- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
Trial completion: Bryostatin Treatment of Moderately Severe Alzheimer's Disease (clinicaltrials.gov) - Mar 27, 2023
P2, N=117, Completed,
in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients. Active, not recruiting --> Completed
- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
Enrollment closed: Bryostatin Treatment of Moderately Severe Alzheimer's Disease (clinicaltrials.gov) - Mar 29, 2022
P2, N=100, Active, not recruiting,
Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS). Recruiting --> Active, not recruiting
- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
Journal: PKCε Activation Restores Loss of PKCε, Manganese Superoxide Dismutase, Vascular Endothelial Growth Factor, and Microvessels in Aged and Alzheimer's Disease Hippocampus. (Pubmed Central) - Mar 19, 2022
The PKCε activators bryostatin and DCPLA methyl ester increased PKCε, associated with an increase in MnSOD mRNA and its protein as well as vascular endothelial growth factor (VEGF), which was inhibited by the mRNA-stabilizing HuR inhibitors...An autopsy-confirmed AD hippocampus showed a decrease in PKCε and MnSOD mRNAs and their proteins and VEGF as well as in microvascular density compared to non-AD controls. In conclusion, the PKCε activation can rescue a decrease in PKCε, MnSOD, and VEGF via posttranscription regulation and alleviate oxidative stress, and in doing so, prevent microvascular loss during aging and AD.
- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
SYNAPTIC RESTORATION FOR NEURODEGENERATIVE DISEASE (HALL E) - Mar 9, 2022 - Abstract #ADPD2022ADPD_878;
In conclusion, the PKCε activation can rescue a decrease in PKCε, MnSOD, and VEGF via posttranscription regulation and alleviate oxidative stress, and in doing so, prevent microvascular loss during aging and AD. The persistence of the observed clinical improvement for > 30 days after the dosing regimen is consistent with restoration of synaptic networks that may enhance cognitive function in AD as well as other neurodegenerative disorders such as Parkinson’s disease, Fragile X mental retardation, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, Zolinza (vorinostat) / Merck (MSD)
Journal, Checkpoint inhibition: Combination Immune Checkpoint Blockade to Reverse HIV Latency. (Pubmed Central) - Sep 9, 2020
The potency of latency reversal was significantly higher following combination IC blockade compared with other latency-reversing agents, including vorinostat and bryostatin. Combination IC blockade should be further explored as a strategy to reverse HIV latency.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope
[VIRTUAL] Bryostatin-1 modulates CNS innate immunity and augments remyelination () - Aug 16, 2020 - Abstract #MSDC2020MSDC_830;
Bryo-1 promotes a regenerative phenotype within CNS-resident microglia, both in vitro and in vivo, with preliminary data suggesting a potential downstream impact on myelin repair. Given its established safety profile in humans in trials of cancer and Alzheimer’s disease, bryo-1 holds promise as a modulator of compartmentalized inflammation in progressive MS.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window. (Pubmed Central) - Aug 11, 2020
Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications...Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal, IO Biomarker: Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy. (Pubmed Central) - Aug 5, 2020
Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, honokiol (HU-002) / Huons, YIV-906 / Kadmon, Yiviva
Biomarker, Review, Journal: Cancer Biomarkers for Integrative Oncology. (Pubmed Central) - Jul 16, 2020
A systematic approach is needed to identify and develop CAM treatment associated biomarkers and to define their role in facilitating clinical decision-making. The expectation is to use these biomarkers in determining potential options for CAM treatment, examining treatment effects and toxicity and/or clinical efficacy in patients with cancer.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, aspirin / Generic mfg.
Journal: Alternate NF-κB independent signaling re-activation of latent HIV-1 provirus. (Pubmed Central) - Jul 8, 2020
We here demonstrate that conventional treatments with Bryostatin-1 and Hexamethylenebisacetammide (HMBA) or Ionomycin synergistically reactivated HIV-1 from latency, even under conditions where NF-κB activation was repressed. Our study provides a molecular proof of concept for the use of anti-inflammatory drugs, like aspirin, capable of inhibiting NF-κB in patients under cART during the "shock and kill" approach, to avoid potential autoimmune and inflammatory disorders that can be elicited by combinations of LRAs.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Review, Journal: Neuro-regeneration Therapeutic for Alzheimer's Dementia: Perspectives on Neurotrophic Activity. (Pubmed Central) - Jul 7, 2020
Several autopsy studies have indicated that dementia in life is a consequence of lost synaptic networks in the brain, while many clinical trials targeting neurotoxic amyloid beta (Aβ) have consistently failed to produce therapeutic effects on memory function in AD patients. Restoring cognitive function(s) by activating endogenous repairing/regenerating mechanisms that are synaptogenic and antiapoptotic (preventing neuronal death), however, is emerging as a necessary disease-modifying therapeutic strategy against AD and possibly for other degenerative dementias, such as Parkinson's disease and multi-infarct dementia.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Total synthesis of bryostatin 3. (Pubmed Central) - Jun 14, 2020
Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Munc13 Is a Molecular Target of Bryostatin 1. (Pubmed Central) - Jun 4, 2020
This study characterizes Munc13-1 as a molecular target of bryostatin 1. Considering the crucial role of Munc13-1 in neuronal function, these findings provide strong support for the potential role of Munc13s in the actions of bryostatin 1.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, memantine / Generic mfg.
Clinical, P2 data, Journal: A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease. (Pubmed Central) - Mar 3, 2020
Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin- without memantine- to treat AD.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, Istodax (romidepsin) / Astellas, BMS
[VIRTUAL] HIV-1 GENE EXPRESSION DURING REVERSAL OF LATENCY USING RNA-Seq WITH PROBE ENRICHMENT ([VIRTUAL]) - Mar 2, 2020 - Abstract #CROI2020CROI_820;
We were able to measure HIV-1 transcription after reactivation from latency using a variety of latency reversal agents and compare HIV-1 gene expression across conditions. Analysis of differential host gene expression will yield insight into host factors necessary for HIV-1 reactivation in latently infected resting memory CD4+ T cells in persons with HIV.
- |||||||||| Istodax (romidepsin) / Astellas, BMS
[VIRTUAL] ROMIDEPSIN COMBINED WITH PRO-APOPTOTIC DRUGS REDUCE INTEGRATED HIV DNA ([VIRTUAL]) - Mar 2, 2020 - Abstract #CROI2020CROI_818;
Using CD4+ T-cells from PLWH on ART ex vivo, reduction of integrated HIV DNA could be significantly enhanced using the combination of romidepsin with either a PI3K or Bcl-2 inhibitor. The addition of a pro-apoptotic drug could potentially provide the kill needed for effective shock and kill.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Bryostatin-1 As A Potential Modulator Of Innate Immune Phenotype And Remyelination In The Central Nervous System (Exhibit Hall A, Convention Center - Board no. P284) - Feb 21, 2020 - Abstract #ACTRIMSForum2020ACTRIMS_FORUM_357;
Bryo-1 promotes a regenerative phenotype within CNS-resident microglia, both in vitro and in vivo, with preliminary data suggesting a potential downstream impact on myelin repair. Given its established safety profile in humans in trials of cancer and Alzheimer’s disease, bryo-1 holds promise as a modulator of compartmentalized inflammation in progressive MS.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Review, Journal: The Phylum Bryozoa as a Promising Source of Anticancer Drugs. (Pubmed Central) - Jan 24, 2020
The bryozoan antitumor compounds discovered until now show a wide range of chemical diversity and biological activities. Therefore, more research focusing on the isolation of secondary metabolites with potential anticancer properties from bryozoans and other overlooked taxa covering wider geographic areas is needed for an efficient bioprospecting of natural products.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, Farydak (panobinostat) / Novartis, Istodax (romidepsin) / Astellas, BMS
Clinical, Journal: Latency Reversal Agents Affect Differently the Latent Reservoir Present in Distinct CD4+ T Subpopulations. (Pubmed Central) - Jan 16, 2020
Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, Farydak (panobinostat) / Novartis, Istodax (romidepsin) / Astellas, BMS
Clinical, Journal, Combination therapy: Polyanionic carbosilane dendrimers as a new adjuvant in combination with latency reversal agents for HIV treatment. (Pubmed Central) - Nov 29, 2019
Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs. We showed for the first time that nanoparticles, in this case, G3-S16 anionic carbosilan dendrimer may play an important role in new treatments against HIV-1 infection.
- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
Journal, CAR T-Cell Therapy: Modulation of Target Antigen Density Improves CAR T Cell Functionality and Persistence. (Pubmed Central) - Sep 27, 2019
We showed for the first time that nanoparticles, in this case, G3-S16 anionic carbosilan dendrimer may play an important role in new treatments against HIV-1 infection. We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.See related commentary by Guedan and Delgado, p. 5188.
- |||||||||| bryostatin 1 (NSC 339555) / Synaptogenix
Trial completion: A Study of Bryostatin in Moderately Severe to Severe Alzheimer's Disease Subjects Not On Memantine (clinicaltrials.gov) - Aug 20, 2019
P2, N=108, Completed,
Our results suggest that exposure to FIR rays attenuates MA-induced impairment in recognition memory via up-regulation of M1 mAChR, Nrf2-dependent GSH induction, and ERKphosphorylation by inhibiting PKCδ phosphorylation by bryostatin-1. Active, not recruiting --> Completed
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Deletion of the C-26 Methyl Substituent from the Bryostatin Analogue Merle 23 has Negligible Impact on Its Biological Profile or Potency. (Pubmed Central) - Jul 19, 2019
Important strides are being made in understanding the structural features of bryostatin 1, a candidate therapeutic agent for cancer and dementia, conferring its potency for protein kinase C and the unique spectrum of biological responses which it induces. A critical pharmacophoric element in bryostatin 1 is a secondary hydroxyl, whereas a primary hydroxyl group plays the analogous role in binding of the phorbol esters to protein kinase C. Here, we describe the synthesis of a bryostatin homolog where the hydroxyl group is primary, as in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with the secondary hydroxyl group.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Synthesis and Biological Evaluation of Fluorescent Bryostatin Analogues. (Pubmed Central) - Jul 7, 2019
The fluorescent compounds showed similar patterns of intracellular distribution in cells, however, arguing against an existing hypothesis that varying patterns of intracellular distribution contributed to the difference in biological activity. In further characterization, the fluorescent compounds revealed a slow rate of cellular uptake; correspondingly, they showed reduced activity for cellular responses that are only transient upon treatment with phorbol ester or bryostatin 1.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Identification of isoform-selective hydroxamic acid derivatives that potently reactivate HIV from latency. (Pubmed Central) - Jun 14, 2019
In addition, they synergise effectively with the protein kinase C modulators bryostatin-1 and INDY, an inhibitor of the dual-specificity tyrosine phosphorylation regulated kinase 1A. We conclude that the combinations of new hydroxamic acid derivatives and bryostatin-1 or INDY could be a new tool for HIV reactivation in the cure efforts.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Protein kinase C activator bryostatin-1 modulates proteasome function. (Pubmed Central) - May 17, 2019
Direct additions of bryostatin-1 into cell lysates prepared from neuron-like differentiated SH-SY5Y, Jurkat cells, and cultured skin fibroblasts were unable to increase proteasome activity indicating that bryostatin-1 can only modulate proteasome activity when added to live cell culture systems. Standard PKC inhibitors blocked bryostatin-1 induced proteasome activity modulation suggesting that enhancement of proteasome activity was mediated by PKC modulation.
- |||||||||| Journal: T cell toxicity of HIV latency reversing agents. (Pubmed Central) - May 15, 2019
Our comparison of LRAs identified differences in cytotoxicity between LRA classes and members within a class and suggests that some LRAs such as bryostatin and BET inhibitors may also downregulate inhibitory receptors on activated HIV-specific CD8 + T cells. These findings may guide the use of LRAs that have the capacity to preserve or restore CD8 + T cell immunity.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: RNA-induced epigenetic silencing inhibits HIV-1 reactivation from latency. (Pubmed Central) - Apr 20, 2019
The active maintenance of epigenetic silencing by shRNAs acting on the HIV-1 LTR impedes HIV-1 reactivation from latency. Our "block and lock" approach constitutes a novel way of enforcing HIV-1 "super latency" through a closed chromatin architecture that renders the virus resistant to a range of latency reversing agents.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience, Keytruda (pembrolizumab) / Merck (MSD)
Journal: PD-1 blockade potentiates HIV latency reversal ex vivo in CD4 T cells from ART-suppressed individuals. (Pubmed Central) - Apr 16, 2019
Conversely, PD-1 blockade with the monoclonal antibody pembrolizumab enhances HIV production in combination with the latency reversing agent bryostatin without increasing T cell activation. Our results suggest that the administration of immune checkpoint blockers to HIV-infected individuals on ART may facilitate latency disruption.
- |||||||||| bryostatin 1 (NSC 339555) / Neurotrope BioScience
Journal: Chemoenzymatic Dissection of Polyketide β-Branching in the Bryostatin Pathway. (Pubmed Central) - Apr 5, 2019
Using novel chemoenzymatic techniques, we have validated these as the missing enoyl-CoA hydratase and donor acyl carrier protein, essential components of the β-branching cassette of the bryostatin pathway. Together, this cassette installs the vinyl methylester moieties essential to the activity of bryostatins.
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