tanespimycin (BMS-722782)

Upon 1064 nm laser irradiation, USGRV-17-AAG exhibits a high photothermal conversion efficiency (65.1%) and thus can achieve temperature responsive release of tanespimycin (17-AAG), an inhibitor of HSP90...Additionally, USGRV-17-AAG exhibited efficient photothermal conversion (65.1%) under 1064 nm laser irradiation and enabled temperature-responsive drug release through the action of surface-modified upper critical solution temperature (UCST) polymers. This nanocarrier, with enhanced NIR-II photothermal therapy, might offer a promising solution for anti-tumor treatment.

PCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.

Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

High CLIC1 expression samples were more sensitive to camptothecin, cisplatin, doxorubicin, erlotinib, paclitaxel, rapamycin, clofarabine, tanespimycin, methotrexate, everolimus, TAK-733, trametinib and AZD8330. Single-cell analysis unveiled that CLIC1 was expressed ubiquitously in tumor cells and tumor microenvironment. Overall, CLIC1 was a promising treatment vulnerability in glioma.

Consistent with this, in silico docking studies revealed that capsaicin binding to the ATP binding site of Hsp90 was distinct from classical N-terminus Hsp90 inhibitors, indicating a novel mechanism of action. Collectively, these findings support the use of capsaicin as a chemical scaffold to develop novel Hsp90 N-terminus inhibitors as well as its ability to be a potential cancer co-therapeutic.

It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.

We first identified the lncRNA PVT1/STAT5B positive feedback loop for bladder carcinogenesis, and found a potentially effective drug for BC.

Further study showed that Tim-AIII promoted HSP90 expression and Tim-AIII induced cell death was blocked by the HSP90 inhibitor tanespimycin, indicating that HSP90 was the main target of Tim-AIII to further trigger intracellular events...Tim-AIII, by binding and forming a complex with HSP90, further targeted and degraded GPX4, ultimately induced ferroptosis in NSCLC. These findings provided solid evidence that Tim-AIII can serve as a potential candidate for NSCLC treatment.

We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

Here, we use size-exclusion chromatography in combination with mass spectrometry (SEC-MS) to characterize the early changes in native protein complexes following treatment with the HSP90 inhibitor tanespimycin (17-AAG) for 8 h in the HT29 colon adenocarcinoma cell line...We present this dataset as a resource for the HSP90, proteostasis, and cancer communities (https://www.bioinformatics.babraham.ac.uk/shiny/HSP90/SEC-MS/), laying the groundwork for future mechanistic and therapeutic studies related to HSP90 pharmacology. Data are available via ProteomeXchange with identifier PXD033459.

Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.

Additionally, this in silico analysis found that the anticancer agents and HSP90 inhibitors such as ganetespib, retaspimycin, and tanespimycin would have considerable potential in the treatment of BC. However, these findings need to be further confirmed by laboratory and clinical studies for validating their potential applications. The online version contains supplementary material available at 10.1007/s13205-022-03422-w.

16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC value of 0.21 μM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.

Five bioactive compounds (prostaglandin J2, tanespimycin, semustine, 5182598, and flunarizine) were identified using Connectivity Map. Thus, the results of this study indicate potential biomarkers that could have applications in the development of immune therapy for breast cancer. However, more in vivo, and in vitro studies are required to further verify these results.

High throughput screening identified the HDAC inhibitor, vorinostat and the HSP90 inhibitor, tanespimycin plus the JAK inhibitor, cerdulatinib as the most effective agents against cells expressing the MYB-TYK2 alteration. Importantly, these findings indicate that activating TYK2 alterations can function as driver oncogenes rather than passenger or secondary events in disease development. In addition, our data provide evidence for use of vorinostat and cerdulatinib in the treatment regimens of patients with this rare yet aggressive type of high-risk ALL that warrants further investigation in the clinical setting.

CO gas generating poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) was designed for rapid release of tanespimycin (17-AAG) in transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC)...McA-RH7777 tumor-implanted rats treated by TACE using PLGA/17-AAG/NaHCO MS presented a complete therapeutic response. All these findings suggest that developed tumor microenvironment-responsive gas-generating MS can be efficiently applied to TACE therapy of HCC.

Finally, five compounds (fulvestrant, tanespimycin, mifepristone, tretinoin, and harman) were predicted as potential treatments for glioma. Among them, mifepristone and tretinoin were proven to inhibit the cell cycle and DNA repair in glioma. This study highlights the potential pathogenesis of the circRNA-miRNA-mRNA regulatory network and identifies novel therapeutic options for glioma.

Here, we investigated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors, geldanamycin (GDN) and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), in a panel of glioma tumor cell lines with various genetic alterations...Therefore, the BBB would compromise their cytotoxic effects only partially. We hypothesize that GBM patients may benefit from 17-AAG either as a single agent or in combination with other drugs.

We also identified Tanespimycin as a drug exerting inhibitory effects on metastatic LMS subtype and therefore can serve a potential treatment for this type of sarcoma. These results provide new insights into the pathogenesis, diagnosis, treatment, and prognosis of sarcomas and provide new directions for further study of sarcoma.

Docetaxel, as an inhibitor of microtubules, augmented the expression of Ac‑α‑tubulin, VDAC1 and Bax induced by tanespimycin and increased the degree of caspase activation. Therefore, it can be asserted that the acetylation of α‑tubulin and VDAC1 upregulation or oligomerization induced by tanespimycin may lead to mitochondrial permeability and consequently induce the apoptosis of lung cancer cells. These findings provide evidence for the use of a combination of drugs that target VDAC1 and tubulin to induce tumour cell apoptosis.

Compounds 5b, 5k and 8a showed potent HSP90 inhibitory activities with IC values in nanomolar range; 71.32, 25.07 and 56.78 nm, respectively, against Tanespimycin (IC of 86.45 nm)...Docking studies into the active site of HSP90 N-terminal domain showed good agreement with the obtained biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated where compound 5k had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed antibreast targeted therapy.

They were characterized by potent effect against breast cancer in particular with IC of 11.73, 8.56, 7.35 and 9.48 μM, respectively against Doxorubicin (IC 4.17 μM). HSP90 ATPase activity inhibition assay were conducted where compound 5d exhibited the best IC with 1.58 μM compared to Tanespimycin (IC = 2.17 μM)...Molecular docking studies suggested mode of interaction to HSP90 via hydrogen bonding. ADME properties prediction of the active compounds suggested that they could be used as orally absorbed anticancer drug candidates.