zelavespib intravenous (PU-H71 IV) / Memorial Sloan-Kettering Cancer Center, Samus Therap - LARVOL DELTA

COMBINED INHIBITION OF HSP90 AND CDK9 OVERCOMES VENETOCLAX-RESISTANCE IN AML (EHA 2026) - "Importantly, in vivo administration of the HSP90i (PU-H71): CDK9i (Enitociclib, Lead Discovery Centre GmbH) combination was well tolerated in preclinical NSG mouse models. Consistently, in vivo evaluation using the TP53 -null (HL60) AML model demonstrated a significant (p < 0.05) reduction in leukemia progression with the combination compared to monotherapies or the vehicle group. Summary/Conclusion Combined HSP90 and CDK9 inhibition synergistically overcomes VEN resistance by disrupting key survival networks, particularly in TP53 -deficient AML, offering a promising therapeutic strategy for high-risk AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2 • BCL2L1 • CDC37 • CDK9 • HSP90AA1 • KMT2A • MCL1 • NPM1 • TP53

PU-H71 alters metabolism to suppress growth in pancreatic cancer (AACR 2026) - "Together, these findings indicate that PU-H71 disrupts PDAC survival by simultaneously perturbing metabolic programming and growth signaling networks. Our results identify PU-H71 as a promising therapeutic agent for targeting the crosstalk between metabolism and signaling programs that promote PDAC growth and therapeutic resistance."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

High-throughput screening identifies HSP-90 inhibitor for pancreatic cancer therapy (AACR 2025) - "Pathway analysis revealed that PU-H71 acts by disrupting multiple metabolic pathways. Our findings identify PU-H71 as a potent therapeutic candidate for PDAC treatment."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDC37 • HSP90AA1

Targeting histone deacetylation, cell cycle regulators and heat shock proteins as novel therapeutic strategies for penile cancers. (PubMed, NPJ Precis Oncol) - "A paclitaxel, ifosfamide, and cisplatin-based regimen achieves response rates around 65%...Compared to standard chemotherapy (e.g. cisplatin, 5-FU, ifosfamide, irinotecan), treatment with romidepsin, quisinostat (HDAC inhibitors (i)), palbociclib (CDK4/6i), or 17-AAG and PU-H71 (HSP90i) reduced cell viability, induced apoptosis, and led to G2 / M cell cycle arrest in most PeCa cells. This research underscores the therapeutic potential of using HDAC, CDK4/6, and HSP90 inhibitors for PeCa management and reveals additional promising targets and biomarkers for future strategies."

Journal • Genito-urinary Cancer • Oncology • Penile Cancer • Solid Tumor • CDC37 • HIF1A

Comprehensive molecular profiling of penile carcinoma reveals histone deacetylation, cell cycle regulators and heat shock proteins as targetable therapeutic strategies (DKK 2026) - "Current treatment options include surgery, radiotherapy, and the TIP regimen (paclitaxel, ifosfamide, cisplatin), despite the latter achieving moderate response rates of 15 - 55 %...Functional assays assessed the efficacy of standard chemotherapeutic drugs as compared to inhibitors targeting HDAC (romidepsin, quisinostat), CDK4/6 (palbociclib, ribociclib), and HSP90 (17-AAG, PU-H71)... Compared to standard therapeutic agents such as cisplatin, 5-FU, ifosfamide, and irinotecan, treatment with romidepsin, quisinostat, palbociclib, 17-AAG, and PU-H71 notably reduced viability, induced apoptosis, and caused an accumulation in the G2 / M cell cycle phase in most PeCa cell lines. Our findings highlight HDAC, CDK4/6, and HSP90 inhibitors as promising therapeutic options for PeCa while providing a resource for novel putative biomarker and future targeted therapies."

Genito-urinary Cancer • Oncology • Penile Cancer • Solid Tumor • ANXA5 • CDC37 • HIF1A

PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - P1 | N=63 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

CDK7 enables adaptive gene transcription required by stromal cells to support distinct T-cell lymphoma phenotypes and represents a novel microenvironment-directed therapeutic target (ASH 2025) - "Among these, ten drugs including the XPO1 inhibitor Selinexor, the HSP90 inhibitor PU-H71 andthe translation inhibitor Omacetaxine exhibited enhanced anti-lymphoma activity specifically in the co-culture setting, whereas four compounds showed reduced efficacy. Treatment with YKL-5-124significantly reduced the tumor burden compared to vehicles. Cytokine profiling (immunoblotting array)and ELISA of culture medium of YKL-5-124 treated EL4-CAFs showed reduced levels of pro-inflammatorycytokines such as CXCL12, IL6, CCL2, ICAM-1, and CXCL1 indicating that CDK7 is necessary in establishingpro-lymphomagenic IN-CAF phenotypes.In conclusion, CDK7 activity is required to sustain specific pro-tumoral crosstalk interactions of matchedCAFs and PTCL cells, which can be exploited therapeutically."

IO biomarker • Stroma • Hematological Malignancies • Lymphoma • T Cell Non-Hodgkin Lymphoma • CAFs • CCL2 • CDC37 • CDK7 • COL1A1 • COL1A2 • CXCL1 • CXCL12 • CXCR4 • EIF4E • ICAM1 • IL6 • MMP8

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

The molecular characterization of penile carcinomas for the identification of new therapeutic targets (DGU 2025) - "This study accentuates the cytotoxic efficacy of inhibitors targeting HDAC, CDK4/6, or HSP90 as novel strategies for the treatment and identification of PeCa."

Genito-urinary Cancer • Oncology • Penile Cancer • Solid Tumor • Urethral Cancer • ANXA5 • CDC37 • CDK4 • HIF1A • HSP90AA1

Epichaperomes: redefining chaperone biology and therapeutic strategies in complex diseases. (PubMed, RSC Chem Biol) - "Chemical biology has been instrumental in uncovering the unique nature of epichaperomes, with small molecules like PU-H71 elucidating their biology and demonstrating their therapeutic potential by dismantling pathological scaffolds and restoring normal protein-protein interaction networks. By targeting epichaperomes, we unlock the potential for network-level interventions and personalized medicine, offering transformative possibilities for diseases driven by protein-protein interaction network dysregulation."

Journal • Review • CNS Disorders • Oncology

Epichaperome-targeted myocardial imaging by 124I-PU-H71 PET. (PubMed, Clin Transl Imaging) - "Our study finds human myocardial epichaperome expression, as quantified by 124I-PU-H71 PET. Our data indicates PU-H71 PET merits further study as a myocardial epichaperome biomarker, with potential application in drug development, possibly as a biomarker in subclinical cardiac dysfunction."

Journal • Cardiovascular • CNS Disorders • Oncology

PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - P1 | N=63 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Epichaperome Inhibition by PU-H71-Mediated Targeting of HSP90 Sensitizes Glioblastoma Cells to Alkylator-Induced DNA Damage. (PubMed, Cancers (Basel)) - "These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor • CDC37 • EGFR • HSP90AA1

PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond. (PubMed, Front Pharmacol) - "Additionally, the present report also suggests the promising role of PU-H71 in JAK2-dependent myeloproliferative neoplasms. Eventually, our report sheds more light on the multiple functions of HSP90 protein as well as the potential therapeutic benefit of its selective inhibitor PU-H71 in the context of an array of diseases, laying the foundations for the development of novel therapeutic approaches that could achieve better treatment outcomes."

Journal • Review • B Cell Non-Hodgkin Lymphoma • Breast Cancer • Hematological Disorders • Hematological Malignancies • Hepatocellular Cancer • Lymphoma • Multiple Myeloma • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL6 • CDC37 • EGFR • HSP90AA1 • HSP90AB1 • JAK2

Shifting from Epigenetics to the Epichaperome: HSP90 as a therapeutic target for H3K27M Diffuse Midline Glioma (DMG) (SNO 2024) - "HSP90 inhibitors, PU-H71 and PU-HZ151, effectively reduced viability of DMG lines in vitro in the low nanomolar range and result in caspase mediated cell death (p<0.0001 1 uM, p<0.05 500 nM, n=6). To enhance the therapeutic efficacy of epichaperome inhibition, we employed the CSNK2A1 kinase inhibitor, CX-4945, in combination with PU-HZ151, resulting in the effective ablation of DMG patient cells in vitro. These data highlight the potential of epichaperome inhibitors for DMG treatment, as they target multiple DMG oncogenic pathways."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CDC37 • HSF1 • HSP90AA1

The interaction of HOP, stress proteins, and PIWI in the mechanism of canalization underscores the susceptibility of Biomphalaria glabrata to Schistosoma mansoni infection (ASTMH 2024) - "With praziquantel being the single drug for schistosomiasis, which is only effective in killing adult parasites but not any larval stages...To determine the involvement of HSPs in the snail-schistosome interaction, we hypothesized that stress inhibitor drugs, such as curcumin and PU-H71, affecting Hsp70 and Hsp90, respectively, would affect the outcome of infection in susceptible snails...By using gene silencing studies with siRNA corresponding to HOP, results showed that suppressing the expression of HOP prevented schistosome infection in the snail host. This data provides evidence that the interaction of HOP with Hsp70, Hsp90, and PIWI maintains cell homeostasis by a mechanism known as canalization in the snail-schistosome relationship."

Infectious Disease • CDC37 • HSP90AA1

Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding. (PubMed, Proteins) - "Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94-selective inhibitor PU-H36, and of Grp94 with the non-selective inhibitor PU-H71...To understand the role of helix 1 in ligand selectivity, we tested the binding of PU-H36 and other Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 is the major determinant of selectivity for Site 2 targeted ligands and also influences the rate of ATPase activity in Hsp90 paralogs."

Journal • CDC37 • HSP90AA1

A Novel Combination Therapy Targets Sonic Hedgehog Signaling by the Dual Inhibition of HMG-CoA Reductase and HSP90 in Rats with Non-Alcoholic Steatohepatitis. (PubMed, Eur J Pharm Sci) - "Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo...These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders."

Combination therapy • Journal • Preclinical • Fibrosis • Hepatology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • CDC37 • COL1A1 • GLI1 • GLI2 • HSP90AA1 • PTCH1 • TGFB1 • TIMP1 • TNFA

FLT3 and IRAK4 Inhibitor Emavusertib in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol) - "The FLT3 and IRAK4 inhibitor emavusertib (CA4948), the MCL1 inhibitor S63845, the BCL2 inhibitor venetoclax, and the HSP90 inhibitor PU-H71 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells in vitro. The combination of CA4948 and BH3-mimetics may be effective in the treatment in FLT3-mutated AML with differential target specificity for MCL1 and BCL2 inhibitors. Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML."

Combination therapy • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD34 • CDC37 • FLT3 • IRAK4 • ITGAM • KIT • NPM1

PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - P1 | N=63 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells. (PubMed, Cell Death Dis) - "Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone."

Journal • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABL1 • BCR • CDK7 • PTPRC

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action. (PubMed, Biomedicines) - "In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases."

Journal • CNS Disorders • Oncology

HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol) - "Elevated susceptibility to PU-H71 and venetoclax was associated with primary AML with CD117 > 80% and CD11b < 45%. The combination of HSP90 inhibitor PU-H71 and MCL1 inhibitor S63845 may be a candidate treatment for FLT3-mutated AML with moderate CD34 positivity while the combination of HSP90 inhibitor PU-H71 and BCL2 inhibitor venetoclax may be more effective in the treatment of primitive AML with high CD117 and low CD11b positivity."

Combination therapy • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CD34 • FLT3 • ITGAM • KIT • TP53

Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells. (PubMed, Blood) - "Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34

IN VITRO ACQUIRED RESISTANCE TO THE ORAL MYELOID KINASE INHIBITOR TUSPETINIB CREATES SYNTHETIC LETHAL VULNERABILITY TO VENETOCLAX (EHA 2023) - P1/2 | "TUS-resistant cells (TUS/R) were 60-fold resistant to gilteritinib (FLT3 inhibitor) but not to quizartinib (FLT3 inhibitor). There was no observed resistance to azacitidine, luxeptinib (lymphoid & myeloid kinase inhibitor), brequinar (DHODH inhibitor), zelavespib (HSP90 inhibitor), or IMP-1088 (NMT1/2 inhibitor), and a small degree of hypersensitivity (<2-fold) of TUS/R cells to luxeptinib, brequinar, and IMP-1088... Resistance to TUS in MOLM-14 cells required prolonged high-level drug exposure. The fact that FLT3 remained fully inhibited in TUS/R cells growing in 75 nM TUS suggests that resistance is not due to a mutation of FLT3. Drug resistance in TUS/R cells in the absence of TUS over 60 days indicates a stable phenotype, distinct from "persister cell resistance" in which resistance fades during subsequent passages."

Preclinical • Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • FLT3 • JAK1 • KIT • SYK