BACE1

Beta-secretase 1

Score: 0.630 Price: $0.63 Medium Druggability Status: active Wiki: BACE1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

384

DEBATES

3D Protein Structure

🧬 BACE1 — PDB 6EQM Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.48

Clinical Stage

Phase III

Target Class

Protease

Safety

0.30

Druggability Analysis

Drug Development0.45

Structural Tractability0.95

Target Class0.85

Safety Profile0.30

Key Metrics

PDB Structures:

375

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (3 compounds)

3 Discontinued

Therapeutic Areas:

Alzheimer's disease Mild cognitive impairment Neurodegeneration Amyloidosis Cognitive decline prevention

Druggability Rationale: BACE1 exhibits high druggability (0.80 score) with an established catalytic aspartyl protease pocket, extensive structural data (375 PDB structures at 1.25Å resolution), and proof-of-concept small molecule inhibitors demonstrating target engagement. However, clinical translation has been severely hindered by mechanism-based toxicity from complete protease inhibition and lack of efficacy in symptomatic Alzheimer's disease, suggesting druggability alone is insufficient without addressing on-target safety liabilities.

Mechanism: Small molecule inhibitor of aspartyl protease activity

Drug Pipeline (3 compounds)

3 Discontinued

Known Drugs:

Verubecestat (discontinued) — Alzheimer's disease

Lanabecestat (discontinued) — Alzheimer's disease

Atabecestat (discontinued) — Alzheimer's disease

Structural Data:

PDB (375) ✓AlphaFold ✓Cryo-EM —

1PY1 1SGZ 1TQF 1UJJ 1UJK+370 more

UniProt: A0A7P0T924

Binding Pocket Analysis:

BACE1 possesses a well-characterized bilobed catalytic pocket formed by two aspartyl residues typical of aspartyl proteases, with a deep S1/S1' specificity pocket accommodating peptide substrates; high-resolution structures reveal opportunities for selective inhibitor design through targeting allosteric conformational states or substrate-competitive mechanisms rather than irreversible active site occupation.

🧬 3D Protein Structure

🧬 BACE1 — PDB 6EQM Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

BACE1 selectivity versus BACE2 (a related aspartyl protease with distinct substrate specificity) is achievable and was maintained in failed clinical candidates, but the broader challenge is avoiding off-target effects on other proteases and managing substrate-dependent toxicity from broad Aβ pathway inhibition rather than achieving isoform selectivity.

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Clinical Trials (8)

Relevant trials from ClinicalTrials.gov

Active

Completed

Total Enrollment

5,772

By Phase

EARLY_PHASE1: 1 · PHASE1: 3 · PHASE2: 1 · PHASE3: 2 · Unknown: 1

An Open-Label Study Investigating MK-8931 in Participants With Mild and Moderate Hepatic Insufficiency (MK-8931-016) Completed

PHASE1 NCT02910739 n=16

Amnestic Mild Cognitive Impairment, Alzheimer's Disease, Prodromal Alzheimer's Disease

Interventions: MK-8931

Sponsor: Merck Sharp & Dohme LLC | Started: 2016-10-11

A Study of Lanabecestat (LY3314814) in Healthy Participants Completed

PHASE1 NCT02663128 n=18

Healthy

Interventions: Lanabecestat

Sponsor: AstraZeneca | Started: 2016-01-31

A Study of Lanabecestat (LY3314814) in Healthy Participants When Taken With Rosuvastatin Completed

PHASE1 NCT03019549 n=42

Healthy

Interventions: Lanabecestat, Rosuvastatin

Sponsor: AstraZeneca | Started: 2017-01-12

Characterization of T-Cell Response in Participants Previously Treated With JNJ-54861911 (Atabecestat) Completed

EARLY_PHASE1 NCT03587376 n=9

Alzheimer Disease

Interventions: Atabecestat

Sponsor: Janssen Research & Development, LLC | Started: 2018-05-30

Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019) Terminated

PHASE3 NCT01953601 n=1454

Amnestic Mild Cognitive Impairment, Alzheimer's Disease, Prodromal Alzheimer's Disease

Interventions: Verubecestat 12 mg (Parts 1 and 2), Verubecestat 40 mg (Parts 1 and 2), Placebo (Part 1)

Sponsor: Merck Sharp & Dohme LLC | Started: 2013-11-05

A Study of Lanabecestat (LY3314814) in Participants With Mild Alzheimer's Disease Dementia Terminated

PHASE3 NCT02783573 n=1722

Alzheimer's Disease

Interventions: Lanabecestat, Placebo

Sponsor: AstraZeneca | Started: 2016-07-01

An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738) Terminated

PHASE2 NCT01739348 n=2211

Alzheimer's Disease

Interventions: Verubecestat (Part I and Part II), Verubecestat (Part I and Part II), Verubecestat (Part I and Part II)

Sponsor: Merck Sharp & Dohme LLC | Started: 2012-11-30

The Study of microRNA 107 (miRNA 107) and Beta-amyloid Precursor Protein-cleaving Enzyme 1 (BACE1) Messenger Ribonucleic Unknown

Unknown NCT01819545 n=300

Alzheimer's Disease

Sponsor: Shanghai Mental Health Center | Started: 2012-01

Linked Hypotheses (1)

Palmitoylation-Targeted BACE1 Trafficking Disruptors0.407

Linked Experiments (0)

No linked experiments

Scoring Dimensions

Knowledge Graph (20)

Debate History (0)

No debates yet

BACE1

3D Protein Structure

Druggability & Clinical Context

🧬 3D Protein Structure

Selectivity & Safety Considerations

3D Protein Structure

Clinical Trials (8)

Linked Hypotheses (1)

Linked Experiments (0)

Scoring Dimensions

Knowledge Graph (20)

activates (4)

associated with (4)

biomarker for (2)

expressed in (1)

implicated in (2)

inhibits (1)

regulates (3)

therapeutic target (3)

Debate History (0)