- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date: PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - Jan 14, 2025
P1, N=63, Active, not recruiting,
Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Review, Journal: PU-H71 (NSC 750424): a molecular masterpiece that targets HSP90 in cancer and beyond. (Pubmed Central) - Nov 20, 2024
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal: Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding. (Pubmed Central) - Oct 30, 2024
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
The interaction of HOP, stress proteins, and PIWI in the mechanism of canalization underscores the susceptibility of Biomphalaria glabrata to Schistosoma mansoni infection (Convention Center - Hall I-1 (1st Floor); In-Person-Only) - Oct 11, 2024 - Abstract #ASTMH2024ASTMH_2352;
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date: PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - Jan 16, 2024
P1, N=63, Active, not recruiting,
Moreover, the combination of CA4948 and PU-H71 may be a candidate combination treatment in FLT3-mutated AML. Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal, Combination therapy, IO biomarker: HSP90 Inhibitor PU-H71 in Combination with BH3-Mimetics in the Treatment of Acute Myeloid Leukemia. (Pubmed Central) - Sep 27, 2023
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal, IO biomarker: Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells. (Pubmed Central) - Jun 20, 2023
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion, Trial completion date, Trial primary completion date, Metastases: The First-in-human Phase I Trial of PU-H71 in Patients With Advanced Malignancies (clinicaltrials.gov) - Mar 28, 2023
P1, N=47, Completed,
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. Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Mar 2023 | Trial primary completion date: Jul 2023 --> Mar 2023
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal: Specific gene module pair-based target identification and drug discovery. (Pubmed Central) - Feb 3, 2023
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.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date: PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - Nov 22, 2022
P1, N=63, Active, not recruiting,
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. Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, zelavespib intravenous (PU-H71 IV) / Samus Therap, Nutlin-3 / EMD Serono
Epichaperome Inhibition Targets Kinase and TP53 Mutant Therapy Resistant AML (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4063;
The BCL-2 inhibitor venetoclax (VEN)/hypomethylation agent (HMA) combination achieves high response rates, improves outcomes for many patients with AML and is now considered standard of care for patients older or unfit to receive intensive chemotherapy...Importantly, in a 1,000: 1 mixture of TP53-WT and TP53-R248W mutant isogenic Molm13 cells, MDM2 inhibitor nutlin3a selectively killed TP53-WT but enriched TP53-mutant Molm13 cells, as expected, and VEN treatment also favored the outgrowth of TP53-mutant cells...Inhibition of epichaperomes by PU-H71 targets AML cells/stem/progenitor cells, enhances VEN activity, and prevents the outgrowth of nutlin- or VEN-resistant TP53-mutant AML cells. This concept has entered clinical evaluation in MPN-derived secondary AML.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Impact of Epichaperome Inhibitor PU-H71 on Anti-Tumor T Cell Responses and Its Implications for Immune and Cellular Therapy (ENMCC - 388-390) - Nov 4, 2022 - Abstract #ASH2022ASH_3457;
Our data suggest that PU-H71 improves the in vivo efficiency of CAR-T cells in a B-ALL mouse model. In addition to its previously demonstrated direct anti-tumor effect, PU-H71 also had an adjuvant effect on anti-tumor T cell responses while not aggravating GvHD, which supports its clinical evaluation in the post-transplant setting or in combination with immune therapies like CAR-T cells.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap, Tecartus (brexucabtagene autoleucel) / Gilead, AZD4573 / AstraZeneca
Targeting the HSP90-MYC-CDK9 Axis to Overcome Dual Resistance to BTK Inhibition and CAR-T Therapy in Mantle Cell Lymphoma (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2376;
Targeting HSP90 with two independent inhibitors PU-H71 or 17-AAG was also potent in MCL preclinical models...Conclusion Our data demonstrated that an unexpected but novel axis led by HSP90-MYC-CDK9 drives the dual resistance to BTKi and CAR T therapies. Our study sheds light on the underlying mechanism of CAR-T resistance in addition to BTKi resistance in MCL and provides compelling preclinical evidence for therapeutic targeting of the HSP90-MYC-CDK9 axis to overcome the dual resistance in patients with MCL.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Journal: Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. (Pubmed Central) - Oct 29, 2022
The transcriptomic studies demonstrate striking changes in neuroinflammatory and heat shock protein (HSP) chaperone systems in the disease process. Treatment with the HSP90 inhibitor PU-H71 is used to address the putative dysfunctional HSP chaperone system and produces a strong reduction of pathology and neurodegeneration, highlighting the potential of AstTau as a rapid and reproducible tool for drug discovery.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap, icapamespib (PU-AD) / Samus Therap
HSP90 inhibition as a novel therapy for Diffuse Intrinsic Pontine Glioma (DIPG) (West/Central Hall) - Sep 28, 2022 - Abstract #SNO2022SNO_640;
Treating DIPG with PU-H71 successfully reduced tumor cell viability but PU-H71 has poor brain penetration. To overcome this, a molecular isoform of PU-H71 has been developed, PU-HZ151, which will be used to test the in vivo efficacy of HSP90 inhibition for DIPG.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date, Metastases: The First-in-human Phase I Trial of PU-H71 in Patients With Advanced Malignancies (clinicaltrials.gov) - Jun 10, 2022
P1, N=47, Active, not recruiting,
To overcome this, a molecular isoform of PU-H71 has been developed, PU-HZ151, which will be used to test the in vivo efficacy of HSP90 inhibition for DIPG. Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2022 --> Jul 2023
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion, Trial completion date, Trial primary completion date, Metastases: PU-H71 With Nab-paclitaxel (Abraxane) in Metastatic Breast Cancer (clinicaltrials.gov) - Dec 20, 2021
P1b, N=12, Completed,
This novel model represents a technological advance that will allow for the rapid recapitulation of neurodegeneration in a manipulatable system that promises to accelerate drug development for AD. Active, not recruiting --> Completed | Trial completion date: May 2022 --> Dec 2021 | Trial primary completion date: May 2022 --> Dec 2021
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Preclinical, Journal: Inhibition of HSP90 reverses STAT3-mediated muscle wasting in cancer cachexia mice. (Pubmed Central) - Dec 16, 2021
Active, not recruiting --> Completed | Trial completion date: May 2022 --> Dec 2021 | Trial primary completion date: May 2022 --> Dec 2021 Our results demonstrate that the HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might serve as a potential therapeutic target for the treatment of cancer cachexia.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Clinical, P1 data, Journal: First-in-Human Trial of Epichaperome-Targeted Positron Emission Tomography in Cancer Patients. (Pubmed Central) - Nov 29, 2021
Our results demonstrate that the HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might serve as a potential therapeutic target for the treatment of cancer cachexia. Our first-in-human results demonstrate the safety and feasibility of non-invasive in vivo detection of tumor epichaperomes using I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date: PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - Nov 22, 2021
P1, N=63, Active, not recruiting,
Our first-in-human results demonstrate the safety and feasibility of non-invasive in vivo detection of tumor epichaperomes using I-PU-H71 PET, supporting clinical development of PU-H71 and other epichaperome-targeted therapeutics. Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
RNA Binding Protein Syncrip Is Required for the Low-Output HSC By Sustaining Proteome Quality (GWCC - B216-B217, Level 2) - Nov 5, 2021 - Abstract #ASH2021ASH_1617;
Similar results were obtained with the epichaperome probe PU-FITC, which consists of HSP90 inhibitor PU-H71 conjugated to FITC...Overall, SYNCRIP is required for maintenance of protein homeostasis and cell polarity of the reserve HSCs. Our study uncovers a new regulatory axis that controls stem cell stress responses to preserve HSC self-renewal.
- |||||||||| sildenafil / Generic mfg.
Journal: Sildenafil triggers tumor lethality through altered expression of HSP90 and degradation of PKD2. (Pubmed Central) - Jul 10, 2021
Furthermore, the involvement of low doses of PU-H71, an HSP90-inhibitor currently under clinical evaluation, in combination with low concentrations of Sildenafil, synergistically and negatively impacted on the viability of cancer cells in vivo. Taken together, our study suggests that repurposing of already approved drugs, alone or in combination with oncology-dedicated compounds, may represent a novel cancer therapeutic strategy.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date, Metastases: The First-in-human Phase I Trial of PU-H71 in Patients With Advanced Malignancies (clinicaltrials.gov) - Jun 9, 2021
P1, N=47, Active, not recruiting,
Taken together, our study suggests that repurposing of already approved drugs, alone or in combination with oncology-dedicated compounds, may represent a novel cancer therapeutic strategy. Trial completion date: Jul 2021 --> Jul 2022 | Trial primary completion date: Jul 2021 --> Jul 2022
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date, Metastases: PU-H71 With Nab-paclitaxel (Abraxane) in Metastatic Breast Cancer (clinicaltrials.gov) - Jan 20, 2021
P1b, N=12, Active, not recruiting,
These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted. Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022
- |||||||||| ibrutinib / Generic mfg.
Preclinical, Journal: Destabilization of ROR1 enhances activity of ibrutinib against chronic lymphocytic leukemia in vivo. (Pubmed Central) - Jan 6, 2021
However, immunoblotting validation confirmed that Ibrutinib treatment dramatically deprived HSP90 inhibitors, 17-DMAG, AUY922 or PU-H71, of inducing the degradation of BTK, BLK, LCK or LYN, but not ROR1. Collectively, our data suggested that depletion of ROR1 induced by targeting HSP90 might facilitate the enhancement of Ibrutinib activity against CLL.
- |||||||||| doxorubicin hydrochloride / Generic mfg.
Journal: Hsp90 inhibition aggravates adriamycin-induced podocyte injury through intrinsic apoptosis pathway. (Pubmed Central) - Dec 17, 2020
Mechanistically, Hsp90 inhibition with PU-H71 enhances the activation of intrinsic apoptotic pathway, and moreover, blockade of podocyte apoptosis with zVAD-fmk (aVAD), a pan-caspase inhibitor, abrogates effects of Hsp90 inhibition on filtration barrier function of ADR-treated podocytes, thus demonstrating that Hsp90 inhibition aggravates ADR-induced podocyte injury through intrinsic apoptosis pathway. In sum, this study reveals a detrimental role of Hsp90 inhibition in podocyte injury, which may offer it as a potential therapeutic target in NS therapy.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Enrollment closed, Trial completion date, Trial primary completion date: PET Imaging of Cancer Patients Using 124I-PUH71: A Pilot Study (clinicaltrials.gov) - Nov 20, 2020
P1, N=63, Active, not recruiting,
A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned. Recruiting --> Active, not recruiting | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021
- |||||||||| PU-H71 IV / Samus Therap
Journal: Physical plasma-triggered ROS induces tumor cell death upon cleavage of HSP90 chaperone. (Pubmed Central) - Oct 25, 2020
Pre-sensitization of cancer cells with subliminal doses of PU-H71, an HSP90 inhibitor currently under clinical evaluation, followed by treatment with cold-plasma, synergistically and negatively impacted on the viability of cancer cells. Taken together, cold-plasma can be used in conjunction with pharmacologic treatment in order to target the expression and activity of HSP90 and the downstream client proteins implicated in various cancer cell capabilities.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Enrollment change, Trial completion date, Trial termination, Combination therapy: Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis (clinicaltrials.gov) - Oct 22, 2020
P1, N=4, Terminated,
Taken together, cold-plasma can be used in conjunction with pharmacologic treatment in order to target the expression and activity of HSP90 and the downstream client proteins implicated in various cancer cell capabilities. N=30 --> 4 | Trial completion date: Dec 2020 --> Mar 2020 | Active, not recruiting --> Terminated; Samus is focusing all of their efforts in myelofibrosis on the new oral formulation of PU-H71.
- |||||||||| PU-H71 / Samus Therap
Journal: Dual Binding to Orthosteric and Allosteric Sites Enhances the Anticancer Activity of a TRAP1-Targeting Drug. (Pubmed Central) - Sep 4, 2020
In addition to tight binding with the ATP binding site through the PU-H71 moiety, SMTIN-C10 interacts with the E115 residue in the N-terminal domain through the TPP moiety, and subsequently induces structural transition of TRAP1 to a tightly packed closed form. The data indicate the existence of a druggable allosteric site neighboring the orthosteric ATP pocket that can be exploited to develop potent TRAP1 modulators.
- |||||||||| zelavespib intravenous (PU-H71 IV) / Samus Therap
Trial completion date, Trial primary completion date, Metastases: The First-in-human Phase I Trial of PU-H71 in Patients With Advanced Malignancies (clinicaltrials.gov) - Aug 10, 2020
P1, N=47, Active, not recruiting,
The data indicate the existence of a druggable allosteric site neighboring the orthosteric ATP pocket that can be exploited to develop potent TRAP1 modulators. Trial completion date: Jul 2020 --> Jul 2021 | Trial primary completion date: Jul 2020 --> Jul 2021
- |||||||||| [VIRTUAL] New Therapies in Development for Myelofibrosis () - Jul 14, 2020 - Abstract #SOHO2020SOHO_149;
P1/2, P1b,
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 1b study that is assessing the safety and efficacy of PU-H71 in ruxolitinib-treated patients with primary or secondary MF (NCT03935555) is underway...Hematological responses, reduction in spleen volume, and improvement of symptoms were noted, and PRM-151 was very well tolerated.11 Bcl-2/Bcl-xL inhibition Navitoclax is an orally bioavailable inhibitor of the anti-apoptotic Bcl-2 family of proteins (primarily Bcl-xL)...Conclusions Besides the agents highlighted herein, spanning new JAK inhibitors (momelotinib, pacritinib), epigenetic modifiers (CPI-0610), and inhibitors of telomerase (imetelstat), HSP90, and HDM2, other investigational drugs, such as LCL161, parsaclisib, and KRT-232 are currently evaluated in clinical trials (Table 1). After many years with ruxolitinib as the sole drug to treat MF, it is exciting to witness many promising novel drugs, based on various biological mechanisms, enter early and late phase clinical trials and usher the way to a new era in treatment of MF.
|
