Jeselhy (pimitespib) / Otsuka, Taiho - 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

BrUOG 387: Phase Ib investigator-initiated trial of a heat shock protein 90 inhibitor (HSP90i) combined with a CDK4/6i in advanced breast cancer progressing on CDK4/6i and in solid tumors with retinoblastoma (Rb)-deficiency (IND163592). (ASCO 2023) - P1 | "CDK4/6i (palbociclib at dose previously tolerated up to 125 mg daily PO D1-21 of 28 day cycle) in combination with HSP90i (TAS-116/pimitespib starting at 120 mg 5 days on 2 days off, for D1-28 of cycle) is used in 3+3 dose-de-escalation design. OS, PFS, TTP, and DOR will be summarized using methods of Kaplan and Meier. Clinical trial information: NCT05655598."

Metastases • P1 data • Bladder Cancer • Breast Cancer • Eye Cancer • Febrile Neutropenia • Genito-urinary Cancer • HER2 Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Oncology • Retinal Disorders • Retinoblastoma • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Urothelial Cancer • CDK4 • HER-2 • HIF1A • HSP90AA1 • PGR • SLC2A1 • SMURF2

A Study of Velzatinib in Participants With Metastatic and/or Unresectable GIST After Imatinib, Sunitinib, Regorafenib, and Pimitespib (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • PDGFRA

AB122 Platform Study (clinicaltrials.gov) - P1 | N=917 | Recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | Trial completion date: May 2026 ➔ Jun 2027 | Trial primary completion date: May 2026 ➔ Jun 2027

Trial completion date • Trial primary completion date • Alveolar Soft Tissue Sarcoma • Biliary Cancer • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Head and Neck Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Study of Velzatinib in Participants With Metastatic and/or Unresectable GIST After Imatinib, Sunitinib, Regorafenib, and Pimitespib (clinicaltrials.gov) - P2 | N=24 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P2 trial • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • PDGFRA

Evolution of Hsp90 Targeting: From Stress Biology to Clinical Translation. (PubMed, Cell Stress Chaperones) - "The first regulatory approval of an Hsp90 inhibitor, Pimitespib, for refractory gastrointestinal stromal tumor, marks a translational milestone that validates this framework clinically. Combination studies have further mapped where Hsp90 inhibition is most informative and most effective, demonstrating that benefit is strongest when deployment is guided by defined client dependency, proteostasis burden, immune context, or biomarker selection. Together, these advances position Hsp90 inhibitor research as a major source of mechanistic insight into molecular chaperones and as a foundation for biomarker-guided, context-aware targeting of proteostasis in oncology and beyond."

Journal • Review • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • CDC37 • HSP90AA1

Design, Synthesis, and Evaluation of a Novel-Labeled Small Molecule Inhibitor-Based PET/SPECT Tracer Targeting HSP90. (PubMed, J Med Chem) - "Several HSP90 inhibitors are in use or late-stage trials: pimitespib is approved in Japan for intestinal tumors, hypericin sodium under US regulatory review, and WP-1303 in Phase III development...Clinical evaluation confirmed translational potential, enabling tumor delineation and high-contrast imaging (SUVmax ∼ 5). This probe supports comprehensive cancer management and may guide clinical application of emerging HSP90 inhibitors."

Journal • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

Internalization of B7-H3 is enhanced by cholesterol disruption in esophageal cancer cells (AACR 2026) - "While the pimitespib enhanced trastuzumab-mediated HER2 internalization, enoblituzumab-mediated B7-H3 internalization was not affected. These results suggest that membrane cholesterol, rather than HSP90, might affect the stability of B7-H3 on the cell membrane. In conclusion, membrane cholesterol disruption could enhance the internalization efficacy of HER2 and B7-H3 molecules."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CD276 • CDC37 • HSP90AA1

Synergy of BCL-2 and MEK/HDAC inhibition in IBC and non-IBC models: Potential for a first IBC specific therapy (AACR 2026) - "We then performed follow-up combination screens using Pimitespib (HSP90 inhibitor) and Navitoclax (BCL-2 inhibitor), the top hits within their respective classes, testing them against the same 1,200+ compound library to identify synergistic partners. This study shows for the first time a trend towards IBC-specific synergistic drug interactions. These findings suggest potential mechanistic differences in apoptotic regulation and may guide rational development of targeted combination therapies for IBC. Future studies will assess whether these in vitro synergy trends translate into subtype-specific therapeutic responses in vivo.AI disclosure: AI was used only for language editing; content was verified by the authors."

IO biomarker • B Cell Lymphoma • Breast Cancer • Inflammatory Breast Cancer • Lymphoma • Oncology • Solid Tumor • BCL2 • CDC37 • IRF4

Pimitespib (TAS-116), an HSP90 inhibitor, overcomes resistance to androgen receptor pathway inhibitors in prostate cancer by simultaneously targeting several key resistance mechanisms (AACR 2025) - "Antitumor efficacy was evaluated in two castration-resistant prostate cancer (CRPC) xenograft models (LNCaP-Xeno-IL-6 and VCaP). Pimitespib enhanced the efficacy of three ARPIs (enzalutamide, darolutamide, and abiraterone) in the four prostate cancer cell lines. Pimitespib effectively addresses ARPI resistance in mCRPC by rapidly inhibiting AR and GR nuclear translocation and reducing the protein levels of AR, GR, AR-V7, and AKT. In addition, our findings highlight the potential of combining pimitespib with ARPIs for the treatment of mCRPC patients who have progressed on ARPI therapy."

Castration-Resistant Prostate Cancer • Gastrointestinal Stromal Tumor • Genito-urinary Cancer • Oncology • Prostate Cancer • Sarcoma • Solid Tumor • CDC37 • IL6

The cyclopeptide enniatin a inhibits the chaperone hsp90 and induces mitophagy in breast cancer cells (AACR 2025) - "Except for the Pimitespib (TAS-116), approved for clinical use in Japan in 2022, no Hsp90 inhibitors have yet been approved by the FDA...We also show that targeting Hsp90 by EnnA reduced the level of cox4, a component of the electron transport chain, leading to parkin-mediated mitophagy. Our data indicate that EnnA represents a member of a new class of Hsp90 inhibitors that impair mitochondrial function in cancer cells and is a promising compound to treat breast cancer."

Breast Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

CHAPTER-GIST-101: A phase I trial of pimitespib and imatinib in patients with gastrointestinal stromal tumors refractory to imatinib (Sarcoma-RC 2026) - P1 | "The ExP is a global, open-label, randomized part evaluating efficacy and safety with PIMI + IM, PIMI monotherapy followed by IM re-challenge, and sunitinib (SU) in each arm of 20 pts. Legal entity responsible for the study Taiho Pharmaceutical Co., LTD. Funding Taiho Pharmaceutical Co., LTD."

Clinical • P1 data • Stroma • Gastric Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BRAF • CDC37 • KIT • PDGFRA

Astragalus Polysaccharide Nanoparticles Alleviate Sepsis-Induced Myocardial Injury by Targeting the HSP90AA1/NLRP3 Signaling Pathway. (PubMed, Int J Nanomedicine) - "These effects were suppressed by TAS-116. APS-CS/TPP protect against septic myocardial injury by inhibiting the HSP90AA1/NLRP3 signaling pathway."

Journal • Infectious Disease • Septic Shock • CDC37 • HSP90AA1 • IL1B • IL6 • NLRP3 • TNFA

Quality-of-life outcomes with pimitespib in patients with advanced gastrointestinal stromal tumor: results from the randomized, double-blind, placebo-controlled, phase III, CHAPTER-GIST-301 study. (PubMed, ESMO Open) - "Pimitespib as a new treatment option in the fourth-line setting did not negatively impact HRQoL overall, with the exception of diarrhea and appetite loss, in patients with metastatic GIST."

Clinical • HEOR • Journal • P3 data • Anorexia • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

HSP90 inhibition disrupts telomere maintenance and promotes chromosomal instability (CIN) in cancer cells. (PubMed, Res Sq) - "Methods Four HSP90 inhibitors (TAS-116, XL-888, SNX-2112, 17-AAG) were tested at each compound's cell-specific LC50 in HT1080 (linear and circular HACs) and HEK293 (linear HAC) cells, with GRN163L as a positive control. Conclusions TAS-116 consistently disrupts telomere maintenance-driving linear HAC loss, telomere shortening, reduced FISH signal, elevated TIFs, and increased MNi-thereby validating the HAC-based framework for discriminating telomere-directed activity. These findings support the therapeutic promise of HSP90 inhibition against telomere maintenance in cancer."

Journal • Oncology • CDC37 • HSP90AA1 • TERF2

A Study of Pimitespib in Combination With Imatinib in Patients With GIST (CHAPTER-GIST-101) (clinicaltrials.gov) - P1 | N=78 | Active, not recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Targeting Hsp90 in Cancer for 25 Years: Failure of Previous Clinical Trials and New Hope for Future Therapeutics. (PubMed, Cells) - "A critical unanswered question remains: which form of the dual inhibitions caused the observed toxicity in humans that led to the spectacular failure of the trials and which underlies the limited efficacy that might be the real reason for the only approval of the orally administered ATP-binding inhibitor, Pimitespib (TAS-116), in 2022 by Japan? We suggest that addressing this question could prompt a paradigm shift in the design of next-generation anti-Hsp90 cancer therapeutics."

Journal • Review • Oncology • 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

Pooled safety analysis of pimitespib for the treatment of patients with advanced gastrointestinal stromal tumors. (PubMed, Int J Clin Oncol) - P, P1 | "This analysis suggests that most ADRs associated with pimitespib are manageable and reversible, thus supporting its use in patients with advanced GIST."

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Ophthalmology • Sarcoma • CDC37 • HSP90AA1

Efficacy and safety of pimitespib in gastrointestinal tumors. (PubMed, Surg Today) - "Pimitespib may offer a tolerable and effective treatment option for patients with unresectable or recurrent GISTs in clinical practice."

Journal • Review • Anorexia • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

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

In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance. (PubMed, Signal Transduct Target Ther) - "Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • CDC37 • HSP90AA1

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