verubecestat (MK-8931) / Merck (MSD) - LARVOL DELTA

Discontinued BACE1 Inhibitors in Phase II/III Clinical Trials and AM-6494 (Preclinical) Towards Alzheimer's Disease Therapy: Repurposing Through Network Pharmacology and Molecular Docking Approach. (PubMed, Pharmaceuticals (Basel)) - "This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer's disease (AD). This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand-hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer's disease, warranting further in silico refinement and experimental validation."

Journal • P2/3 data • Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • AKT1 • BCL2 • BCL2L1 • CASP3 • CASP8 • CDC37 • HSP90AA1 • HSP90AB1 • STAT3

Metal-Supramolecular Drug Delivery System Empowered Meningeal Lymphatic Vessels-Bridged Intracranial-Peripheral Dual Immune Modulation for Reversing Glioblastoma Immune Suppression. (PubMed, Adv Sci (Weinh)) - "Using coordination-driven self-assembly of lipoic acid (LA), iron ions (Fe3+), and bovine albumin (BSA), we engineered nanoassemblies with Verubecestat (MK-8931) encapsulated and with vascular endothelial growth factor C (VEGF-C) and c(RGDfK) conjugated...This MLVs-bridged intracranial-peripheral dual immunomodulation strategy effectively transforms immunologically "cold" GBM into "hot" tumors, resulting in potent tumor eradication and significantly prolonged survival in orthotopic GBM models. It not only presents a novel paradigm for synergistic GBM immunotherapy but also provides an alternative brain drug delivery approach."

Journal • Brain Cancer • Glioblastoma • Immune Modulation • Immunology • Oncology • Solid Tumor • VEGFC

In Silico Investigation of Amidine-Based BACE-1 Inhibitors Against Alzheimer's Disease: SAR, Pharmacokinetics, Molecular Docking and Dynamic Simulations. (PubMed, Pharmaceuticals (Basel)) - "These important interactions are absent in the reference compound verubecestat. The multi-step computational analysis suggests that compound 9.7 is a promising and selective BACE-1 inhibitor. Its favorable ADME profile, favorable docking interactions, and stable MD simulation behavior highlight its potential as a hit compound for further optimization in the development of anti-Alzheimer's agents."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • APP

MULTI-OMIC CHARACTERIZATION OF BRAIN AND BIOFLUID RESPONSES TO ADUCANUMAB AND VERUBECESTAT IN AN AMYLOID MOUSE MODEL (ADPD 2026) - "These results showcase the utility of pharmacogenomic approaches in preclinical animal testing of candidate therapeutics, and highlight the broad and often adverse molecular consequences of candidate anti-amyloid treatments."

Preclinical • APOE

Rescuing Verubecestat: An Integrative Molecular Modeling and Simulation Approach for Designing Next-Generation BACE1 Inhibitors. (PubMed, Int J Mol Sci) - "Rationally designed VER derivatives, particularly VERMOD-33 and VERMOD-57, displayed enhanced binding energetics, stable inhibitory dynamics, and favorable pharmacokinetic properties compared with native VER. These findings provide a computational framework for rescuing VER and support further synthesis and experimental validation of next-generation BACE1 inhibitors for Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • BACE1

Drug Development. (PubMed, Alzheimers Dement) - "This screening strategy has been used to characterize a variety of mechanisms of action in 5XFAD mice including the small molecules levetiracetam and verubecestat, and the murinized/chimeric monoclonal antibody aducanumab. Using the unbiased and rigorous screening approaches of the PTC, we have identified divergent effects of sex on PK measures (including plasma and brain exposures), efficacy (e.g., amyloid lowering) and behavioral effects (including side-effects) in all compounds tested. These data in the mice were consistent with clinical data demonstrating differential effects of sex on therapeutic benefits and limitations reported for each of these compounds Using rigorous and unbiased screening approaches that are powered to detect effects of sex in animal models can be used to predict differential effects of sex on therapeutic benefit and limitations of novel compounds being investigated for the treatment of AD."

Journal • Preclinical • Review • Alzheimer's Disease • CNS Disorders

Modeling amyloid plaque turnover dynamics improves characterization of drug effects. (PubMed, Alzheimers Dement (N Y)) - "The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions."

Journal • Alzheimer's Disease • CNS Disorders

Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non-Human Primates. (PubMed, Proteomics) - "The β-secretase BACE1 (β-site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM-1. This study demonstrates the suitability of VCAM-1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF."

Journal • Alzheimer's Disease • CNS Disorders • VCAM1

App and dna damage create a feedforward loop that contributes to alzheimer's disease pathogenesis (Neuroscience 2025) - "This damage was blocked by application of a BACE1 inhibitor (verubecestat) or a γ-secretase inhibitor L685458...The linkage appears to be bi-directional and paints the picture of a pathway with the potential to become a dangerous feed-forward loop. Our findings reveal a novel role for full length APP in AD pathogenesis through its relationship with DNA damage."

Alzheimer's Disease • Ataxia • CNS Disorders • Movement Disorders • APP

Advancing Amyloid Aggregation Research: A Focus on Innovative Therapies, Molecular Modeling and Nano-Delivery Systems in Alzheimer's Disease. (PubMed, Curr Drug Targets) - "Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise, though challenges such as BBB penetration and toxicity still remain. Combination therapies, along with advancements in diagnostics and drug delivery technology, are essential for finding effective treatments for Alzheimer's, Parkinson's, and other neurodegenerative diseases. Future research should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic selectivity, and refining drug delivery systems to enable more precise, targeted interventions, to ultimately reduce the progression of disease at the molecular level."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Gene Therapies • Inflammation • Movement Disorders • Parkinson's Disease

Soluble VCAM-1 may serve as a pharmacodynamic CSF marker to monitor BACE2 activity in non-human primates. (PubMed, Mol Cell Proteomics) - "One CSF protein, vascular cell adhesion protein 1 (VCAM-1), was only reduced upon inhibition with verubecestat, but not upon BACE1-selective inhibition with the antibody. We conclude that VCAM-1 is a promising biomarker candidate for monitoring BACE2 inhibition in CSF, which is instrumental for the development of BACE1-selective inhibitors for the prevention of AD."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • CHD1 • SEZ6 • VCAM1

House Dust Mite Exposure Increases Amyloid Β Expression and Disrupt Epithelial Integrity In Vitro (ATS 2025) - "Separately, transepithelial electrical resistance (TEER) was assessed in HDM and exogenous Aβ (2nM) treated cells in ALI in absence/ presence of 10nM beta secretase 1 (BACE1) inhibitor (verubecestat)...The effect of HDM on TEER was inhibited in the presence BACE1 inhibitor, suggesting the role of Aβ regulation in epithelial inflammatory changes. In conclusion, HDM induces Aβ in epithelial cells and regulates the development and progression of asthmatic changes by disrupting the epithelial barrier in-vitro."

Preclinical • Alzheimer's Disease • Asthma • CNS Disorders • Fibrosis • Immunology • Inflammation • Respiratory Diseases • APP

Combination of Epigallocatechin-3-Gallate and Tramiprosate Prevent Accumulation of Intracellular Aβ and Dysfunctional Autophagy-Lysosomal Pathway at Earliest Stage of Transdifferentiation of Mesenchymal Stromal Cells into PSEN1 E280A Cholinergic-like Neurons. (PubMed, Int J Mol Sci) - "To reverse the PSEN1 E280A phenotype, we used rapamycin (RAP), verubecestat (VER), compound E (CE), epigallocatechin-3-gallate (EGCG), and tramiprosate (TM) in WT and mutant ChLNs. Given that this investigation is based on a single menstrual blood sample from WT and PSEN1 E280A, our results should be considered exploratory. Larger sample sizes are needed."

Journal • Alzheimer's Disease • CNS Disorders • CASP3 • CD73 • MAP1A

Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy. (PubMed, Sci Rep) - "This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Furthermore, the development of the SIMANA ( https://simana.streamlit.app/ ) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts."

Journal • Alzheimer's Disease • CNS Disorders

Shedding new light on BACE1-mediated modulation of IL-6 signaling: Implications for neural activity and synaptic plasticity in mice. (PubMed, Cytokine) - "Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out. Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning."

Journal • Preclinical • IL6 • IL6R

Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold. (PubMed, Bioorg Med Chem) - "Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. 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."

Journal • Alzheimer's Disease • CNS Disorders

Safety concerns associated with BACE1 inhibitors - past, present and future. (PubMed, Expert Opin Drug Saf) - "However, clinical trials of inhibitors like atabecestat, verubecestat, and lanabecestat have faced challenges, including limited efficacy and significant adverse effects. The trial results underscore the need for CNS-specific BACE1 inhibitors to reduce adverse effects. Future research should focus on optimizing drug design and identifying additional therapeutic avenues, such as prostate cancer and insulin resistance."

Journal • Review • Alzheimer's Disease • CNS Disorders • Genito-urinary Cancer • Hepatology • Mood Disorders • Oncology • Prostate Cancer • Psychiatry • Solid Tumor • APP

Developing Topics. (PubMed, Alzheimers Dement) - "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."

Journal • Alzheimer's Disease • CNS Disorders • Aβ42 • CSF Aβ42

Magnesium-Phenolic Nanoeditor Refining Gliomatous T Cells for Metalloimmunotherapy. (PubMed, ACS Nano) - "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."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NKG2D

Membrane-Targeted Quantum Dot-Based BACE1 Activity Sensors for In Vitro and In Cellulo Assays. (PubMed, ACS Appl Mater Interfaces) - "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."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • APP

MODEL-AD Pre-Clinical Testing Core: A Precision Medicine Pipeline for Preclinical Testing of Alzheimer’s Disease Therapeutic Candidates (AAIC 2024) - "Result : Validation of this pipeline using both small molecule and biologic tool compounds including the evaluation of verubecestat, levetiracetam, and aducanumab revealed the importance of critical quality control (QC) steps when executing preclinical studies. 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."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Mechanistic Disease Modeling to Inform Potential Strategies for Early Interventions with BACE inhibition (AAIC 2024) - "Background: The β-secretase-1 inhibitors (BACEi), including verubecestat, were extensively studied in prodromal to moderate AD and demonstrated early cognitive decline (negative effect) at doses achieving >50% inhibition of amyloid production... 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."

Alzheimer's Disease • CNS Disorders • Aβ42 • CSF Aβ42

The β-Secretase 1 Enzyme as a Novel Therapeutic Target for Prostate Cancer. (PubMed, Cancers (Basel)) - "Furthermore, BACE1 gene expression and activity was confirmed in several established PCa cell lines (LNCaP, C4-2B-enzalutamide sensitive [S], C4-2B-enzalutamide resistant [R], 22Rv1-S, 22Rv1-R, PC3, DU145, and TRAMP-C1) by real-time PCR and fluorometric assay, respectively. 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."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BACE1

Systematic in silico analysis of clinically tested drugs for reducing amyloid beta plaque accumulation in Alzheimer's disease (CTAD 2023) - "To that end, we developed a quantitative systems pharmacology (QSP) model using eight different Aβ targeting approaches (aducanumab, lecanemab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat). A QSP model calibrated to clinical data for multiple drugs with different target species and modalities enables meaningful comparisons between therapeutic strategies. The model simulations provide novel insights into clinical results and guidance for future therapeutic development."

Clinical • Alzheimer's Disease • CNS Disorders

Principles of Design of Clinical Trials for Prevention and Treatment of Alzheimer's Disease and Aging-Associated Cognitive Decline in the ACH2.0 Perspective: Potential Outcomes, Challenges, and Solutions. (PubMed, J Alzheimers Dis Rep) - "The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived iAβ, in prevention of AD and treatment of AACD...Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive iAβ depletion, contends that targeted degradation of iAβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential iAβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials."

Journal • Alzheimer's Disease • CNS Disorders • Targeted Protein Degradation