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    6ms
    High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia. (PubMed, Biochem Pharmacol)
    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.
    Journal
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    KMT2A (Lysine Methyltransferase 2A) • PAX5 (Paired Box 5)
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    Venclexta (venetoclax) • paclitaxel • JQ-1 • vincristine • dexamethasone • luminespib (AUY922) • SNX-5422
    1year
    APPLICATIONS OF HIGH-THROUGHPUT DRUG SCREENING AS DRUG REPURPOSING STRATEGY FOR POOR OUTCOME SUBGROUPS OF PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2023)
    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
    Clinical
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    KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)
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    Venclexta (venetoclax) • Mekinist (trametinib) • paclitaxel • JQ-1 • vincristine • dexamethasone • luminespib (AUY922) • Duvyzat (givinostat) • SNX-5422
    over3years
    Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells. (PubMed, Anticancer Res)
    AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells.
    Journal
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    BCL2 (B-cell CLL/lymphoma 2) • CASP3 (Caspase 3)
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    luminespib (AUY922) • SNX-5422
    almost4years
    Mild microwave ablation combined with HSP90 and TGF‑β1 inhibitors enhances the therapeutic effect on osteosarcoma. (PubMed, Mol Med Rep)
    In addition, the results indicated that the expression of cytochrome c, caspase‑3 and caspase‑9 were upregulated in response to the treatment, which indicated that the mitochondrial apoptotic signalling pathway had been activated. These findings may provide a novel strategy for the development of microwave ablation in osteosarcoma treatment, which could effectively kill tumour cells without damaging the surrounding normal tissues.
    Journal
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    CASP3 (Caspase 3) • CASP9 (Caspase 9)
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    SNX-5422