^
    4ms
    Recent advances in HSP90 inhibitors as targeted cancer therapy: Chemical scaffolds, isoform selectivity, and clinical progress. (PubMed, Bioorg Chem)
    Despite extensive research, pimitespib remains the only approved HSP90 inhibitor, while others like ganetespib (STA-9090) and onalespib (AT13387) are undergoing clinical trials with variable outcomes (varying efficacy and tolerability profiles). Over the past five years, significant progress has been made in the medicinal chemistry and chemical biology of HSP90 inhibitors. This review comprehensively summarizes advancements from 2020 to 2024 in the discovery and development of HSP90 inhibitors, spanning natural products and synthetic small molecules, with detailed discussions on their preclinical and clinical development, alongside the challenges faced in translating these inhibitors into effective anticancer agents.
    Review • Journal
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    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53)
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    TP53 mutation
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    ganetespib (ADX-1612) • Jeselhy (pimitespib) • onalespib (AT13387)
    10ms
    New tetrahydroisoquinolines bearing nitrophenyl group targeting HSP90 and RET enzymes: synthesis, characterization and biological evaluation. (PubMed, BMC Chem)
    Moreover, the molecular docking study was applied and the result showed that compounds 8b bind to the RET enzyme with binding energies of - 6.8 kcal/mol in comparison with standard alectinib, which exhibits a binding energy of - 7.2 kcal/mol. Compound 3 can bind with HSP 90 with a binding energy (ΔG) of - 6.8 kcal/mol, which was comparable to the standard Onalespib (- 7.1 kcal/mol).
    Journal
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    ANXA5 (Annexin A5) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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    Alecensa (alectinib) • onalespib (AT13387)
    10ms
    Inhibiting HSP90 changes the expression pattern of PINK1 and BNIP3 and induces oxidative stress in colon cancer cells. (PubMed, Mol Biol Rep)
    Targeting HSP90 in colon cancer cells disrupts their survival by decreasing PINK1 and increasing BNIP3, which activates oxidative and endoplasmic reticulum stress, ultimately triggering apoptosis.
    Journal
    |
    ANXA5 (Annexin A5) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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    onalespib (AT13387)
    10ms
    Genetically Defined Organoid Models Reveal Mechanisms Driving Squamous Cell Neoplastic Evolution and Identify Potential Therapeutic Vulnerabilities. (PubMed, bioRxiv)
    Lastly, our high-throughput, single-organoid-resolution drug screens unexpectedly revealed PIK3CA -driven organoids exhibited sensitivity to Mitomycin C and Onalespib. This study provides novel mechanistic insights into early neoplastic evolution and underscores the value of genetically-defined organoid models for investigating cancer biology and identifying targeted therapies.
    Journal
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    TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • KMT2C (Lysine Methyltransferase 2C) • ANXA1 (Annexin A1) • SMAD3 (SMAD Family Member 3)
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    TP53 mutation • PIK3CA mutation
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    mitomycin • onalespib (AT13387)
    1year
    Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov)
    P1; Active, not recruiting --> Terminated; Drug supply issues
    Combination therapy • Trial termination • Surgery • Metastases
    |
    BRAF V600E • BRAF V600 • BRAF V600K
    |
    THXID® BRAF Kit • cobas® 4800 BRAF V600 Mutation Test
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • onalespib (AT13387)
    over1year
    Onalespib in Treating Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck Receiving Radiation Therapy and Cisplatin (clinicaltrials.gov)
    P1, N=2, Active, not recruiting, National Cancer Institute (NCI)
    Trial completion date • Metastases
    |
    cisplatin • onalespib (AT13387)
    almost2years
    Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov)
    P1, N=29, Active, not recruiting, National Cancer Institute (NCI)
    Trial completion date • Surgery • Metastases
    |
    onalespib (AT13387) • AT7519
    almost2years
    Final survival outcomes and post-hoc tumor gene expression pathway analyses of complete responders from a phase Ib clinical trial of HSP90 inhibitor onalespib and paclitaxel in patients with advanced triple-negative breast cancer (AACR 2024)
    Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and showed anti-tumor activity in patients with advanced TNBC. Gene expression analysis of patient tumor samples suggest that TNBCs with greater activation of immune checkpoint pathways and those with proteins dependent on HSP90 activity, including p53 and HER2, may be more susceptible to HSP90 inhibition.ClinicalTrials.gov study identification: NCT02474173
    P1 data • Retrospective data • Clinical • PD(L)-1 Biomarker • IO biomarker • Metastases
    |
    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • JAK2 (Janus kinase 2) • PD-1 (Programmed cell death 1) • FGFR4 (Fibroblast growth factor receptor 4) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • KRT17 (Keratin 17) • IRF6 (Interferon Regulatory Factor 6) • MMP7 (Matrix metallopeptidase 7)
    |
    nCounter® Breast Cancer 360™ Panel
    |
    paclitaxel • onalespib (AT13387)
    almost2years
    Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer. (PubMed, Ther Adv Med Oncol)
    Combination therapy showed antitumor activity in patients with advanced TNBC. Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.
    P1 data • Journal • Combination therapy • Metastases
    |
    HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    paclitaxel • onalespib (AT13387)
    2years
    System analysis based on the pyroptosis-related genes identifes GSDMD as a novel therapy target for skin cutaneous melanoma. (PubMed, J Transl Med)
    In this study, we constructed a prognostic model based on PRGs and identified GSDMD as a potential therapeutic target, which provide new insights into SKCM treatment.
    Journal
    |
    CASP3 (Caspase 3) • IL18 (Interleukin 18) • NLRP3 (NLR Family Pyrin Domain Containing 3) • GSDMC (Gasdermin C) • GSDMD (Gasdermin D)
    |
    gemcitabine • onalespib (AT13387)
    2years
    Erlotinib Hydrochloride and Onalespib Lactate in Treating Patients With Recurrent or Metastatic EGFR-Mutant Non-small Cell Lung Cancer (clinicaltrials.gov)
    P1/2, N=11, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2023 --> Sep 2024
    Trial completion date • Metastases
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR exon 20 insertion • EGFR L861Q • EGFR G719X • EGFR exon 20 mutation
    |
    erlotinib • onalespib (AT13387)
    2years
    An immune and epigenetics-related scoring model and drug candidate prediction for hepatic carcinogenesis via dynamic network biomarker analysis and connectivity mapping. (PubMed, Comput Struct Biotechnol J)
    Of them, two market drugs approved by the Food and Drug Administration (AT-13387 and KU-55933) have emerged as candidates for HCC study. This new signature panel may serve as a potential prognostic marker, engendering the possibility of novel personalized therapy with classification of HCC patients.
    Journal
    |
    YBX1 (Y-Box Binding Protein 1) • PSMD1 (Proteasome 26S Subunit Non-ATPase 1)
    |
    onalespib (AT13387) • KU-55933