Jeselhy (pimitespib) / Otsuka - LARVOL DELTA

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

Tick-Tock: Cancer Cell Division Cycle Clocks Strike Midnight. (PubMed, Int J Mol Sci) - "To induce these potential forced overgrowth effects, we suggest targeting the cell division cycle regulatory enzyme, the anaphase-promoting complex/cyclosome (APC/C), to suppress-but not inhibit-its activity. We conclude by proposing experiments to test this hypothesis in which an APC/C inhibitor, such as a low level of proTAME, is combined with the clinically approved heat-shock protein 90 (HSP90)-inhibitor pimitespib (TAS-116) or the pre-clinical molecule tanespimycin, which, to the best of our knowledge, are combinations that have not been investigated before."

Journal • Review • Oncology • CDC37 • HSP90AA1

Pimitespib for advanced gastrointestinal stromal tumor: a plain language summary of the CHAPTER-GIST-301 study. (PubMed, Future Oncol) - No abstract available

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Strong Hsp90α/β Protein Expression in Advanced Primary CRC Indicates Short Survival and Predicts Response to the Hsp90α/β-Specific Inhibitor Pimitespib. (PubMed, Cells) - "Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies...Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy."

Journal • Colorectal Cancer • Oncology • Solid Tumor • BRAF • CDC37 • HER-2 • HSP90AA1

A phase 1 study of PARP inhibitor (niraparib) plus HSP90 inhibitor (pimitespib) in solid tumors: Dose-expansion results from the NiraPim (EPOC2102) study. (ASCO 2025) - P1 | "In cohort A, one patient with hormone receptor-positive breast cancer achieved partial response post-olaparib progression... The dose-expansion part demonstrated a manageable safety profile and potential efficacy at the recommended dose of niraparib plus pimitespib. Clinical benefit was observed in both BRCA-associated cancers resistant to PARP inhibitors and PARP inhibitor-naive non-BRCA associated cancers, supporting further investigation in biomarker-selected populations."

P1 data • Anorexia • Breast Cancer • Fatigue • Genito-urinary Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Leiomyosarcoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Sarcoma • Solid Tumor • Urothelial Cancer • BRCA • CDC37 • CDK12 • HRD

Structural Insights into Selectively Targeting Candida albicans Hsp90. (PubMed, Biochemistry) - "We support these studies with crystal structures of five diverse human Hsp90 ligands in complex with CaHsp90, as well as the structure of this protein with a nonhydrolyzable ATP analog. We demonstrate the structural basis for the selectivity of the human Hsp90 inhibitor TAS116 for CaHsp90, features that may be exploited in the future development of improved CaHsp90 inhibitors."

Journal • CDC37 • HSP90AA1

Pimitespib therapy for a patient with PDGFRA D842V-mutant gastrointestinal stromal tumor. (PubMed, Clin J Gastroenterol) - "Regorafenib was introduced but failed immediately owing to tumor penetration. Although based on a single case, this report demonstrates a significant metabolic response to pimitespib in PDGFRA-mutant GIST. More cases are required to fully elucidate the efficacy of this therapy against such rare tumors."

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • PDGFRA

Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity. (PubMed, J Med Chem) - "TAS-116 has been approved for the treatment of gastrointestinal stromal tumors...Importantly, compound 39 displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment."

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

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 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

Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells. (PubMed, Cancer Sci) - "In human breast cancer xenograft mouse models, pimitespib downregulated RAD51 proteins and augmented the antitumor effects of PARP inhibitors. These findings highlight the potential of pimitespib as a therapeutic agent in combination with PARP inhibitors to treat PARP inhibitor-insensitive cancers."

Journal • Breast Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • CDC37 • RAD51

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

Pimitespib in patients with advanced gastrointestinal stromal tumors in Japan: an expanded access program. (PubMed, Int J Clin Oncol) - "Pimitespib was well tolerated and effective in patients with advanced GIST in real-world practice in Japan. No new safety signals were identified."

Journal • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Hematological Disorders • Oncology • Ophthalmology • Pain • Sarcoma

A Study of Pimitespib in Combination with Imatinib in Patients with GIST (CHAPTER-GIST-101) (clinicaltrials.gov) - P1 | N=78 | Recruiting | Sponsor: Taiho Pharmaceutical Co., Ltd. | Active, not recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

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. | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

CHAPTER-Platform-201: Phase 2 trial of pimitespib plus enzalutamide for patients with metastatic castration-resistant prostate cancer. (ASCO-GU 2025) - "Pts who had received taxanes for mCRPC are excluded. Enrollment began in July 2023 and is currently ongoing."

Clinical • Metastases • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • CDC37 • HSP90AA1

Treatment patterns in patients with advanced gastrointestinal stromal tumor in Japan: An administrative claims database study. (ASCO-GI 2025) - "Tyrosine kinase inhibitors, including imatinib, sunitinib, and regorafenib, and the HSP90 inhibitor, pimitespib have been approved for advanced GIST in Japan, but few studies have examined the nationwide trend in treatment patterns. This is the first real-world study to provide insights into the patient characteristics and current treatment patterns for advanced GIST in Japan. The treatment patterns are consistent with the Japanese Clinical Practice Guidelines."

Claims database • Clinical • Metastases • Stroma • Gastrointestinal Cancer • Oncology • CDC37

Combination of HSP90 Inhibitors and HSP70 Inducers Prevent Hydrochloric Acid-Induced Pulmonary Fibrosis in Rabbits. (PubMed, Int J Mol Sci) - "We exposed New Zealand White Rabbits to hydrochloric acid (HCl, 0.1 N, 1.5 mL/kg), one of the top five chemicals most commonly involved in accidental exposures and inhalation injuries worldwide, and treated animals with either the orally available HSP90 inhibitor TAS-116 (1.7 mg/kg 5x/week) or TAS-116 combined with the HSP70 inducer, geranylgeranyl acetone (GGA, 50 mg/kg, 3x/week)...The use of HSP70 inducers may be a helpful tool to improve the profile of HSP90 inhibitors and reduce their minimal effective dose and side effects. Further investigation is required to explore the exact synergistic mechanism behind the antifibrotic profile of HSP90 inhibitors and HSP70 inducers."

Journal • Preclinical • Cardiovascular • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • CDC37

CHAPTER-GIST-101: A phase I study of pimitespib combined with imatinib in patients with imatinib-refractory gastrointestinal stromal tumor (ESMO Asia 2024) - P1 | "The ExP is a global, open-label, randomized part evaluating the efficacy and safety with PIMI + IM, PIMI monotherapy followed by IM re-challenging, and sunitinib (SU) in each arm of 20 pts. Exploratory pharmacogenomics analysis is also measured. The study recruits pts from Australia, China, Japan, Singapore, and Taiwan."

Clinical • P1 data • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • BRAF • CDC37 • KIT • PDGFRA