- |||||||||| 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
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.
- |||||||||| luminespib (AUY922) / Ligand
Journal, PARP Biomarker: Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells. (Pubmed Central) - Apr 23, 2021
In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90)...This compound, 12c shows the most potent HSP90 inhibitory activity with an IC value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively...In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment.
- |||||||||| sodium chlorite (NP001) / Neuraltus, Clinigen, luminespib (AUY922) / Ligand, nicotine (NC001) / Neurocea
Journal: Optimized HSP90 mediated fluorescent probes for cancer-specific bioimaging. (Pubmed Central) - Apr 2, 2021
Herein, a highly efficient tumor-targeting fluorescent probe (NP-001), which is integrated with 4-hydroxy-1,8-naphthalimide and NVP-AUY922, for tumor imaging has been established...NP-002, a resorcinol-blocked probe which prevented binding with an amino acid residue of the HSP90 ATP binding pocket, was also synthesized as a control...Moreover, pharmacokinetic studies and histological analysis also indicated that NP-001 had a relatively longer retention time and showed no major organ-related toxicities. Overall, these encouraging data suggest that NP-001 is a promising new candidate for the early diagnosis of metastatic disease as well as targeted tumor imaging.
- |||||||||| VE-821 / EMD Serono, Vertex, luminespib (AUY922) / Ligand, KU-55933 / AstraZeneca
Journal: Cooperative treatment effectiveness of ATR and HSP90 inhibition in Ewing's sarcoma cells. (Pubmed Central) - Mar 23, 2021
In addition, we report the first X-ray crystal structures of C. neoformans Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms. Our study reveals that HSP90 and ATR inhibitor combination treatment may be an effective therapeutic approach for Ewing's sarcoma irrespective of the p53 status.
- |||||||||| luminespib (AUY922) / Ligand
Preclinical, Journal: The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice. (Pubmed Central) - Feb 26, 2021
Furthermore, AUY-922 maintained normal 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 NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.
- |||||||||| luminespib (AUY922) / Ligand
Review, Journal: HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF). (Pubmed Central) - Feb 20, 2021
HSP90 inhibition modulates a complex subset of kinases and interferes with intracellular signaling pathways and proteome regulation. In this review, we evaluated the current evidence and rationale for the use of HSP90 inhibitors in the treatment of pulmonary fibrosis, discussed the intracellular pathways involved, described the limitations of the current understanding and provided insights for future research.
- |||||||||| luminespib (AUY922) / Ligand
Journal: P53 Regulates the Redox Status of Lung Endothelial Cells. (Pubmed Central) - Feb 9, 2021
In contrast, P53 induction by Nutlin or the Hsp90 inhibitor AUY922 exerted the opposite effects, namely, suppressed that lipid oxidation marker...Furthermore, the increased reactive oxygen species production due to P53 suppression was associated with lung hyperpermeability responses. In conclusion, P53 supports endothelial barrier function, at least in part, via the modulation of the reactive oxygen species.
- |||||||||| ibrutinib / Generic mfg.
Preclinical, Journal: Destabilization of ROR1 enhances activity of ibrutinib against chronic lymphocytic leukemia in vivo. (Pubmed Central) - Jan 6, 2021
However, immunoblotting validation confirmed that Ibrutinib treatment dramatically deprived HSP90 inhibitors, 17-DMAG, AUY922 or PU-H71, of inducing the degradation of BTK, BLK, LCK or LYN, but not ROR1. Collectively, our data suggested that depletion of ROR1 induced by targeting HSP90 might facilitate the enhancement of Ibrutinib activity against CLL.
- |||||||||| luminespib (AUY922) / Ligand
Journal: Luminespib counteracts the Kifunensine-induced lung endothelial barrier dysfunction. (Pubmed Central) - Oct 26, 2020
Our results indicate that the UPR inducer Luminespib counteracts the effects of Kifunensine in both human and bovine lung endothelial cells. Hence, we suggest that UPR manipulation may serve as a promising therapeutic strategy against potentially lethal respiratory disorders, including the ARDS related to COVID-19.
- |||||||||| melphalan / Generic mfg.
Journal: Inhibition of HSP90 overcomes melphalan resistance through downregulation of Src in multiple myeloma cells. (Pubmed Central) - Oct 2, 2020
We demonstrated that treatment with KW-2478 decreased expression of Src, a client of HSP90, and suppressed the activity of ERK, Akt, and NF-κB. Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM.
- |||||||||| luminespib (AUY922) / Ligand, Herceptin (trastuzumab) / Roche
Phase classification, Combination therapy, Metastases: Combination of AUY922 With Trastuzumab in HER2+ Advanced Breast Cancer Patients Previously Treated With Trastuzumab (clinicaltrials.gov) - Sep 2, 2020
P1/2, N=45, Completed,
Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM. Phase classification: P2 --> P1/2
- |||||||||| Loprox gel/cream/shampoo/topical suspension (ciclopirox topical) / Bausch Health
Journal: Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer. (Pubmed Central) - Aug 27, 2020
In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients.
- |||||||||| luminespib (AUY922) / Ligand
Journal: Effects of Heat Shock Protein 90 Inhibition In the Lungs. (Pubmed Central) - Aug 1, 2020
We employed human lung microvascular endothelial cells to investigate the effects of the Hsp90 inhibitors 17-AAG, AUY-922 and 17-DMAG in the unfolded protein response (UPR) and viability of lung cells...Thus, the present study suggests that the barrier protective effects of Hsp90 inhibition in the lung microvasculature are highly probable to be associated with the activation of the UPR. Hence, the development of novel compounds which stochastically capacitate the repairing elements of UPR, may deliver new therapeutic possibilities against the severities of the acute respiratory distress syndrome.
- |||||||||| luminespib (AUY922) / Ligand
Journal: Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922. (Pubmed Central) - Jun 18, 2020
A combined approach consisting of HSF-1 k.d. and low concentrations of the Hsp90 inhibitor NVP-AUY922 reduces the Hsp90 client protein Akt and potentiates radiosensitization, which involves an impaired homologous recombination mediated by Rad51. Our findings are key for clinical applications of Hsp90 inhibitors with respect to adverse hepatotoxic effects.
- |||||||||| ganetespib (ADX-1612) / Aldeyra, luminespib (AUY922) / Ligand
Development of HER2 targeted HSP90 inhibitors delivery system (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3237;
HER2-HBD recombinant system based on biological affinity between HSP90i and HBD was not required chemical reaction to conjugate antibody and drug. This system might be useful targeted delivery systems for HSP90i without tailored conjugation method to develop antibody-drug conjugate (ADC) and also applied to develop targeted delivery systems for biological inhibitor drugs.
- |||||||||| [VIRTUAL] EX VIVO DRUG TESTING HIGHLIGHTS APOPTOSIS PATHWAYS AS TARGETS IN ADULT B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA () - May 16, 2020 - Abstract #EHA2020EHA_613;
Glucocorticoids, BCL2 inhibitors, idasanutlin (MDM2 inhibitor), luminespib (HSP90 inhibitor), daporinad (NMPRT inhibitor), and plicamycin (antineoplastic antibiotic) were widely effective...Navitoclax, a pan-BCL2 family inhibitor, was highly effective (DSS>20: 89% [17/19]) in our cohort, whereas the BCL2 selective venetoclax was effective only in a distinct subset of patients (DSS>20: 32% [6/19])...Dose-dependent thrombocytopenia has limited its use, but a therapeutic window may exist in rational combinations, such as TKIs in PhposALL. In addition, leukotriene antagonist montelukast was effective in a subset of PhposALL samples, and the mechanisms of sensitivity can be related to leukotriene receptor overexpression.
- |||||||||| Piqray (alpelisib) / Novartis, Zykadia (ceritinib) / Novartis, Tabrecta (capmatinib) / Incyte, Novartis
Trial completion, Metastases: A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov) - Jan 21, 2020
P2, N=66, Completed,
In conclusion, P53 supports BBB integrity, at least in part, by reducing lipid peroxidation. Recruiting --> Completed
- |||||||||| luminespib (AUY922) / Ligand
Journal: Ablation of elongation factor 2 kinase enhances heat-shock protein 90 chaperone expression and protects cells under proteotoxic stress. (Pubmed Central) - Jan 10, 2020
In eEF2K mouse embryonic fibroblasts (MEFs), inhibition of HSP90 by its specific inhibitor AUY922 promoted the accumulation of ubiquitinated proteins...Up-regulation of HSP90 likely protects cells from protein folding stress, arising, for example, from faster rates of polypeptide synthesis due to the lack of eEF2K. Our findings indicate that eEF2K and HSPs closely cooperate to maintain proper proteostasis and suggest that concomitant inhibition of HSP90 and eEF2K could be a strategy to decrease cancer cell survival.
- |||||||||| luminespib (AUY922) / Ligand
Journal: HER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-based PET Imaging. (Pubmed Central) - Dec 24, 2019
Our findings indicate that eEF2K and HSPs closely cooperate to maintain proper proteostasis and suggest that concomitant inhibition of HSP90 and eEF2K could be a strategy to decrease cancer cell survival. These data underline the potential of HER3-based PET imaging to noninvasively provide information about HER3 expression and to identify patients not-responding to targeted therapies due to HER3 recovery.
- |||||||||| luminespib (AUY922) / Ligand
Journal: Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity. (Pubmed Central) - Dec 19, 2019
Further characterization of anti-HIV activity of these molecules suggests that 2l has ∼3.5 fold better therapeutic index than AUY922, the second generation HSP90 inhibitor...Further, 2l mediated inhibition of HSP90 attenuates HIV-1 LTR driven gene expression. Taken together, structural rationale, modeling studies and characterization of biological activities suggest that this novel scaffold can attenuate HIV-1 replication significantly within the host and thus opens a new horizon to develop novel anti-HIV therapeutic candidates.
- |||||||||| luminespib (AUY922) / Ligand
Journal: EGFR exon 20 insertion mutations display sensitivity to Hsp90 inhibition in preclinical models and lung adenocarcinomas. (Pubmed Central) - Nov 22, 2019
P2
Further study of luminespib and other hsp90 inhibitors in this population is warranted. The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
- |||||||||| Completely agree, look data for poziotinib, nazartinib, pyrotinib, TAS6417, TAK788, tarloxotinib, luminespib, WZ8040, WZ4002, and profound data around combos (Twitter) - Oct 10, 2019
- |||||||||| fluorouracil / generics
Preclinical, Journal: Colorectal cancer Consensus Molecular Subtypes translated to preclinical models uncover potentially targetable cancer-cell dependencies. (Pubmed Central) - Sep 28, 2019
The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology. We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group.
- |||||||||| doxorubicin hydrochloride / generics
Biomarker, Journal: Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma. (Pubmed Central) - Aug 6, 2019
...Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines...In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane)...Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2-and AKT-pathways by luminespib and ganetespib treatment. Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.
- |||||||||| Piqray (alpelisib) / Novartis, Zykadia (ceritinib) / Novartis, Tabrecta (capmatinib) / Incyte, Novartis
Enrollment open, Trial completion date, Trial primary completion date, Metastases: A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients With Advanced Non-small Cell Lung Cancer (clinicaltrials.gov) - Jul 25, 2019
P2, N=85, Recruiting,
Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC. Active, not recruiting --> Recruiting | Trial completion date: Feb 2019 --> Sep 2019 | Trial primary completion date: Feb 2019 --> Sep 2019
|
