luminespib (AUY922)

We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. 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.

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.

KRIBB11 inhibited HSP70 and HSP90 upregulation through treatment with AUY922, an HSP90 inhibitor, and enhanced the cytotoxic effect of AUY922, suggesting a salvage role of HSF1-dependent HSP induction in response to drug treatment. Finally, treatment of mice with KRIBB11 reduced ATL tumor growth. Therefore, this study provides a strong rationale to target HSF1 and validates the anti-ATL activity of KRIBB11.

These consist of the Bcl-2 inhibitor ABT-199 (Venetoclax), the HSP90 inhibitors AUY922 (Luminespib), EC144, PF-04929113, NVP-HSP990, the BET bromodomain inhibitor JQ1, the microtubule polymer stabilizer Paclitaxel, as well as two agents of the classical chemotherapy for BCP-ALL, the glucocorticoid Dexamethasone and the antimitotic Vincristine...In the combination setting, we managed to couple Givinostat, our previously established compound active for CRLF2r ALL cases, with Trametinib (ZIP synergy 7.04 and 16.83 for MUTZ-5 and MHH-CALL-4 respectively) or Venetoclax (ZIP synergy 9.23 and 5.03), thus providing a successful synergistic targeting further confirmed in CRLF2r ALL blasts, whose synergistic mechanism of action is currently investigated. 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

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.

The efficacy of mobocertinib, amivantamab and poziotinib in NSCLC with EGFR exon 20 insertion mutations is promising. 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.

Preclinical in vitro studies were performed to validate the efficacy of HSP90 inhibitors (STA9090, AUY922, HSP990), with PI3K inhibitors; PIK75 (investigational) or clinically available BGT226, and their pairwise combinations, in NCI-H295R and SW13 ACC cells. 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.

In addition, we obtained four drugs with potential efficacy for OS: AUY922, bortezomib, lenalidomide, and Z.LLNle.CHO. 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.

Interventional studies reported outcomes for TKIs (mobocertinib, poziotinib, osimertinib, afatinib, CLN-081, DZD9008), a monoclonal antibody (amivantamab), and a heat shock protein 90 inhibitor (luminespib). 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.

Drug sensitivity analysis showed that low-risk scores were related to anti-cancer agents like AICAR and Axitinib, whereas high-risk scores were connected with certain drugs such as AUY922. 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.

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.

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.

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.

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.

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.

Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922. 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.

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.

Treatment with 6b showed no vision toxicity (IC > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC and has no effect in hERG test. 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.

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.

In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.

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.

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.

AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells.

Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib's activity in bortezomib-resistant myeloma cells...Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter.

P1/2, N=45, Completed, Novartis Pharmaceuticals | Phase classification: P2 --> P1/2

Together our data indicates that HSP90 inhibition with AUY922 can limit the acquisition of metastatic and drug resistant phenotypes in A549 cells at low, clinically appropriate doses.

In clinical studies, TAK-788 showed promising results with a 43% confirmed ORR (n=12/28) and a 7.3-month median PFS in refractory patients; ORR for JNJ-372 was 30% in TKI-naïve patients (22% confirmed, n =27 ); poziotinib, luminespib, afatinib, and cisplatin/pemetrexed resulted in <20% ORR. Legal entity responsible for the study: The authors. Funding: Millennium Pharmaceuticals, Inc.

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.

Our findings indicate an effective action of NVP-AUY922 in combined with DOX in this cell line. These results can predict the treatment outcome in this model.

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.

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.

P2, N=66, Completed, Novartis Pharmaceuticals | Recruiting --> Completed