onalespib (AT13387) / Otsuka - LARVOL DELTA

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

Acute and Early Circulating Tumor DNA Dynamics in Metastatic Triple-Negative Breast Cancer Targeted Therapy Phase Ib/II Clinical Trials (SABCS 2025) - P1b, P2 | "Furthermore, there is littleknown regarding TF dynamics in the hours immediately after initiation of systemic therapy –including whether there is a 'surge' in ctDNA. Banked plasma samples were identified from four completed phase Ib/II clinical trialsenrolling patients with mTNBC: heat shock protein 90 (HSP90) inhibitor onalespib with paclitaxel(NCT02474173), MEK inhibitor trametinib alone and in combination with AKT inhibitorGSK2141795/uprosertib (NCT01964924), multi-kinase inhibitor cabozantinib monotherapy(NCT02260531), and JAK1/2 inhibitor ruxolitinib monotherapy(NCT01562873)... There was no significant 'surge' in ctDNA TF within minutes to 24-hours of infusionof a targeted therapy, cytotoxic chemotherapy, or both in combination. Stability or decline ofctDNA TF 14-28 days after initiation of targeted therapy trial was associated with objectiveresponse and prolonged PFS. This supports further research on ctDNA dynamics immediatelyafter..."

Circulating tumor DNA • Clinical • Metastases • P1/2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • HSP90AA1

Preclinical evaluation of the synergistic effect of heat shock protein 90 inhibitors with temozolomide and external beam radiotherapy in glioblastoma models. (SNO 2025) - "However, due to insufficient efficacy or toxicity, only TAS116 (pimitespib) was approved for clinical use in advanced gastrointestinal tumors in Japan2... In U-87 MG-WT cells, IC50 values were determined for Geldanamycin (53 nM), Onalespib (135 nM), BIIB021 (97 nM), NVP-HSP990 (35 nM), and NMS-E973 (193 nM)... U-87 MG cell viability assays showed nanomolar-range IC50 values for all Hsp90 inhibitors. A trend towards reduced colony formation was observed following monotherapy and combination therapy. Ongoing in vitro experiments include assays for viability, clonogenic survival, and DNA damage following monotherapy, dual, and triple combination treatments using Hsp90 inhibitors, TMZ and EBRT in additional cell lines."

Preclinical • Brain Cancer • Gastric Cancer • Gastrointestinal Cancer • Glioblastoma • High Grade Glioma • Solid Tumor • CDC37 • IDH1

Preclinical evaluation of the synergistic effect of heat shock protein 90 inhibitors with temozolomide and external beam radiotherapy in glioblastoma models. (WFNOS 2025) - "However, due to insufficient efficacy or toxicity, only TAS116 (pimitespib) was approved for clinical use in advanced gastrointestinal tumors in Japan2... In U-87 MG-WT cells, IC50 values were determined for Geldanamycin (53 nM), Onalespib (135 nM), BIIB021 (97 nM), NVP-HSP990 (35 nM), and NMS-E973 (193 nM)... U-87 MG cell viability assays showed nanomolar-range IC50 values for all Hsp90 inhibitors. A trend towards reduced colony formation was observed following monotherapy and combination therapy. Ongoing in vitro experiments include assays for viability, clonogenic survival, and DNA damage following monotherapy, dual, and triple combination treatments using Hsp90 inhibitors, TMZ and EBRT in additional cell lines."

Preclinical • Brain Cancer • Gastric Cancer • Gastrointestinal Cancer • Glioblastoma • Solid Tumor • CDC37 • IDH1

Preclinical evaluation of [ 11 C]Onalespib for Heat Shock Protein 90 (HSP90) cancer imaging (EANM 2025) - "Binding specificity was assessed by pre-incubation with vehicle or Hsp90 inhibitors (Onalespib, HSP990, TAS-116, PU-H71, Ganetespib) prior to tracer exposure. While tumour uptake is modest, [¹¹C]Onalespib offers a promising scaffold for Hsp90-targeted imaging and potential theranostic applications. Further studies optimizing tumour delivery and exploring radiolabelling with longer-lived isotopes could enhance its translational potential."

Preclinical • Brain Cancer • Gastrointestinal Disorder • Glioblastoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CDC37 • HSP90AA1

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."

Journal • Review • Oncology • CDC37 • HER-2 • TP53

Acute circulating tumor DNA dynamics during and after infusional therapy initiation. (ASCO 2025) - "In this study of > 300 plasma timepoints during the first cycle of treatment on a phase Ib clinical trial, there was no significant 'surge' in ctDNA TF within minutes to 24 hours of infusion of onalespib, paclitaxel or both in combination. However, there was a significant decline in TF over the first full cycle of therapy. This suggests that despite ctDNA half-life of minutes-to-hours, consistent change in TF may not be detectable for days or weeks, providing important insight in the design of studies evaluating ctDNA change as a minimally-invasive biomarker."

Circulating tumor DNA • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37

Genetically-defined organoid models reveal early mechanisms of squamous neoplastic progression and therapeutic vulnerabilities in squamous cell carcinoma (AACR 2025) - "However, intriguingly, genetically-engineered organoids with PIK3CA mutations demonstrated heightened sensitivity to mitomycin C and onalespib. In summary, this study provides critical insights into the mechanisms of early squamous neoplastic progression and underscores the utility of genetically-defined organoid platforms for forward genetic studies in cancer. These rigorously validated models offer a powerful platform for identifying genome-guided therapies and advancing precision oncology."

Esophageal Cancer • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA1 • CDKN2A • PIK3CA • SMAD3

The role of heat shock protein 90 in idiopathic pulmonary fibrosis: state of the art. (PubMed, Eur Respir Rev) - "Experimental drugs such as geldanamycin and its derivatives 17-AAG (17-N-allylamino-17-demethoxygeldanamicin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxigeldanamycin), along with AUY-922, 1G6-D7, AT-13387, TAS-116 and myricetin, have been found to reduce lung fibrosis in both in vivo and in vitro models, supporting the role of this emerging target. This review aims to illustrate the structure and biological function of HSP 90 in the context of IPF pathobiology, as well as perspective application of this molecule as a biomarker and therapeutic target for IPF."

Journal • Review • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • HSP90AA1 • TGFB1

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 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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 • Oncology • ANXA5 • CDC37 • HSP90AA1

Enhancing glioblastoma therapy: unveiling synergistic anticancer effects of Onalespib - radiotherapy combination therapy. (PubMed, Front Oncol) - "Moreover, the combination treatment indicated potential for enhancing cell cycle arrest and apoptosis, suggesting promising anti-tumor effects. These findings demonstrate that HSP90 inhibition may be a promising strategy to enhance the efficacy of radiotherapy in the treatment of GBM, potentially leading to improved outcomes for patients battling this challenging disease."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Immune Modulation • Immunology • Oncology • Solid Tumor • CDC37

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 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Hypopharyngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

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 • Colon Cancer • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • ANXA5 • CDC37 • HSP90AA1

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 • Oncology • Squamous Cell Carcinoma • ANXA1 • CDKN2A • KMT2C • NOTCH1 • PIK3CA • SMAD3 • TP53

Enhancing glioblastoma therapy: unveiling synergistic anticancer effects of Onalespib - radiotherapy combination therapy (Front Oncol) - "The proteomic analysis of glioblastoma cells treated with Onalespib, radiation, and their combination revealed significant alterations in protein expression profiles, involved in growth signaling, immune modulation pathways and angiogenesis. Moreover, the combination treatment indicated potential for enhancing cell cycle arrest and apoptosis, suggesting promising anti-tumor effects."

Preclinical • Glioblastoma

Enhancing Glioblastoma Therapy: Unveiling Synergistic Anticancer Effects of Onalespib -Radiotherapy Combination Therapy (Front Oncol) - "The proteomic analysis of glioblastoma cells treated with Onalespib, radiation, and their combination revealed significant alterations in protein expression profiles, involved in growth signaling, immune modulation pathways and angiogenesis."

Preclinical • Glioblastoma

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 | N=22 | Terminated | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Terminated; Drug supply issues

Combination therapy • Metastases • Surgery • Trial termination • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

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 | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Sep 2025

Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Investigating NanoLuc-EGFR engineered cell lines for real-time monitoring of EGFR protein dynamics in live cells. (PubMed, Biochem Biophys Res Commun) - "Using this cell line model, we observed that AT13387 and H84T BanLec induce EGFR degradation in A549-HiBiT cells, with the results confirmed by immunoblotting. In contrast, Erlotinib, Osimertinib, and Cetuximab inhibit EGFR phosphorylation without altering total EGFR levels, as validated by the HiBiT luciferase assay. The NanoLuc-EGFR cell line marks a significant advancement in understanding protein regulation and serves as an instrumental platform for investigating targeted therapies that modulate protein kinases, especially those that induce protein degradation."

Journal • Preclinical • Targeted Protein Degradation • EGFR

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 | Sponsor: National Cancer Institute (NCI)

Metastases • Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

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) - P1b | "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"

Clinical • IO biomarker • Metastases • P1 data • Retrospective data • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • CTLA4 • FGFR4 • HER-2 • IRF6 • JAK2 • KRT17 • MMP7 • PD-1 • PD-L1 • PIK3R1 • TGFB3 • TGFBR2

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 | Sponsor: National Cancer Institute (NCI)

Metastases • Surgery • Trial completion date • Oncology • Solid Tumor

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) - P1b | "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."

Combination therapy • Journal • Metastases • P1 data • Breast Cancer • Neutropenia • Solid Tumor • Triple Negative Breast Cancer • HSP90AA1

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 • Cutaneous Melanoma • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • CASP3 • GSDMC • GSDMD • IL18 • NLRP3