onalespib (AT13387) / Otsuka - LARVOL DELTA

Heat shock protein 90 inhibition synergizes with standard of care combination treatment of glioblastoma in preclinical models (EANO 2026) - "However, due to toxicity or insufficient efficacy, only TAS116 (pimitespib) has been approved for clinical use as monotherapy in advanced gastrointestinal tumors in Japan...Preclinical studies have demonstrated a synergistic anticancer effect of the Hsp90 inhibitor onalespib in combination with external beam radiotherapy (EBRT) in malignant gliomas, next to synergy of onalespib with temozolomide (TMZ)... Cell viability assays in U‑87 MG-WT, M059J, and M059K GBM models demonstrated nanomolar‑range EC₅₀ values for all tested Hsp90 inhibitors. Early triple‑combination experiments indicate a trend toward synergistic interactions among onalespib, TMZ, and EBRT. Ongoing in vitro experiments include cell viability analysis, clonogenic survival, and protein alterations following monotherapy, dual-, and triple-combination treatments using blood-brain barrier-penetrating Hsp90 inhibitors alongside TMZ and EBRT."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CDC37

First in vivo evaluation of the radiolabelled Hsp90 inhibitor [11C]Onalespib for cancer and brain PET imaging. (PubMed, Res Sq) - "Its overexpression in cancers and the clinical development of Hsp90 inhibitors, including the recently approved pimitespib (TAS-116, trade name Jeselhy®), highlights the need for non‑invasive imaging tools to assess Hsp90 expression. In vivo PET/CT and biodistribution confirmed high abdominal accumulation, moderate tumour uptake and negligible brain penetration. Despite rapid metabolism, the tracer demonstrates clear Hsp90 specificity and requires further optimisation to develop a Hsp90-targeted radiotracers."

Journal • Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor • CDC37

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 • HER2 Positive 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 enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism. (PubMed, Toxicol Appl Pharmacol) - "In vivo, onalespib remodels the tumor immune microenvironment, promotes CD8+ effector T-cell infiltration, and enhances the antitumor efficacy of cisplatin without compromising tolerability. Collectively, these findings define a functional HSP90-IDO1 regulatory axis and provide a mechanistic rationale for combination strategies targeting metabolic immune tolerance."

Journal • Breast Cancer • Oncology • Solid Tumor • CD8 • CDC37 • IDO1 • IFNG

Acute circulating tumor DNA dynamics during and after systemic therapy initiation for advanced triple-negative breast cancer. (PubMed, NPJ Breast Cancer) - "Plasma samples from a single-arm clinical trial enrolling patients with triple-negative breast cancer were collected at a variety of time points following infusion of onalespib (day -7), paclitaxel (day 1), and onalespib + paclitaxel (day 8). However, there was significant decline in TF from pre-infusion to D9 (16% to 6.5%, p = 0.004). These findings support further research on ctDNA dynamics immediately after therapy initiation."

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

Using cell-specific late-phase asthma mRNA biomarkers to repurpose drugs that concurrently reverse disease signatures across multiple immune cell-types. (PubMed, PLoS Comput Biol) - "LAR-mRNA biomarkers reflect an asthma-specific inflammatory state that predisposes individuals to late-phase responses, exacerbations, and progression to more severe disease. These findings link systemic biomarkers to airway cellular mechanisms and nominate therapeutic strategies to modulate allergen-driven inflammation."

Biomarker • Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CD40LG • CD8 • GNAS • GZMK • SF3B1

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

Integrating Network Toxicology, Machine Learning, and Experimental Evidence Reveals Candidate Targets and Pathways in PCDD/F-Related Colon Cancer. (PubMed, Food Chem Toxicol) - "Consistent with these in silico findings, exposure of mice to 24 μg/kg TCDF significantly increased the expression of Mmp7 and Hsp90aa1 in murine colonic tissues, increased the levels of proinflammatory cytokines Ifn-γ, Il-1β, and Il-6, and downregulated the expression of Mucin 2 (MUC2). Connectivity Map analysis based on the PCDD/F-related gene signature identified five candidate compounds targeting MMP7 and HSP90AA1, of which four HSP90 inhibitors (tanespimycin, alvespimycin, NVP-AUY922 and AT-13387) showed negative connectivity scores, suggesting potential to reverse the pollutant-induced expression profile."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CDC37 • IFNG • IL1B • IL6 • MMP7 • MUC2

Novel Hsp90 inhibitors as leads for the development of radiotheragnostics for Meitner-Auger electron therapy. (PubMed, Bioorg Chem) - "Onalespib (AT13387), a potent Hsp90 inhibitor in phase III clinical trials, was used as a reference for the design of new compounds harbouring atoms with potential for radiotheragnostics...Finally, less bulky substituents (i.e. bromine) have stronger Hsp90 inhibition properties than more bulky ones (i.e. iodine). Compound 21, in particular, emerged as a lead compound and will be radiolabeled with 76/77Br as a radiotheragnostic agent for PET imaging (76Br) and Meitner-Auger electron therapy (77Br)."

Journal • Oncology • CDC37

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

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

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

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