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

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

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

[VIRTUAL] New Therapies in Development for Myelofibrosis (SOHO 2020) - P1/2, P1b, P2, P3 | "Ruxolitinib blocks excessive proliferation of hematopoietic stem cells and pro-inflammatory cytokine production, which leads to improvement in quality-of-life and spleen volume, thus prolonging survival in MF patients.2 In late 2019, another oral JAK2 inhibitor, fedratinib, was approved for intermediate-2 and high-risk MF...Interim data from the trial demonstrated reduction in spleen volume, BM fibrosis, anemia and blood transfusions, as well as total symptom score improvement in MF patients who were JAK-inhibitor naive7 or had a suboptimal response to ruxolitinib.8 Notably, preclinical studies manifested synergistic lethal activity of combined HSP90 (a chaperone of JAK2) and BET inhibitors in ruxolitinib-resistant post-MPN AML cells,6 and combination treatment of MPN cells with the HSP90 inhibitor PU-H71 and ruxolitinib synergistically reduced p-JAK2 and inhibited the JAK/STAT pathway.9 On the basis of the aforementioned preclinical findings, a phase..."

IO biomarker • Myelofibrosis • Oncology • Polycythemia Vera • BCL2 • BCL2L1 • FLT3 • JAK3 • NFKB1

Identifying and Treating “Progression” in Myelofibrosis (SOHO 2019) - P2a/2b; "In the phase 2, open-label, JAKARTA-2 study of the JAK2 inhibitor fedratinib, patients were only required to have received ruxolitinib for ≥14 days.11 There was also a required washout from ruxolitinib of ≥14 days, during which time splenomegaly and symptoms of MF could have worsened prior to fedratinib initiation...The JAK1/2 inhibitor momelotinib was compared to BAT in ruxolitinib-pretreated patients in the SIMPLIFY-2 study.13 Patients had to have received ruxolitinib for at least 28 days with either a requirement for red blood cell transfusions while on ruxolitinib, or a dose reduction of ruxolitinib to <20 mg twice daily because of grade ≥3 anemia, thrombocytopenia or bleeding...Results are awaited from the dose-ranging PAC203 trial of pacritinib, a relatively non-myelosuppressive JAK2 inhibitor, in which 3 doses of the drug (100 mg daily, 100 mg twice daily and 200 mg twice daily) were tested in previously ruxolitinib-exposed patients...Recently released results..

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Polycythemia Vera • CALR

The First-in-human Phase I Trial of PU-H71 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1 | N=47 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Jul 2023 ➔ Mar 2023 | Trial primary completion date: Jul 2023 ➔ Mar 2023

Metastases • Trial completion • Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Myeloproliferative Neoplasm • Oncology • Solid Tumor • CD4 • JAK2

Identification for and Management of Patients with PV and MF with Ruxolitinib (SOHO 2019) - P1, P1/2, P2; "Therefore, for the best outcome (control of spleen and symptoms, as well as prolonged OS) earlier intervention with higher ruxolitinib dose (maximum safe dose) is recommended.18 Despite the improvements, ruxolitinib has only a limited effect on bone marrow fibrosis, and allogeneic hematopoietic stem cell transplant remains the only curative therapy.11 Target therapies are being studied in myelofibrosis with several clinical trials currently being conducted, such as ruxolitinib in combination with navitoclax (NCT03222609), pomalidomide (NCT01644110), parsaclisib (NCT02718300), PU-H71 (NCT03373877) and TGR-1202 (NCT02493530).The European Leukemia Net (ELN) guidelines recommend phlebotomy to maintain hematocrit levels below 45% and low-dose aspirin for frontline treatment for all patients with PV and cytoreduction therapies with either hydroxyurea or recombinant interferon alpha (rINFα) for high-risk patients (≥60 years old or history of prior thrombosis). Cytoreductiv

Clinical • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • Polycythemia Vera • CALR

Phase 1b Study of the Epichaperome Inhibitor PU-H71 Administered Orally with Ruxolitinib Continuation for the Treatment of Patients with Myelofibrosis (ASH 2019) - P1b; "Enrollment is ongoing. Clinical trial information: NCT03935555."

Clinical • P1 data • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology • HSP90AA1 • JAK2

A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage (ASH 2022) - P1b | "The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted."

Clinical • Combination therapy • P1 data • Bone Marrow Transplantation • Fatigue • Hematological Disorders • Hematological Malignancies • Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Pain • Polycythemia Vera • Thrombocytopenia • Thrombocytosis • Transplantation • HSP90AA1

Specific gene module pair-based target identification and drug discovery. (PubMed, Front Pharmacol) - "Moreover, a gene module pair-based target identification (GMPTI) approach was proposed to predict novel compound-target interactions. Using this method, we have discovered novel inhibitors for three PI3K pathway proteins PI3Kα/β/δ, including PU-H71, alvespimycin, reversine, astemizole, raloxifene HCl, and tamoxifen."

Journal • PIK3CA

Radiosynthesis and preclinical evaluation of [C]SNX-ab as an Hsp90α,β isoform-selective PET probe for in vivo brain and tumour imaging. (PubMed, EJNMMI Radiopharm Chem) - "Our results suggest that [C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/β expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics."

Journal • Preclinical • Brain Cancer • CNS Disorders • CNS Tumor • Glioblastoma • Melanoma • Oncology • Solid Tumor • HSP90AA1