments may offer additional therapeutic options to these patients.
- | Inlyta (axitinib) / Pfizer, luminespib (AUY922) / Ligand
Journal, IO biomarker: A Comprehensive Analysis of Pyroptosis-Related lncRNAs Signature Associated With Prognosis and Tumor Immune Microenvironment of Pancreatic Adenocarcinoma. (Pubmed Central) - Jul 27, 2022
This work explored the significance of the risk model constructed by pyroptosis-related lncRNAs in prognosis prediction and its internal link with the immune microenvironment of PAAD. The results are expected to assist in the diagnosis, prognostic assessment, and management of patients with PAAD.
- | luminespib (AUY922) / Ligand
Journal: Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer. (Pubmed Central) - Jul 23, 2022
The results are expected to assist in the diagnosis, prognostic assessment, and management of patients with PAAD. The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.
- | Journal, Gene Signature, PARP Biomarker, IO biomarker: Machine Learning Screens Potential Drugs Targeting a Prognostic Gene Signature Associated With Proliferation in Hepatocellular Carcinoma. (Pubmed Central) - Jul 17, 2022
The five-gene signature associated with proliferation can be used for survival prediction and risk stratification for HCC patients. Potential drugs targeting this gene signature deserve further attention in the treatment of HCC.
- Jeselhy (pimitespib) / Otsuka
Delayed Treatment with the Novel HSP90 inhibitor TAS-116 Ameliorate Hydrochloric Acid-Induced Pulmonary Fibrosis (TP-8 in thematic poster area) - Jun 22, 2022 - Abstract #ERS2022ERS_2424;
Recently, we reported that HSP90 is upregulated in HCl-induced pulmonary fibrosis and that HSP90 inhibitor AUY-922 mitigates HCl-induced pulmonary fibrosis. Delayed administration of TAS-166 may be used against HCl-induced lung fibrosis.
- | luminespib (AUY922) / Ligand
Journal: A Low Membrane Hsp70 Expression in Tumor Cells With Impaired Lactate Metabolism Mediates Radiosensitization by NVP-AUY922. (Pubmed Central) - Apr 26, 2022
An impaired lipid metabolism in LDH cells reduces the Hsp70 membrane-anchoring sphingolipid globotriaosylceramide (Gb3) and thereby results in a decreased Hsp70 cell surface density on tumor cells. Our results demonstrate that the membrane Hsp70 density, but not cytosolic HSP levels determines the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in LDH cells.
- | Biomarker, Journal, IO biomarker: Identification of Fatty Acid Metabolism-Related lncRNAs as Biomarkers for Clinical Prognosis and Immunotherapy Response in Patients With Lung Adenocarcinoma. (Pubmed Central) - Apr 26, 2022
We constructed a 7-lncRNA prognostic model to predict the OS of patients with LUAD. In addition, the predictive nomogram model based on our established seven fatty acid metabolism-related lncRNA signatures provides better clinical value than that of the traditional TNM staging system in predicting the prognosis of patients with LUAD and presents new insights for personalized treatment.
- | luminespib (AUY922) / Ligand, onalespib (AT13387) / Otsuka
Journal: HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction. (Pubmed Central) - Apr 8, 2022
These two inhibitors also blocked S1SP-mediated barrier dysfunction and loss of VE-cadherin. These data suggest that spike protein subunit 1 can elicit, by itself, direct injury to the endothelium and suggest a role of HSP90 inhibitors in preserving endothelial functionality.
- | ganetespib (ADX-1612) / Aldeyra, luminespib (AUY922) / Ligand
Preclinical, Journal: Different HSP90 Inhibitors Exert Divergent Effect on Myxoid Liposarcoma In Vitro and In Vivo. (Pubmed Central) - Mar 26, 2022
In conclusion, our results indicate that different HSP90 inhibitors, albeit having the same target, can vary significantly in downstream effects and treatment outcomes. These results should be considered before proceeding into clinical trials against MLS or other malignancies.
- | luminespib (AUY922) / Ligand
Preclinical, Journal: Complex Crystal Structure Determination of Hsp90-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922. (Pubmed Central) - Mar 15, 2022
At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90 by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922.
- | luminespib (AUY922) / Ligand
Journal: NVP-AUY922 alleviates radiation-induced lung injury via inhibition of autophagy-dependent ferroptosis. (Pubmed Central) - Mar 1, 2022
Mechanistically, NVP-AUY922 prevented chaperone-mediated autophagy of the GPX4 pathway in vitro and in vivo, and the autophagy inhibitor Baf-A1 significantly increased the level of GPX4 and alleviated lung inflammation. NVP-AUY922 can alleviate RILI by inhibiting chaperone-mediated lysosomal degradation of GPX4, demonstrating its potential as a novel protective agent against RILI.
- | luminespib (AUY922) / Ligand
Journal, Cancer stem cells: Preferential radiosensitization to glioblastoma cancer stem cell-like cells by a Hsp90 inhibitor, N-vinylpyrrolidone-AUY922. (Pubmed Central) - Feb 15, 2022
The mechanisms underlying radiosensitization by NVP-AUY922 are discussed in relation to the properties of cancer stem cells. Overall, HIF-1α inhibition by NVP-AUY922 may induce higher sensitization of cancer stem cells to radiation.
- | Inrebic (fedratinib) / BMS, luminespib (AUY922) / Ligand
Journal: Screening Novel Drug Candidates for Kidney Renal Clear Cell Carcinoma Treatment: A Study on Differentially Expressed Genes through the Connectivity Map Database. (Pubmed Central) - Feb 4, 2022
The above results indicated that fedratinib, LY 344864, geldanamycin, AS-605240, and luminespib could be used as candidates for KIRC therapy. The findings from this study will make contributions to the treatment of KIRC in the future.
- Halaven (eribulin mesylate) / Eisai
Targeted treatment options for childhood hepatoblastoma using high-throughput drug screening ([VIRTUAL]) - Feb 3, 2022 - Abstract #ESMOTAT2022ESMO_TAT_145;
The screen revealed many new promising compounds for HB treatment. The efficacy of these agents should be confirmed in in vivo models in the future.
- luminespib (AUY922) / Ligand
"Synthesis and Lead Optimization of isoxazole acetamide derivatives as an anti-HIV agent" (Virtual Room (Marriott Marquis San Diego Marina)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_1618;
These findings concluded HSP90 as a promising target to overcome the limitations of the current antiviral drug discovery approach.Our previously synthesized isoxazole acetamide analog 2l having a 3.5 times better therapeutic index (TI) than AUY922, a second-generation HSP90 inhibitor...In this study, activity cliffs arising due to trivial structural change (6g vs 6d as shown in Figure 1) by Structure-activity Landscape index (SALI) analysis. This analysis aided 3-D pharmacophore generation that further will be used in virtual screening for the discovery and development of alternative antiviral leads for HIV.Figure 1 Activity cliff between isoxazole acetamide analogs 6g & 6d
- | luminespib (AUY922) / Ligand
Journal: NIX protein enhances antioxidant capacity of and reduces the apoptosis induced by HSP90 inhibitor luminespib/NVP-AUY922 in PC12 cells. (Pubmed Central) - Jan 27, 2022
All of these results indicated that high NIX protein level enhances antioxidant capacity of PC12 cells and reduces the apoptosis caused by cell stress, such as induced by luminespib/NVP-AUY922. Therefore, luminespib/NVP-AUY922 might be effective only for PCPG with low NIX level, while targeting NIX could be a further supplement to the therapeutic treatment strategy for PCPG patients with high NIX protein level.
- | Nexavar (sorafenib) / Bayer, Amgen
Biomarker, Journal, PARP Biomarker, IO biomarker: BTBD10 is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma. (Pubmed Central) - Jan 26, 2022
The IC50 scores of Sorafenib, Navitoclax, Veliparib, Luminespib, and Imatinib were found to be lower in BTBD10 high-expressing HCC group. BTBD10 negatively regulates tumor immunity in HCC and exhibits adverse effect on the prognosis of HCC, which could be a potential target for immunotherapy.
- | Preclinical, Journal: Heat Shock Protein 90 Inhibitor Effects on Pancreatic Cancer Cell Cultures. (Pubmed Central) - Jan 20, 2022
Novel Hsp90 inhibitors can be developed as antipancreatic cancer agents. Their chemical structures are simpler, and they are likely to exhibit lower side effects than the much more complex inhibitors used as controls.
- | temozolomide / Generic mfg.
Biomarker, Journal, Heterogeneity, PARP Biomarker: A heat shock protein 90 inhibitor reduces oncoprotein expression and induces cell death in heterogeneous glioblastoma cells with EGFR, PDGFRA, CDK4, and NF1 aberrations. (Pubmed Central) - Jan 11, 2022
Their chemical structures are simpler, and they are likely to exhibit lower side effects than the much more complex inhibitors used as controls. Taken together, AUY922 led to GBM cell death via apoptosis and autophagy, and reduced the mRNA and protein expression of EGFR, PDGFRA, CDK4, and NF1in heterogeneous GBM cells.
- | ganetespib (ADX-1612) / Aldeyra, luminespib (AUY922) / Ligand
Journal: Evolution of kinase polypharmacology across HSP90 drug discovery. (Pubmed Central) - Jan 4, 2022
We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.
- | luminespib (AUY922) / Ligand
Journal: Analysis of Genome-Wide Alternative Splicing Profiling and Development of Potential Drugs in Lung Adenocarcinoma. (Pubmed Central) - Nov 7, 2021
Among them, NVP-AUY922 had the lowest IC50 value and might become a potential drug to prolong a patient's survival. In conclusion, our study established a potential prognostic signature for LUAD patients, revealed a splicing network between AS and SFs and possible immune escape mechanism, and provided several small-molecule drugs to inhibit tumorigenesis.
- | luminespib (AUY922) / Ligand
Journal: AUY922 induces retinal toxicity through attenuating TRPM1. (Pubmed Central) - Nov 6, 2021
Our study demonstrates the pathology of AUY922-induced retinal toxicity in vivo. TRPM1 is an HSP90 client, regulates photoreceptor morphology and function, and mediates AUY922-induced cytotoxicity.
- | luminespib (AUY922) / Ligand
Preclinical, Journal: Heat-activated nanomedicine formulation improves the anticancer potential of the HSP90 inhibitor luminespib in vitro. (Pubmed Central) - Nov 4, 2021
Cytotoxicity assays were used to determine the optimal drug ratios for treatment of luminespib in combination with cisplatin or vinorelbine in non-small cell lung cancer cells. The formulation and drug combination work presented in this paper offer the potential for resuscitation of the clinical prospects of a promising anticancer agent.
- | luminespib (AUY922) / Ligand
Journal: The HSP90 Inhibitor, AUY-922, Protects and Repairs Human Lung Microvascular Endothelial Cells from Hydrochloric Acid-Induced Endothelial Barrier Dysfunction. (Pubmed Central) - Oct 28, 2021
AUY-922 also prevented the HCl-induced activation of RhoA and MLC2 and the internalization of plasmalemmal VE-cadherin. We conclude that, by increasing the expression of cytoprotective proteins, interfering with actomyosin contractility, and enhancing the expression of junction proteins, inhibition of HSP90 may represent a useful approach for the management of HCl-induced endothelial dysfunction and acute lung injury.
- | luminespib (AUY922) / Ligand
Journal: HSP90 inhibition acts synergistically with heat to induce a pro-immunogenic form of cell death in colon cancer cells. (Pubmed Central) - Oct 27, 2021
Also, the combined treatments increased Calreticulin exposure, CD47 downregulation, and HSP70 release compared to the sham-exposed cells. Sub-ablative heating can act synergistically with the clinically relevant HSP90 inhibitor NVP-AUY922 to induce a pro-immunogenic form of cell death in colon cancer cells.
- | luminespib (AUY922) / Ligand
Journal: Fatty acid oxidation is an adaptive survival pathway induced in prostate tumors by heat shock protein 90 inhibition. (Pubmed Central) - Sep 2, 2021
AUY922 (luminespib), a new-generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer...This combination warrants further preclinical and clinical investigation as a novel strategy to overcome resistance to HSP90 inhibition. Implications: Metabolic pathways induced in tumor cells by therapeutic agents may be critical but targetable mediators of treatment resistance.
- | luminespib (AUY922) / Ligand
Preclinical, Journal: The Role of HSP70 in the Protective Effects of NVP-AUY922 on Multiple Organ Dysfunction Syndrome in Endotoxemic Rats. (Pubmed Central) - Aug 24, 2021
These results indicated that NVP possessed the anti-inflammatory and antioxidant effects on LPS-induced acute inflammation, which might be associated with HSP70 and HO-1, leading to prevent MODS in sepsis. NVP might be considered as a novel therapeutic strategy in the prevention of sepsis-induced MODS.
- | luminespib (AUY922) / Ligand
Preclinical, Journal: Post-treatment with a heat shock protein 90 inhibitor prevents chronic lung injury and pulmonary fibrosis, following acute exposure of mice to HCl. (Pubmed Central) - Aug 18, 2021
Furthermore, AUY-922 improved lung function, decreased the overexpression and accumulation of extracellular matrix proteins and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to HCl. We conclude that AUY-922, and possibly other HSP90 inhibitors, successfully block the adverse effects associated with acute exposures to HCl and may represent an effective antidote against HCl-induced chronic lung injury and fibrosis.
- | luminespib (AUY922) / Ligand, Gilotrif (afatinib) / Boehringer Ingelheim
Preclinical, Journal: Ring-opening of five-membered heterocycles conjugated 4-isopropylresorcinol scaffold-based benzamides as HSP90 inhibitors suppressing tumor growth in vitro and in vivo. (Pubmed Central) - Aug 13, 2021
The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer.
- | luminespib (AUY922) / Ligand, tanespimycin (BMS-722782) / BMS
Preclinical, Journal: Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells. (Pubmed Central) - Jun 10, 2021
Similar events occurred in the lungs of mice treated with AUY-922. Thus, our study demonstrates that Hsp90 inhibition triggers the activities of the unfolded protein response, and suggests that this molecular machinery contributes in the protective action of Hsp90 inhibitors in the lung microvasculature.
- || luminespib (AUY922) / Ligand
Clinical, Journal, PARP Biomarker: Transferrin Modified GSH Sensitive Hyaluronic Acid Derivative Micelle to Deliver HSP90 Inhibitors to Enhance the Therapeutic Efficacy of Brain Cancers. (Pubmed Central) - Jun 3, 2021
Moreover, biochemical index and histological analysis revealed synthesized micelle does not show any significant cytotoxicity to the selected major organs. Overall, a synthesized micelle is the best carrier for AUY922 to enhance the therapeutic efficiency of brain cancer.
- | luminespib (AUY922) / Ligand
Preclinical, Journal: Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs. (Pubmed Central) - Jun 3, 2021
Interestingly, this Hsp90 inhibitor abolished the LPS-induced pIRE1α suppression, a major component of the unfolded protein response. Our study elucidates the molecular pathways involved in the progression of murine inflammation and supports our efforts on the development of new therapeutics against lung inflammatory diseases and sepsis.
- | luminespib (AUY922) / Ligand
Journal: Discovery of novel heat shock protein (Hsp90) inhibitors based on luminespib with potent antitumor activity. (Pubmed Central) - May 13, 2021
Animal studies indicated that compared to luminespib, their activities were superior in A2780 or NCI-H1975 tumor xenograft models. A molecular modeling study demonstrated that compound 4a could fit nicely into the N-terminal ATP binding pocket.
- | luminespib (AUY922) / Ligand
Journal: Loss of ARID1A promotes epithelial-mesenchymal transition and sensitizes pancreatic tumors to proteotoxic stress. (Pubmed Central) - May 4, 2021
Here, we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo...While loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibits potential as a biomarker for PDAC patients who may benefit by HSP90-targeting drugs treatment.
- | luminespib (AUY922) / Ligand
Journal: Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains. (Pubmed Central) - Apr 27, 2021
We present the first NMR study of the interaction between heat shock protein 90 (Hsp90) and amino (N)-terminal inhibitors 17-AAG, and AUY922, and carboxy (C)-terminal modulators SM253, and LB51...We also show that C-terminal inhibitor LB51 binds to the C-terminus with a more significant spectroscopic change than previously reported using NMR binding studies of C-terminal inhibitors novobiocin and silybin. These data provide key insights into how the allosteric inhibitor SM253 controls the C-terminal co-chaperones and confirms the binding domain of LB51.