Secretases play a central role in the biology of neurodegenerative diseases by regulating the proteolytic processing of key neuronal substrates. Dysregulation of secretase activity is strongly implicated in the initiation and progression of Alzheimer's disease, making these enzymes highly relevant targets for CNS drug discovery and high-throughput screening.
We present a dedicated Secretase-focused Screening Set designed to support Alzheimer's disease drug discovery programs targeting secretase-driven pathways.
Key Features
- 970 secretase-focused screening compounds
- Predicted activity towards BACE1 and gamma-secretase complex
- Aimed at Alzheimer's disease and CNS drug discovery
- Ligand-based selection from refined bioactivity data
- High chemical diversity and CNS-relevant profiles
- Suitable for HTS, hit identification, and mechanistic studies
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.comfor any additional information and price quotations
Representative screening compounds from the Screening Library
Background information
Despite extensive research targeting Alzheimer's disease, there appear to be no effective disease-modifying therapies. One of the major challenges is identifying compounds that can selectively modulate enzymes involved in amyloidogenic processing without disrupting essential physiological functions.
Secretases, particularly BACE1, sit at the top of the amyloid cascade and represent a critical intervention point. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease primarily expressed in neurons and responsible for the initial cleavage of amyloid precursor protein (APP) [1]. This cleavage generates the C99 fragment, which is subsequently processed by γ-secretase to produce amyloid-beta (Aβ) peptides [2].
In Alzheimer's disease, BACE1 levels and activity are elevated, especially in regions with high amyloid plaque density. This overactivity drives increased production of neurotoxic Aβ species such as Aβ₄₂, promoting plaque formation, neuroinflammation, synaptic dysfunction, and cognitive decline [2]. While early BACE1 inhibitors effectively reduced Aβ levels, their clinical development was limited by adverse cognitive effects, reflecting the enzyme’s broader physiological roles. These clinical outcomes have shifted research toward fine-tuned modulation rather than complete enzyme inhibition, reinforcing the need for carefully designed screening libraries enriched with biologically relevant chemotypes [3].
Gamma-secretase is a multi-subunit intramembrane protease complex that plays a central role in Alzheimer’s disease because it performs the final cleavage of the amyloid precursor protein (APP) after β-secretase, generating amyloid-β (Aβ) peptides of varying lengths. A key pathological link is that shifts in γ-secretase cleavage (“processivity”) can increase the relative production of longer, aggregation-prone species such as Aβ42 (and Aβ43), which seed oligomers and plaques more readily than shorter peptides; many familial Alzheimer’s disease mutations in presenilin or APP bias the system in this direction. [4]
Compound Selection
This Secretase-focused Screening Set comprises 970 small molecules selected from our proprietary HTS Compound Collection, using a ligand-based virtual screening strategy. Compound selection was performed using 2D molecular fingerprints, applying a Tanimoto similarity cutoff ≥ 0.85 to identify compounds structurally related to known BACE1 and gamma-secretase complex modulators.
Reference compounds were sourced from refined ChEMBL bioactivity data, ensuring inclusion of experimentally validated activities. This similarity-driven approach enriched the library with bioactive scaffolds linked to established BACE1 and γ-secretase mechanisms of action, while preserving high chemical diversity, CNS-relevant drug-like physicochemical properties, favorable ADME/Tox profiles, and suitability for high-throughput screening (HTS) and downstream in vitro and in vivo studies.
The resulting compound selection includes over 700 drug-like screening compounds predicted to be BACE1 modulators and around 250 compounds targeting the gamma-secretase complex. This focused set complements our proprietary Alzheimer’s Disease Screening Library by providing target-centric chemical coverage for secretase-related screening, hit identification, and mechanistic studies. It is optimized for early-stage drug discovery and CNS-focused screening campaigns.
Fig. 1. Mechanism of amyloid plaque formation.
Reference:
- Bao, Hong, and Yong Shen. “Unmasking BACE1 in aging and age-related diseases.” Trends in molecular medicine vol. 29,2 (2023): 99-111. doi:10.1016/j.molmed.2022.11.008.
- Bi, Danlei et al. “BACE1-dependent cleavage of GABAA receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease.” Neuron vol. 113,7 (2025): 1051-1064.e6. doi:10.1016/j.neuron.2025.01.030.
- Wang, Y., Cui, Y., Liu, J. et al. Krüppel-like factor 5 accelerates the pathogenesis of Alzheimer’s disease via BACE1-mediated APP processing. Alz Res Therapy 14, 103 (2022). https://doi.org/10.1186/s13195-022-01050-3
- Yang G, Zhou R, Guo X, Yan C, Lei J, Shi Y. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049. Epub 2020 Dec 28. PMID: 33373587.