Jeselhy (pimitespib) / Otsuka - LARVOL DELTA

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

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

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 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

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