- |||||||||| atabecestat (JNJ-54861911) / J&J, verubecestat (MK-8931) / Merck (MSD), elenbecestat (E2609) / Eisai, Biogen
Journal: Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold. (Pubmed Central) - Feb 22, 2025
Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Journal, IO biomarker: Magnesium-Phenolic Nanoeditor Refining Gliomatous T Cells for Metalloimmunotherapy. (Pubmed Central) - Jan 15, 2025
Studies on T-cell-deficient and wild-type mouse models support the immunomodulating feasibility of Mg2+@MK-8931@MPP. This gliomatous CTL-tailored strategy concurrently broadens metalloimmunotherapy to glioblastoma treatment and highlights the necessity of enforcing gliomatous CTLs' functionality.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Journal: Developing Topics. (Pubmed Central) - Jan 12, 2025
Mechanistic model-based simulations suggest that moderate level BACEi interventions very early in the process of amyloid plaque accumulations could lead to substantial delays in progression. The time to differentiation from untreated marker responses was long for tau-based markers, suggesting that demonstration of effects during a typical trial timeline may be challenging.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Preclinical, Journal: Membrane-Targeted Quantum Dot-Based BACE1 Activity Sensors for In Vitro and In Cellulo Assays. (Pubmed Central) - Nov 15, 2024
In vitro, the sensor demonstrated stability under acidic conditions, and using high-throughput plate reader assays, we determined BACE1 activity in-line with literature values and enabled the obtainment of the inhibitor constant of verubecestat, a small molecule inhibitor. The sensor was also transitioned to cellular experiments, where it demonstrated sensitivity to BACE1 activity and its modulation upon inhibitor treatment in a neuroblastoma cell line.
- |||||||||| Aduhelm (aducanumab) / Neurimmune, Eisai, verubecestat (MK-8931) / Merck (MSD)
MODEL-AD Pre-Clinical Testing Core: A Precision Medicine Pipeline for Preclinical Testing of Alzheimer (201 ABC (Pennsylvania Convention Center)) - Jun 19, 2024 - Abstract #AAIC2024AAIC_5710;
Conclusion : Based on our experience executing rigorous screening strategies with QC checkpoints provide insight to the challenges of conducting translational studies in animal models. The PTC pipeline, an NIA resource, is accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), thus enabling unbiased studies that support clinical translation.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Mechanistic Disease Modeling to Inform Potential Strategies for Early Interventions with BACE inhibition (118 ABC (Pennsylvania Convention Center)) - Jun 19, 2024 - Abstract #AAIC2024AAIC_3508;
Mechanistic model-based simulations suggest that moderate level BACEi interventions very early in the process of amyloid plaque accumulations could lead to substantial delays in progression. The time to differentiation from untreated marker responses was long for tau-based markers, suggesting that demonstration of effects during a typical trial timeline may be challenging.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Journal: The ?-Secretase 1 Enzyme as a Novel Therapeutic Target for Prostate Cancer. (Pubmed Central) - Jan 11, 2024
Treatment with a pharmacological inhibitor of BACE1 (MK-8931) strongly reduced the proliferation of PCa cells in in vitro and in vivo models, analyzed by multiple assays (MTT, clonogenic, and trypan blue exclusion assays and IHC)...Furthermore, analysis of tumor tissue using the prostate cancer-specific pathway array revealed the alteration of several genes involved in PCa growth and progression including Forkhead O1 (FOXO1). All together, these findings suggest BACE1 as a novel therapeutic target in advanced PCa.
- |||||||||| atabecestat (JNJ-54861911) / J&J, verubecestat (MK-8931) / Merck (MSD), umibecestat (CNP520) / Novartis, Amgen, Banner Alzheimer's Institute
Human CSF pharmacoproteomics establishes in vivo-relevant BACE1 substrates as pharmacodynamic biomarkers for chronic BACE inhibition in clinical trials (Elicium 2 (RAI Amsterdam Convention Centre)) - Jul 6, 2023 - Abstract #AAIC2023AAIC_9013;
A reduction of the inhibitor dose to less than 50% BACE1 inhibition may be an appropriate strategy to avoid side effects in future clinical trials with BACE inhibitors. Our analysis also demonstrates that proteomics enables pharmacodynamic studies of multiple CSF proteins in single measurements, which are suitable for precision medicine approaches in future clinical trials with BACE inhibitors.
- |||||||||| verubecestat (MK-8931) / Merck (MSD), Mycamine (micafungin) / Astellas
Preclinical, Journal: In Silico Identification and In Vitro Validation of Repurposed Compounds Targeting the RSV Polymerase. (Pubmed Central) - Jun 28, 2023
We also validated Micafungin's inhibition of the RSV RdRP using an in vitro transcription assay. These findings contribute to RSV drug development and hold promise for broad-spectrum antivirals targeting the non-segmented negative-sense (NNS) RNA viral polymerases, including those of rabies (RABV) and Ebola (EBOV).
- |||||||||| verubecestat (MK-8931) / Merck (MSD), lanabecestat (AZD3293) / AstraZeneca, Eli Lilly, elenbecestat (E2609) / Eisai, Biogen
Journal: BACE-1 Inhibitors Targeting Alzheimer's Disease. (Pubmed Central) - Jun 13, 2023
The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.
- |||||||||| Journal: ?-Secretase-1: In Silico Drug Reposition for Alzheimer's Disease. (Pubmed Central) - May 17, 2023
These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer's disease, especially those targeting BACE-1.
- |||||||||| Tazverik (tazemetostat) / Eisai, Ipsen
PK/PD data, Preclinical, Journal: Pharmacokinetics of Herb-Drug Interactions of Plumbagin and Tazemetostat in Rats by UPLC-MS/MS. (Pubmed Central) - Oct 13, 2022
The C of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC and AUC of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t was prolonged from 10.56 h to 11.73 h. A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Preclinical, Journal: Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice. (Pubmed Central) - Jul 20, 2022
At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Preclinical, Journal: An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities. (Pubmed Central) - Jun 15, 2022
Comparison of isogenic App knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic App, knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
P3 data, PK/PD data, Clinical Trial,Phase III, Journal: An Investigation of Instability in Dried Blood Spot Samples for Pharmacokinetic Sampling in Phase 3 Trials of Verubecestat. (Pubmed Central) - Apr 13, 2022
P2/3, P3
Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks.
- |||||||||| verubecestat (MK-8931) / Merck (MSD), lanabecestat (AZD3293) / AstraZeneca, Eli Lilly
Journal: BACE1 controls synaptic function through modulating release of synaptic vesicles. (Pubmed Central) - Mar 15, 2022
Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients.
- |||||||||| DEVELOPING BETA-SECRETASE INHIBITORS FOR TREATMENT OF ALZHEIMER’S DISEASE () - Mar 9, 2022 - Abstract #ADPD2022ADPD_1122;
The capability of BACE1 to apply such a therapeutic candidate for AD therapy has just been examined during the previous decade. There is proof indicate that the 1 inhibitor administrating time is critical and make big difference in how successful they are in curing AD.
- |||||||||| verubecestat (MK-8931) / Merck (MSD), lanabecestat (AZD3293) / AstraZeneca, Eli Lilly
Journal: Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. (Pubmed Central) - Sep 29, 2021
Our model explains the results of clinical trials and provides guidance for future therapeutic development. In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.
- |||||||||| Review, Journal: Selective Secretase Targeting for Alzheimer's Disease Therapy. (Pubmed Central) - Sep 17, 2021
Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.
- |||||||||| verubecestat (MK-8931) / Merck (MSD), neflamapimod (VX-745) / EIP Pharma, lanabecestat (AZD3293) / AstraZeneca, Eli Lilly
Clinical Results with Novel Approaches that Reverse BFCN Dysfunction (Ballroom) - Aug 7, 2021 - Abstract #CTAD2021CTAD_12;
In the case of BACE inhibition, clinical evidence supporting the approach to target BFCN dysfunction was provided in a combined retrospective analysis of phase 3 clinical trials conducted with verubecestat and lanabecestat, respectively, in which the effects of these BACE inhibitors on specific cognitive domains were evaluated...In the case of p38α inhibition, results of a phase 2, 91-patient, 16-week, placebo-controlled study (“AscenD-LB”) with the specific p38α kinase inhibitor neflamapimod (at 40mg TID) demonstrated statistically significant, clinically relevant effect size (0.5) improvement relative to placebo in a cognitive test battery assessing attention and executive function...Finally, dose-dependent improvement relative to placebo was seen in hallucination severity and frequency, another outcome considered related to cholinergic dysfunction. The results of the AscenD-LB study, the totality of which indicates a substantial positive effect on BFCN function, are to be confirmed in a 160-patient phase 2b study that is planned to commence in the fourth quarter of 2021.
- |||||||||| Review, Journal: BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease. (Pubmed Central) - Jul 9, 2021
Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.
- |||||||||| https://t.co/2kmoEtPV2I and after semagacestat, bapineuzumab, solanezumab, gantenerumab, crenezumab, verubecestat, lanabecestat, atabecestat, umibecestat, & elenbecestat had ALL failed to prove the amyloid-beta hypothesis. Stunning. (Twitter) - Jun 9, 2021
- |||||||||| (3/6) These are: Semagacestat, Avagacestat, Solanezumab, CAD106, Crenezumab, Gantenerumab, Avagacestat, Verubecestat, Atabecestat, Lanabecestat, Crenezumab, Elenbecestat, Umibecestat, Donanemab. (Twitter) - Jun 9, 2021
- |||||||||| verubecestat (MK-8931) / Merck (MSD)
Journal: BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain. (Pubmed Central) - Mar 2, 2021
P2/3
There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.
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