BACE1

Beta-secretase 1

Score: 0.567 Price: $0.57 Medium Druggability Status: active Wiki: BACE1

🧠 Neurodegeneration

HYPOTHESES

8

PAPERS

0

KG EDGES

384

DEBATES

1

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:

3

Approved:

0

In Clinical Trials:

0

Drug Pipeline (3 compounds)

3 Discontinued

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

🧬 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

0

Completed

4

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 Disruptors0.693

Linked Experiments (0)

No linked experiments

Scoring Dimensions

Knowledge Graph (20)

activates (4)

P38→BACE1BACE1→MTORBACE1→AKTBACE1→NLRP3

biomarker for (4)

SYNAPTOPHYSIN→BACE1BACE1→NFLBACE1→SYNAPTOPHYSINNFL→BACE1

expressed in (1)

inhibits (1)

regulates (7)

ST6GAL1→BACE1MAX→BACE1BACE1→FUT8JAK2-STAT1→BACE1C1Q→BACE1

▸ Show 2 more

BACE1→ST6GAL1BACE1→MAX

therapeutic target (3)

EGFR→BACE1BACE1→APPBACE1→EGFR

Debate History (1)

Should BACE1 (Beta-secretase 1) be prioritized as a therapeutic target for neuro2026-04-21