BACE1

Summary

BACE1 (beta-secretase 1, HGNC:933) is a protein-coding gene on chromosome 11q23.3, encoding Beta-secretase 1 (P56817). Responsible for the proteolytic processing of the amyloid precursor protein (APP).

This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer’s disease patients.

Source: NCBI Gene 23621 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 69 total
• Druggable target: yes — 26 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012104

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:933
Approved symbol	BACE1
Name	beta-secretase 1
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	Asp2
Ensembl gene	ENSG00000186318
Ensembl biotype	protein_coding
OMIM	604252
Entrez	23621

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000313005, ENST00000392937, ENST00000428381, ENST00000445823, ENST00000509916, ENST00000510630, ENST00000510915, ENST00000513780, ENST00000514464, ENST00000528053, ENST00000530824, ENST00000679585, ENST00000680271, ENST00000680681, ENST00000680800, ENST00000680971, ENST00000681714, ENST00000681753, ENST00000896512, ENST00000927849

RefSeq mRNA: 7 — MANE Select: NM_012104 NM_001207048, NM_001207049, NM_001411039, NM_012104, NM_138971, NM_138972, NM_138973

CCDS: CCDS44739, CCDS44740, CCDS44741, CCDS55786, CCDS55787, CCDS8383, CCDS91601

Canonical transcript exons

ENST00000313005 — 9 exons

Exon	Start	End
ENSE00002041784	117285698	117289807
ENSE00002719959	117315535	117316256
ENSE00003694855	117296873	117296961
ENSE00003695531	117290488	117290659
ENSE00003696159	117295131	117295347
ENSE00003698958	117293054	117293188
ENSE00003699113	117293871	117294008
ENSE00003700609	117290900	117291049
ENSE00003701731	117291712	117291813

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 97.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.2558 / max 762.3993, expressed in 1636 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122486	24.3303	1635
122483	0.5370	74
122480	0.2667	124
122484	0.0629	24
122482	0.0572	34
122481	0.0017	1

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	97.98	gold quality
body of pancreas	UBERON:0001150	97.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.86	gold quality
spinal cord	UBERON:0002240	97.78	gold quality
corpus callosum	UBERON:0002336	97.00	gold quality
stromal cell of endometrium	CL:0002255	96.96	gold quality
subthalamic nucleus	UBERON:0001906	96.88	gold quality
medulla oblongata	UBERON:0001896	96.16	gold quality
pancreas	UBERON:0001264	95.95	gold quality
ventral tegmental area	UBERON:0002691	95.77	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.72	gold quality
inferior olivary complex	UBERON:0002127	95.57	gold quality
superior vestibular nucleus	UBERON:0007227	95.53	gold quality
midbrain	UBERON:0001891	95.29	gold quality
substantia nigra	UBERON:0002038	95.19	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.89	gold quality
pons	UBERON:0000988	94.88	gold quality
cranial nerve II	UBERON:0000941	94.68	gold quality
prefrontal cortex	UBERON:0000451	94.66	gold quality
globus pallidus	UBERON:0001875	94.39	gold quality
medial globus pallidus	UBERON:0002477	94.37	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.18	gold quality
islet of Langerhans	UBERON:0000006	93.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.47	gold quality
cortical plate	UBERON:0005343	93.40	gold quality
substantia nigra pars compacta	UBERON:0001965	93.10	gold quality
adrenal tissue	UBERON:0018303	93.06	gold quality
Ammon’s horn	UBERON:0001954	92.97	gold quality
parietal lobe	UBERON:0001872	92.84	gold quality
frontal cortex	UBERON:0001870	92.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	22.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, FLOT2, GATA1, HIF1A, HSF1, IFNGR1, NCOR1, NFATC2, NFIA, NFKB1, NFKB, PPARG, RELA, SP1, SPI1, STAT1, STAT3, TCF3, TCF7L2, TFAP2A, TNF, YY1

miRNA regulators (miRDB)

236 targeting BACE1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6845-3P	99.94	66.88	1439

Literature-anchored findings (GeneRIF, showing 40)

• BACE1 is in the distal Golgi membrane with a minor presence in the endoplasmic reticulum, endosomes, and plasma membrane in human neuroblastoma SHEP cells and in mouse Neuro-2a cell lines (PMID:11466313)
• BACE has a loose substrate specificity and the substrate recognition site in BACE extends over several amino acids (PMID:11741910)
• beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial ALzheimer’s disease mutations. (PMID:11744168)
• Intracellular localization of BACE affects sleavage site specificity; processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer’s disease brain (PMID:11847218)
• Our data are consistent with a role for the cytoplasmic domain in regulating BACE trafficking and localization. (PMID:11860271)
• A model of the three-dimensional structure of the beta-secretase zymogen has been constructed. (PMID:11922623)
• BACE1 interacts with nicastrin (PMID:12054507)
• Splice variants of the beta-site APP-cleaving enzyme BACE1 are found in human brain and pancreas (BACE1) (PMID:12054559)
• Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity (PMID:12093293)
• Results show an increase in protein expression of BACE in the cortex of Alzheimer’s disease patients compared to age-matched controls (PMID:12112088)
• endocytosis and intracellular transport of memapsin 2, mediated by its cytosolic domain, may involve the binding of GGA1 and GGA2 (PMID:12135764)
• Crystal structure analysis of memapsin-2 catalytic unit complexed with its inhibitor OM00-3 defines locations and functions of new binding pockets S3’ and S4’. (PMID:12206667)
• Activity levels are increased in brain regions affected by amyloid deposition and remain increased despite significant neuronal and synaptic loss in Alzheimer disease (PMID:12223024)
• Oxidative stress induces increased BACE protein levels and activity in NT2 neurons accompanied by an increase in amyloid beta protein precursor. (PMID:12270690)
• BACE mRNA amounts were similar in the hippocampus and cerebellum of Alzheimer’s patients and controls. (PMID:12438920)
• Results describe a decrease in alpha-secretase (81% of normal) and a large increase in beta-secretase activity (185%) in sporadic Alzheimer’s disease temporal cortex. (PMID:12445809)
• An isoenzyme specifically truncates amyloid beta-peptide after its presenilin-dependent generation. (PMID:12471021)
• elevated expression and enzymatic activity in the brain of sporadic Alzheimer disease patients (PMID:12514700)
• The association of beta-site APP cleaving enzyme (BACE) C786G polymorphism with Alzheimer’s disease. No significant association of this polymorphism with the occurrence of AD can be established. (PMID:12535780)
• Identification of domains for PLSCR1 and BACE binding and their colocalization in the Golgi area and endosomal compartments suggest involvement of PLSCR1 in the intracellular distribution and/or recruitment of BACE into the lipid raft. (PMID:12586838)
• BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle; (b) accumulate in the form of plaque-like inclusions in myositis vacuolated and necrotic muscle fibers (PMID:12618121)
• gamma-secretase cleavage of CT99 is a prerequisite for BACE-mediated processing at Abeta-34 site and therefore, BACE and gamma-secretase activity can be mutually dependent. (PMID:12665519)
• sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; but, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone. (PMID:12707937)
• antagonistic effect with beta-site amyloid precursor protein-cleaving enzyme 2 on beta-amyloid peptide production in cells (PMID:12801932)
• BACE exon 5 polymorphism plays an important role in the development of Alzheimer’s disease, possibly by influencing Abeta(42) protein levels. (PMID:12824768)
• BACE1 sheddase is distinct from alpha-secretase and, inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the beta-site (PMID:12857759)
• These data suggest a possible genetic relation between BACE1 and AD. (PMID:12928915)
• acts on the P-selectin glycoprotein ligand 1, which mediates leukocyte adhesion in inflammatory reactions (PMID:14507929)
• BACE 1 cleavage regulates a common function of APP and APLPs in neurons (PMID:14699153)
• BACE1 gene expression is tightly regulated at the transcriptional level, and transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Abeta in Alzheimer’s disease. (PMID:14701757)
• Homology models of alternatively spliced isoforms B (BACEI-476), C (BACEI-457) and D(BACEI-432) suggest that these should have diminished enzyme activity due to the the loss of key complexing residues (PMID:14748006)
• beta-Secretase activity is enhanced by cellular targeting into intracellular cholesterol-rich microdomains (PMID:14748707)
• BACE elevation may lead to increased amyloid beta peptide production and enhanced deposition of amyloid plaques in sporadic Alzheimer disease patients. (PMID:14978286)
• BACE overexpression is not sufficient to produce beta-amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation. (PMID:14991462)
• Alternative splicing in the BACE-1 5’UTR affects the efficiency of translation initiation (PMID:15034149)
• promotor and 5’ UTR sequence analysis (PMID:15059975)
• transcription response element analysis of 5’ flanking region (PMID:15059977)
• The major structural difference in the bound and unbound memapsin 2 is a large movement of the flap of about 4.5 angstroms at the tip; the flap in the unbound memapsin 2 appears in a novel “open” position permitting access to the active-site cleft. (PMID:15096037)
• memapsin 2 and APP, immunoprecipitated together from cell lysates, suggested that the interaction of these two proteins is part of the native cellular processes [memapsin-2] (PMID:15197182)
• Stimulation of cells with muscarinic agonists increased BACE1 expression up to twofold over basal levels. Similar effects of BACE1 up-regulation were observed when protein kinase C was directly activated by phorbol esters. (PMID:15211591)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	bace1	ENSDARG00000101716
mus_musculus	Bace1	ENSMUSG00000032086
rattus_norvegicus	Bace1	ENSRNOG00000016847
drosophila_melanogaster	Bace	FBGN0032049
drosophila_melanogaster	CG6508	FBGN0032303
drosophila_melanogaster	CG17134	FBGN0032304
drosophila_melanogaster	CG33128	FBGN0053128
caenorhabditis_elegans		WBGENE00000214
caenorhabditis_elegans		WBGENE00000218
caenorhabditis_elegans		WBGENE00012681
caenorhabditis_elegans		WBGENE00012682
caenorhabditis_elegans		WBGENE00012683
caenorhabditis_elegans		WBGENE00013973
caenorhabditis_elegans		WBGENE00017678
caenorhabditis_elegans		WBGENE00019104
caenorhabditis_elegans		WBGENE00019105
caenorhabditis_elegans		WBGENE00077655

Paralogs (9): PGC (ENSG00000096088), CTSD (ENSG00000117984), NAPSA (ENSG00000131400), REN (ENSG00000143839), BACE2 (ENSG00000182240), CTSE (ENSG00000196188), PGA4 (ENSG00000229183), PGA3 (ENSG00000229859), PGA5 (ENSG00000256713)

Protein

Protein identifiers

Beta-secretase 1 — P56817 (reviewed: P56817)

Alternative names: Aspartyl protease 2, Beta-site amyloid precursor protein cleaving enzyme 1, Memapsin-2, Membrane-associated aspartic protease 2

All UniProt accessions (8): A0A7P0T924, A0A7P0TAB4, B7Z3K2, B7Z3Z4, E9PJG7, P56817, Q76KP0, U3KPS1

UniProt curated annotations — full annotation on UniProt →

Function. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Cleaves CHL1.

Subunit / interactions. Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498. Interacts with RTN1; RTN2; RTN3 and RTN4; the interaction leads to inhibition of amyloid precursor protein processing. Interacts with SNX6. Interacts with PCSK9. Interacts with NAT8 and NAT8B. Interacts with BIN1. Interacts (via extracellular domain) with ADAM10 (via extracellular domain). Interacts with SORL1; this interaction may affect binding with APP and hence reduce APP cleavage. Interacts with NRDC AND NRG1.

Subcellular location. Cell membrane. Golgi apparatus. trans-Golgi network. Endoplasmic reticulum. Endosome. Cell surface. Cytoplasmic vesicle membrane. Membrane raft. Lysosome. Late endosome. Early endosome. Recycling endosome. Cell projection. Axon. Dendrite.

Tissue specificity. Expressed at high levels in the brain and pancreas. In the brain, expression is highest in the substantia nigra, locus coruleus and medulla oblongata.

Post-translational modifications. N-Glycosylated. Addition of a bisecting N-acetylglucosamine by MGAT3 blocks lysosomal targeting, further degradation and is required for maintaining stability under stress conditions. Acetylated in the endoplasmic reticulum at Lys-126, Lys-275, Lys-279, Lys-285, Lys-299, Lys-300 and Lys-307. Acetylation by NAT8 and NAT8B is transient and deacetylation probably occurs in the Golgi. Acetylation regulates the maturation, the transport to the plasma membrane, the stability and the expression of the protein. Palmitoylation mediates lipid raft localization. Ubiquitinated at Lys-501, ubiquitination leads to lysosomal degradation. Monoubiquitinated and ‘Lys-63’-linked polyubitinated. Deubiquitnated by USP8; inhibits lysosomal degradation. Phosphorylation at Ser-498 is required for interaction with GGA1 and retrograded transport from endosomal compartments to the trans-Golgi network. Non-phosphorylated BACE1 enters a direct recycling route to the cell surface.

Activity regulation. Inhibited by RTN3 and RTN4.

Domain organisation. DXXLL motif is required for a proper endocytosis and retrograde transport to the trans-Golgi network, as well as for regulation of lysosomal degradation. The transmembrane domain is necessary for its activity. It determines its late Golgi localization and access to its substrate, APP.

Induction. Up-regulated by the Ca(2+)-regulated transcription factor NFATC4.

Similarity. Belongs to the peptidase A1 family.

Isoforms (6)

UniProt ID	Names	Canonical?
P56817-1	A, BACE-1A, BAC-501	yes
P56817-2	B, BACE-1B, BACE-I-476
P56817-3	C, BACE-1C, BACE-I-457
P56817-4	D, BACE-1D, BACE-I-432
P56817-5	5
P56817-6	6

RefSeq proteins (7): NP_001193977, NP_001193978, NP_001397968, NP_036236, NP_620427, NP_620428, NP_620429 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001461	Aspartic_peptidase_A1	Family
IPR001969	Aspartic_peptidase_AS	Active_site
IPR009119	BACE	Family
IPR009120	BACE1	Family
IPR021109	Peptidase_aspartic_dom_sf	Homologous_superfamily
IPR033121	PEPTIDASE_A1	Domain
IPR033874	Memapsin-like	Domain

Pfam: PF00026

Enzyme classification (BRENDA):

• EC 3.4.23.46 — memapsin 2 (BRENDA: 7 organisms, 189 substrates, 722 inhibitors, 12 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
EEISEVNLDAEFRG	1.71	2
M-2420 PEPTIDE	0.0019–0.0083	2
SEVNLDAEFR	4.07	2
((7-METHOXYCOUMARIN-4-YL)ACETYL)-SER-GLU-VAL-ASN	0.0045	1
7-METHOXYCOUMARIN-4-YL-SEVNLDAEFK-2,4-DINITROPHE	0.055	1
ARG-GLU(5-[(2-AMINOETHYL)AMINO]-NAPHTHALENE-1-SU	0.0054	1
RE(EDANS)EVNLDAEFK(DABCYL)R-NH2	12.8	1

UniProt features (92 total): strand 27, helix 12, turn 9, modified residue 8, mutagenesis site 6, lipid moiety-binding region 4, glycosylation site 4, splice variant 4, disulfide bond 3, active site 2, topological domain 2, sequence variant 2, region of interest 2, signal peptide 1, propeptide 1, chain 1, cross-link 1, transmembrane region 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

350 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4L7G	X-RAY DIFFRACTION	1.38
3VF3	X-RAY DIFFRACTION	1.48
5HDZ	X-RAY DIFFRACTION	1.49
2QP8	X-RAY DIFFRACTION	1.5
4B78	X-RAY DIFFRACTION	1.5
4DJX	X-RAY DIFFRACTION	1.5
5HU1	X-RAY DIFFRACTION	1.5
3VEU	X-RAY DIFFRACTION	1.52
5F01	X-RAY DIFFRACTION	1.52
3L5E	X-RAY DIFFRACTION	1.53
5HE4	X-RAY DIFFRACTION	1.53
5HE5	X-RAY DIFFRACTION	1.55
4FM7	X-RAY DIFFRACTION	1.56
4R91	X-RAY DIFFRACTION	1.58
5HDU	X-RAY DIFFRACTION	1.58
4FGX	X-RAY DIFFRACTION	1.59
2VIJ	X-RAY DIFFRACTION	1.6
2VIZ	X-RAY DIFFRACTION	1.6
2VJ7	X-RAY DIFFRACTION	1.6
2VJ9	X-RAY DIFFRACTION	1.6
2WF0	X-RAY DIFFRACTION	1.6
2WF1	X-RAY DIFFRACTION	1.6
3TPP	X-RAY DIFFRACTION	1.6
4B70	X-RAY DIFFRACTION	1.6
4B72	X-RAY DIFFRACTION	1.6
4H3J	X-RAY DIFFRACTION	1.6
4IVT	X-RAY DIFFRACTION	1.6
5HDX	X-RAY DIFFRACTION	1.6
3TPJ	X-RAY DIFFRACTION	1.61
5I3V	X-RAY DIFFRACTION	1.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56817-F1	87.75	0.74

Antibody-complex structures (SAbDab): 1 — 3R1G

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 93; 289

Post-translational modifications (13): 126, 275, 279, 285, 299, 300, 307, 498, 474, 478, 482, 485, 501

Disulfide bonds (3): 216–420, 278–443, 330–380

Glycosylation sites (4): 153, 172, 223, 354

Mutagenesis-validated functional residues (6):

Position	Phenotype
93	decreases beta-cleaved soluble app production.
284	almost abolishes beta-cleaved soluble app production.
498	no effect on endocytosis from the cell surface. increases recycling from endosomes to the cell surface.
498	no effect on endocytosis form the cell surface. decreases recycling from endosomes to the cell surface.
499–500	impairs endocytosis and produces a delayed retrograde transport to the trans-golgi network and delivery to the lysosmes,
501	inhibits ubiquitination. no effect on endocytosis rate. induced protein stability and acculmulation in early and late en

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 277 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_BEHAVIOR, GCM_PTPRD, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, AAGTCCA_MIR422B_MIR422A, LFA1_Q6, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOCC_CELL_SURFACE, TATTATA_MIR374, GOBP_RESPONSE_TO_COPPER_ION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (20): proteolysis (GO:0006508), membrane protein ectodomain proteolysis (GO:0006509), response to lead ion (GO:0010288), protein processing (GO:0016485), amyloid-beta formation (GO:0034205), swimming behavior (GO:0036269), amyloid precursor protein catabolic process (GO:0042987), positive regulation of neuron apoptotic process (GO:0043525), amyloid-beta metabolic process (GO:0050435), detection of mechanical stimulus involved in sensory perception of pain (GO:0050966), prepulse inhibition (GO:0060134), cellular response to copper ion (GO:0071280), cellular response to manganese ion (GO:0071287), presynaptic modulation of chemical synaptic transmission (GO:0099171), signaling receptor ligand precursor processing (GO:0140448), cellular response to amyloid-beta (GO:1904646), amyloid fibril formation (GO:1990000), response to insulin-like growth factor stimulus (GO:1990418), regulation of neuron apoptotic process (GO:0043523), modulation of chemical synaptic transmission (GO:0050804)

GO Molecular Function (9): amyloid-beta binding (GO:0001540), endopeptidase activity (GO:0004175), aspartic-type endopeptidase activity (GO:0004190), peptidase activity (GO:0008233), beta-aspartyl-peptidase activity (GO:0008798), enzyme binding (GO:0019899), protein serine/threonine kinase binding (GO:0120283), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (26): lysosome (GO:0005764), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), multivesicular body (GO:0005771), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), cell surface (GO:0009986), endosome membrane (GO:0010008), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), membrane raft (GO:0045121), recycling endosome (GO:0055037), Golgi-associated vesicle lumen (GO:0070931), hippocampal mossy fiber to CA3 synapse (GO:0098686), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	4
protein metabolic process	2
neuron apoptotic process	2
cellular response to metal ion	2
presynapse	2
endomembrane system	2
cellular anatomical structure	2
neuron projection	2
membrane protein proteolysis	1
response to metal ion	1
proteolysis	1
protein maturation	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
locomotory behavior	1
amyloid precursor protein metabolic process	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
metabolic process	1
sensory perception of pain	1
detection of mechanical stimulus involved in sensory perception	1
startle response	1
negative regulation of response to external stimulus	1
response to copper ion	1
response to manganese ion	1
modulation of chemical synaptic transmission	1
protein processing	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to amyloid-beta	1
supramolecular fiber organization	1
response to hormone	1
regulation of apoptotic process	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
peptide binding	1
peptidase activity	1
endopeptidase activity	1
aspartic-type peptidase activity	1
hydrolase activity	1

Protein interactions and networks

STRING

2758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BACE1	APP	P05067	999
BACE1	PSEN1	P49768	962
BACE1	RTN4	Q9NQC3	916
BACE1	ADAM10	O14672	890
BACE1	CDK5	Q00535	875
BACE1	PSENEN	Q9NZ42	875
BACE1	GZMM	P51124	874
BACE1	MMEL1	Q495T6	861
BACE1	RTN3	O95197	860
BACE1	PSEN2	P49810	851
BACE1	NCSTN	Q92542	835
BACE1	ACHE	P22303	831
BACE1	APLP1	P51693	799
BACE1	IDE	P14735	794
BACE1	APH1A	Q96BI3	793

IntAct

59 interactions, top by confidence:

A	B	Type	Score
BACE1	APP	psi-mi:“MI:0570”(protein cleavage)	0.870
BACE1	APP	psi-mi:“MI:0403”(colocalization)	0.870
APP	BACE1	psi-mi:“MI:0915”(physical association)	0.870
BACE1	APP	psi-mi:“MI:2364”(proximity)	0.870
BACE1	APP	psi-mi:“MI:0194”(cleavage reaction)	0.870
GGA1	BACE1	psi-mi:“MI:0915”(physical association)	0.670
GGA1	BACE1	psi-mi:“MI:0407”(direct interaction)	0.670
BACE1	GGA1	psi-mi:“MI:2364”(proximity)	0.670
BACE1	GGA1	psi-mi:“MI:0403”(colocalization)	0.670
APP	ADAM10	psi-mi:“MI:2364”(proximity)	0.660
PSEN1	BACE1	psi-mi:“MI:0915”(physical association)	0.640
PSEN1	BACE1	psi-mi:“MI:0403”(colocalization)	0.640
IAPP	BACE1	psi-mi:“MI:0570”(protein cleavage)	0.560
BACE1	IAPP	psi-mi:“MI:0407”(direct interaction)	0.560
ITM2B	BACE1	psi-mi:“MI:0915”(physical association)	0.560
ITM2B	BACE1	psi-mi:“MI:0403”(colocalization)	0.560
GGA2	BACE1	psi-mi:“MI:0915”(physical association)	0.540
GGA3	BACE1	psi-mi:“MI:0915”(physical association)	0.540
GGA3	BACE1	psi-mi:“MI:0407”(direct interaction)	0.540

BioGRID (66): BACE1 (Affinity Capture-RNA), BACE1 (Affinity Capture-RNA), CSNK1D (Co-localization), BACE1 (Co-localization), BACE1 (Biochemical Activity), BACE1 (Affinity Capture-Western), GGA1 (Affinity Capture-Western), GGA2 (Affinity Capture-Western), GGA3 (Affinity Capture-Western), GGA1 (Reconstituted Complex), BACE1 (Biochemical Activity), BACE1 (Affinity Capture-MS), BACE1 (Affinity Capture-Western), SORT1 (Affinity Capture-Western), KCNQ1 (Affinity Capture-Western)

ESM2 similar proteins: A6QLU6, B8AT51, P07224, P07225, P09858, P17247, P21214, P27090, P34925, P37173, P38438, P56817, P56818, P56819, P61811, P61812, Q03351, Q07257, Q0JAW2, Q10836, Q15223, Q1KLR6, Q28520, Q2HJ40, Q2V4F9, Q38L25, Q5M900, Q5REF6, Q62312, Q6IS24, Q6NRQ1, Q6QNK2, Q6ZQ11, Q7TT15, Q7TT36, Q80T32, Q86X52, Q8BFR2, Q8BG28, Q8IWK6

Diamond homologs: A8PZM4, O60020, P56817, Q01972, Q05744, Q2HJ40, A0A146F0J0, A1CBR4, A1DDK1, A2R3L3, B0Y1V8, B6HL60, D4AZK1, D4D8U6, E5A7T3, O93885, P03955, P06026, P0CU33, P10602, P11838, P17576, P17946, P20142, P32950, P32951, P41748, P42211, P43094, P43231, P43232, P55325, P56819, P81214, Q03699, Q03700, Q12567, Q29079, Q64411, Q69IF8

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CSNK1D	unknown	BACE1	phosphorylation
USP8	“up-regulates quantity by stabilization”	BACE1	deubiquitination
BACE1	“up-regulates activity”	APP	cleavage
USP8	“up-regulates quantity”	BACE1	deubiquitination
CDK5	“up-regulates activity”	BACE1	phosphorylation
STUB1	“down-regulates quantity”	BACE1	ubiquitination
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	BACE1	polyubiquitination
FBXO2	“down-regulates quantity by destabilization”	BACE1	binding
CDK5/CDK5R1	“up-regulates activity”	BACE1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Amyloid fiber formation	7	37.9×	8e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

69 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1379 predictions. Top by Δscore:

Variant	Effect	Δscore
11:117290485:CA:C	donor_loss	1.0000
11:117290486:A:AC	donor_gain	1.0000
11:117290487:C:CC	donor_gain	1.0000
11:117290487:C:CT	donor_loss	1.0000
11:117290655:TATTG:T	acceptor_gain	1.0000
11:117290657:TTG:T	acceptor_gain	1.0000
11:117290658:TG:T	acceptor_gain	1.0000
11:117290660:C:CC	acceptor_gain	1.0000
11:117291696:T:TA	donor_gain	1.0000
11:117291710:A:AC	donor_gain	1.0000
11:117291711:C:CT	donor_gain	1.0000
11:117291711:CG:C	donor_gain	1.0000
11:117291711:CGG:C	donor_gain	1.0000
11:117291809:TTGTA:T	acceptor_gain	1.0000
11:117291810:TGTA:T	acceptor_gain	1.0000
11:117291811:GTA:G	acceptor_gain	1.0000
11:117291812:TA:T	acceptor_gain	1.0000
11:117291812:TAC:T	acceptor_loss	1.0000
11:117291813:ACTAA:A	acceptor_loss	1.0000
11:117291814:C:CC	acceptor_gain	1.0000
11:117291815:T:G	acceptor_loss	1.0000
11:117293052:A:AC	donor_gain	1.0000
11:117293052:A:C	donor_loss	1.0000
11:117293052:ACCT:A	donor_gain	1.0000
11:117293053:C:CC	donor_gain	1.0000
11:117293053:CCT:C	donor_gain	1.0000
11:117293053:CCTC:C	donor_gain	1.0000
11:117293055:T:TA	donor_gain	1.0000
11:117293185:TGAT:T	acceptor_gain	1.0000
11:117293189:CTAGG:C	acceptor_loss	1.0000

AlphaMissense

3266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:117290508:A:G	F415S	1.000
11:117290534:A:C	F406L	1.000
11:117290534:A:T	F406L	1.000
11:117290536:A:G	F406L	1.000
11:117290568:C:A	G395V	1.000
11:117290568:C:T	G395E	1.000
11:117290569:C:G	G395R	1.000
11:117290569:C:T	G395R	1.000
11:117290574:A:T	V393D	1.000
11:117290612:A:C	C380W	1.000
11:117290613:C:G	C380S	1.000
11:117290613:C:T	C380Y	1.000
11:117290614:A:G	C380R	1.000
11:117290614:A:T	C380S	1.000
11:117290652:A:G	L367P	1.000
11:117290656:A:C	Y366D	1.000
11:117291002:G:C	C330W	1.000
11:117291003:C:G	C330S	1.000
11:117291003:C:T	C330Y	1.000
11:117291004:A:G	C330R	1.000
11:117291004:A:T	C330S	1.000
11:117291026:G:C	F322L	1.000
11:117291026:G:T	F322L	1.000
11:117291027:A:C	F322C	1.000
11:117291028:A:G	F322L	1.000
11:117291770:A:G	L295P	1.000
11:117291776:G:A	T293I	1.000
11:117291779:G:A	T292I	1.000
11:117291782:C:A	G291V	1.000
11:117291782:C:T	G291D	1.000

dbSNP variants (sampled 300 via entrez): RS1000048066 (11:117299994 G>A), RS1000073886 (11:117307881 T>C,G), RS1000323636 (11:117294235 A>G), RS1000331382 (11:117317117 G>T), RS1000432389 (11:117311214 G>C), RS1000529873 (11:117308161 G>A), RS1000581657 (11:117312701 G>T), RS1000767622 (11:117309522 G>T), RS1000825726 (11:117309860 G>A), RS1000948622 (11:117315407 G>A), RS1000992369 (11:117303988 C>T), RS1001055346 (11:117287338 C>T), RS1001067796 (11:117315699 C>A), RS1001318983 (11:117303317 G>A), RS1001451758 (11:117297200 G>A)

Disease associations

OMIM: gene MIM:604252 | disease phenotypes: MIM:614845

GenCC curated gene-disease

Mondo (1): nephronophthisis 15 (MONDO:0013917)

Orphanet (1): Senior-Loken syndrome (Orphanet:3156)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001157_5	Cardiovascular disease risk factors	8.000000e-07
GCST007637_53	Diffusing capacity of carbon monoxide	9.000000e-06
GCST90002395_104	Mean platelet volume	8.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009369	diffusing capacity of the lung for carbon monoxide

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111390 (PROTEIN FAMILY), CHEMBL4822 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

26 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 674,320 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL311498	CIANIDANOL	4	59,647
CHEMBL502	DONEPEZIL	4	43,493
CHEMBL76	CHLOROQUINE	4	58,679
CHEMBL939	GEFITINIB	4	117,814
CHEMBL11608	TYRAMINE	3	38,171
CHEMBL140	CURCUMIN	3	93,882
CHEMBL145	CAFFEIC ACID	3	36,305
CHEMBL1950045	HYDROXYTYROSOL	3	6,641
CHEMBL226335	RUTIN	3	57,988
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL3301601	VERUBECESTAT	3	590
CHEMBL3989948	LANABECESTAT	3	338
CHEMBL4204869	ELENBECESTAT	3	196
CHEMBL473159	PHLOROGLUCINOL	3	35,205
CHEMBL50	QUERCETIN	3	74,559
CHEMBL129482	(+)-EPICATECHIN	2	133
CHEMBL1483796	SPICLOMAZINE	2	464
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL3916243	ATABECESTAT	2	216
CHEMBL444478	ACETOSIDE	2	3,672
CHEMBL583912	(-)-EPICATECHIN	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL150	KAEMPFEROL	1
CHEMBL2177913	AZD-3839	1
CHEMBL2333941	LY-2811376	1
CHEMBL2396989	LY-2886721	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — A1: Pepsin

Most potent curated ligand interactions (32 total), top 25:

Ligand	Action	Affinity	Parameter
compound 6 [PMID: 34553947]	Inhibition	9.89	pKi
compound 15 [PMID: 25699151]	Inhibition	9.52	pIC50
verubecestat	Competitive	9.47	pKi
AM-6494	Inhibition	9.4	pIC50
AMG-8718	Inhibition	9.15	pIC50
PF-06684511	Inhibition	9.15	pIC50
atabecestat	Inhibition	9.1	pKi
compound 16 [PMID: 23412139]	Competitive	8.77	pKi
AZ-4217	Competitive	8.74	pKi
lanabecestat	Competitive	8.66	pIC50
JNJ-67569762	Inhibition	8.57	pIC50
compound 11d [PMID: 23981898]	Competitive	8.4	pIC50
compound 9 [PMID: 26937601]	Inhibition	8.3	pKi
NB-360	Inhibition	8.3	pIC50
compound 2 [PMID: 22911925]	Competitive	8.26	pIC50
elenbecestat	Inhibition	8.15	pIC50
PF-06751979	Inhibition	8.14	pIC50
compound 13 [PMID: 23412139]	Inhibition	8.11	pKi
umibecestat	Inhibition	7.96	pIC50
oxazine 89	Competitive	7.92	pIC50
compound J [PMID: 21907142]	Inhibition	7.74	pIC50
LY2886721	Competitive	7.7	pIC50
example 2 [WO2013004676]	Inhibition	7.59	pIC50
AZD3839	Competitive	7.58	pKi
AZ3971	Competitive	7.52	pIC50

Binding affinities (BindingDB)

5437 measured of 5890 human assays (5901 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.0002 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide	IC50	0.0009 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.0009 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(8R)-10-amino-8-methyl-6,6-dioxo-6lambda6-thia-9-azaspiro[4.5]dec-9-en-8-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.001 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-(difluoromethyl)pyrazine-2-carboxamide	IC50	0.0018 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3-methyl-1,1-dioxo-2,6-dihydro-1,4-thiazin-3-yl]-4-fluorophenyl]-5-(difluoromethoxy)pyridine-2-carboxamide	IC50	0.0057 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3-methyl-1,1-dioxo-2,6-dihydro-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.0061 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3-methyl-1,1-dioxo-2,6-dihydro-1,4-thiazin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.0082 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3-methyl-2,6-dihydro-1,4-thiazin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.011 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(4R,5R)-2-amino-5-fluoro-4,5-dimethyl-6H-1,3-oxazin-4-yl]-4-fluorophenyl]-5-but-2-ynoxypyrazine-2-carboxamide	IC50	0.1 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
US10231967, Example 122	IC50	0.1 nM	US-10231967: Compounds and their use as BACE inhibitors
N2-[(2R,4S,5S)-5-{[N-{[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]carbonyl}-3-(methylsulfonyl)-L-alanyl]amino}-4-hydroxy-2,7-dimethyloctanoyl]-N-(2-methylpropyl)-L-valinamide	KI	0.12 nM
US8865911, 114	IC50	0.14 nM	US-10231967: Compounds and their use as BACE inhibitors
(5S)-2-amino-4’-fluoro-7’-(2-fluoro-3-pyridinyl)-2’-(2-fluoro-4-pyridinyl)-3-methylspiro[imidazole-5,9’-xanthene]-4-one	IC50	0.2 nM	US-8957083: Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
N-[3-[(1R,10R)-8-amino-10-methyl-1-oxo-1lambda6-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-4-fluorophenyl]-5-but-2-ynoxypyrazine-2-carboxamide	IC50	0.2 nM	US-9605006: 5-aryl-1-imino-1-oxo-[1,2,4]thiadiazines
(1R,5S,6S)-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.2 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
US10231967, Example 125	IC50	0.26 nM	US-10231967: Compounds and their use as BACE inhibitors
US8865911, 92 Isomer 2	IC50	0.27 nM	US-10231967: Compounds and their use as BACE inhibitors
(5S)-2-amino-7’-(3-chlorophenyl)-2’-(3,6-dihydro-2H-pyran-4-yl)-4’-fluoro-3-methylspiro[imidazole-5,9’-xanthene]-4-one	IC50	0.3 nM	US-8957083: Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
(7R)-4’-fluoro-7’-(2-fluoro-3-pyridinyl)-2’-(2-fluoro-4-pyridinyl)spiro[imidazo[1,2-c]imidazole-7,9’-xanthene]-5-amine	IC50	0.3 nM	US-8962859: Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
(3,5-dimethyl-1H-pyrazol-1-yl)methyl N-[(1R)-1-{[(1R,3S,4S)-3-hydroxy-1,6-dimethyl-1-{[(1S)-2-methyl-1-[(2-methylpropyl)carbamoyl]propyl]carbamoyl}heptan-4-yl]carbamoyl}-2-methanesulfonylethyl]carbamate	KI	0.3 nM
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide	IC50	0.3 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R,6R)-3-[5-[(3-chloro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-6-fluoro-3,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.33 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-isocyanopyridine-2-carboxamide	IC50	0.358 nM	US-8987254: Tetrahydropyrrolothiazine compounds
N-[3-[(4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-cyano-pyridine-2-carboxamide hydrochloride	IC50	0.358 nM	US-9999624: Combination Alzheimer therapy using anti-N3pGlu Abeta antibodies + a BACE inhibitor
US8865911, 20t	IC50	0.36 nM	US-10231967: Compounds and their use as BACE inhibitors
(3R,6R)-3-[5-[(3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-6-fluoro-3,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.38 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.4 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
N-[3-[(4R,5R)-2-amino-5-fluoro-4,5-dimethyl-6H-1,3-oxazin-4-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.4 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
(7S)-2’-(3,6-dihydro-2H-pyran-5-yl)-4’-fluoro-7’-(2-fluoro-3-pyridinyl)spiro[imidazo[1,2-c]imidazole-7,9’-xanthene]-5-amine	IC50	0.4 nM	US-8962859: Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
(7S)-4’-fluoro-7’-(2-fluoro-3-pyridinyl)-2’-(4-methylphenyl)spiro[imidazo[1,2-c]imidazole-7,9’-xanthene]-5-amine	IC50	0.4 nM	US-8962859: Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use
N-(2-amino-3’-chloro-1’-fluorospiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl)-5-but-2-ynoxypyrazine-2-carboxamide	IC50	0.4 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[2-amino-1’-fluoro-3’-(2-fluoro-4-pyridinyl)spiro[5,6-dihydro-1,3-thiazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-methoxypyridine-2-carboxamide	IC50	0.4 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-but-2-ynoxypyridine-2-carboxamide	IC50	0.4 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbonitrile	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)((S)-3-fluoropyrrolidin-1-yl)methanone	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide	IC50	0.44 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-isocyanopyridine-2-carboxamide	IC50	0.45 nM	US-8987254: Tetrahydropyrrolothiazine compounds
N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-cyanopyridine-2-carboxamide	IC50	0.45 nM	US-9999624: Combination Alzheimer therapy using anti-N3pGlu Abeta antibodies + a BACE inhibitor
N-[3-[(5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-(difluoromethoxy)-3-methylpyridine-2-carboxamide	IC50	0.48 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-(hydroxymethyl)pyrazine-2-carboxamide	IC50	0.482 nM	US-8987254: Tetrahydropyrrolothiazine compounds
N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxypyrazine-2-carboxamide	IC50	0.482 nM	US-9999624: Combination Alzheimer therapy using anti-N3pGlu Abeta antibodies + a BACE inhibitor
(5S)-2-amino-2’-(3,6-dihydro-2H-pyran-4-yl)-4’-fluoro-3-methyl-7’-(5-prop-1-ynyl-3-pyridinyl)spiro[imidazole-5,9’-xanthene]-4-one	IC50	0.5 nM	US-8957083: Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use
N-[3-[(3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-(cyclopropylmethoxy)pyrazine-2-carboxamide	IC50	0.5 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(5S)-5-[3-chloro-5-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]thiophen-2-yl]-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-3-amine	KI	0.5 nM	US-9416129: Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use
(3S)-7’-(2-fluoro-3-pyridinyl)-3’-(2-fluoro-4-pyridinyl)spiro[6,7-dihydro-2H-1,4-oxazepine-3,5’-chromeno[2,3-c]pyridine]-5-amine	IC50	0.5 nM	US-9346827: 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
(3S)-2’-(2,2-dimethylpropoxy)-4’-fluoro-7’-(2-fluoro-3-pyridinyl)spiro[6,7-dihydro-2H-1,4-oxazepine-3,9’-xanthene]-5-amine	IC50	0.5 nM	US-9346827: 5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-fluoropyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.509 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.96	IC50	0.011	nM	CHEMBL3982593
10.85	IC50	0.014	nM	CHEMBL3922902
10.77	Ki	0.017	nM	CHEMBL2179131
10.62	IC50	0.024	nM	CHEMBL4088234
10.51	IC50	0.031	nM	CHEMBL2408786
10.48	IC50	0.033	nM	CHEMBL4212046
10.47	IC50	0.034	nM	CHEMBL4217023
10.44	Ki	0.036	nM	CHEMBL2179138
10.05	IC50	0.09	nM	CHEMBL4561849
10.00	IC50	0.1	nM	CHEMBL3680900
9.96	IC50	0.11	nM	CHEMBL4203860
9.92	Ki	0.12	nM	CHEMBL449300
9.92	Ki	0.12	nM	CHEMBL254740
9.89	Ki	0.13	nM	ATABECESTAT
9.83	IC50	0.149	nM	CHEMBL5863499
9.82	IC50	0.15	nM	CHEMBL2047041
9.82	IC50	0.15	nM	CHEMBL2177305
9.80	IC50	0.16	nM	CHEMBL2152903
9.80	IC50	0.16	nM	CHEMBL3650848
9.80	IC50	0.157	nM	CHEMBL4564324
9.73	IC50	0.186	nM	CHEMBL6009196
9.70	IC50	0.2	nM	CHEMBL2152903
9.70	IC50	0.2	nM	CHEMBL3260839
9.70	IC50	0.2	nM	CHEMBL3349234
9.70	IC50	0.2	nM	CHEMBL3394218
9.70	IC50	0.2	nM	CHEMBL3394226
9.70	IC50	0.2	nM	CHEMBL3394227
9.70	IC50	0.2	nM	CHEMBL3741617
9.70	IC50	0.2	nM	CHEMBL3695737
9.70	IC50	0.2	nM	CHEMBL4588608
9.70	IC50	0.2	nM	CHEMBL4437161
9.70	IC50	0.2	nM	CHEMBL4577527
9.70	EC50	0.2	nM	CHEMBL409875
9.70	IC50	0.2	nM	CHEMBL6043173
9.68	Ki	0.21	nM	CHEMBL5092328
9.68	IC50	0.211	nM	CHEMBL5197518
9.62	IC50	0.241	nM	CHEMBL6020648
9.60	Ki	0.25	nM	CHEMBL3352906
9.60	IC50	0.25	nM	CHEMBL4861687
9.55	IC50	0.28	nM	CHEMBL2152914
9.54	IC50	0.287	nM	CHEMBL5857457
9.52	IC50	0.3	nM	CHEMBL3260838
9.52	Ki	0.3	nM	CHEMBL363255
9.52	Ki	0.3	nM	CHEMBL448008
9.52	IC50	0.3	nM	CHEMBL3354718
9.52	IC50	0.3	nM	CHEMBL3394211
9.52	IC50	0.3	nM	CHEMBL3394216
9.52	IC50	0.3	nM	CHEMBL3394220
9.52	IC50	0.3	nM	CHEMBL3394221
9.52	IC50	0.3	nM	CHEMBL3394224

PubChem BioAssay actives

3585 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-1,3-thiazol-4-yl]-5-methoxypyridine-2-carboxamide	1369218: Inhibition of BACE1 in human H4 cells transfected with wild type APP assessed as reduction in soluble portion of APPbeta level in cells incubated for overnight by ELISA	ic50	<0.0001	uM
(4S,6R)-4-[2,4-difluoro-5-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]phenyl]-4,6-dimethyl-5,6-dihydro-1,3-thiazin-2-amine	1460172: Inhibition of BACE1 in human H4 cells expressing wild type APP695 assessed as reduction in soluble APPbeta level after 18 hrs by ELISA	ic50	<0.0001	uM
2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-N-(6-methoxy-2-pyridinyl)-1,3-thiazole-5-carboxamide	1369218: Inhibition of BACE1 in human H4 cells transfected with wild type APP assessed as reduction in soluble portion of APPbeta level in cells incubated for overnight by ELISA	ic50	<0.0001	uM
N-[2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-1,3-thiazol-4-yl]-4-methoxybenzamide	1369218: Inhibition of BACE1 in human H4 cells transfected with wild type APP assessed as reduction in soluble portion of APPbeta level in cells incubated for overnight by ELISA	ic50	<0.0001	uM
(2,5-dimethyl-1,3-oxazol-4-yl)methyl N-[(2R)-1-[[(4S,5S,7R)-5-hydroxy-2,7-dimethyl-8-[[(2S)-3-methyl-1-(2-methylpropylamino)-1-oxobutan-2-yl]amino]-8-oxooctan-4-yl]amino]-3-methylsulfonyl-1-oxopropan-2-yl]carbamate	1797486: Enzyme Inhibition Measurements from Article 10.1021/ja058636j: “Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.”	ki	0.0001	uM
N-[3-[(1R,5R,6S)-3-amino-2,2,5-trimethyl-1-oxo-1lambda6-thia-4,9-diazabicyclo[4.3.0]nona-1(9),3-dien-5-yl]-4-fluorophenyl]-5-cyano-3-methylpyridine-2-carboxamide	1545230: Inhibition of BACE1 in HEK293 cells harboring APP assessed as reduction in amyloidbeta 40 level incubated for 18 to 20 hrs by AlphaLISA Assay	ic50	0.0001	uM
2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-N-(3-methoxyphenyl)-1,3-thiazole-5-carboxamide	1369218: Inhibition of BACE1 in human H4 cells transfected with wild type APP assessed as reduction in soluble portion of APPbeta level in cells incubated for overnight by ELISA	ic50	0.0001	uM
(2,5-dimethyl-1,3-oxazol-4-yl)methyl N-[(2R)-1-[[(4S,5S,7R)-8-[[(2S)-1-(tert-butylamino)-3-methyl-1-oxobutan-2-yl]amino]-5-hydroxy-2,7-dimethyl-8-oxooctan-4-yl]amino]-3-methylsulfonyl-1-oxopropan-2-yl]carbamate	314082: Binding affinity to recombinant memapsin 2	ki	0.0001	uM
N-[(2S)-3-butylsulfonyl-1-[[(2S,3R)-1-(3,5-difluorophenyl)-4-[(3-ethylphenyl)methylamino]-3-hydroxybutan-2-yl]amino]-1-oxopropan-2-yl]pyrazine-2-carboxamide	292707: Inhibition of BACE expressed in HEK293 cells	ec50	0.0002	uM
(4S)-3’-(3,4-dihydro-2H-pyran-5-yl)-1’-fluoro-7’-(2-fluoro-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1191077: Inhibition of human recombinant BACE1 pre-incubated with enzyme for 60 mins before fluorescent substrate addition FRET method	ic50	0.0002	uM
N-[3-[(1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0002	uM
N-[3-[(1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0002	uM
N-[3-[(4aS,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1545213: Inhibition of BACE1 in human SH-SY5Y cells transfected with APP695 assessed as reduction in amyloidbeta (1 to 40 residues) incubated for 24 hrs by sandwich ELlSA	ic50	0.0002	uM
N-[3-[(10R)-8-amino-7,10-dimethyl-1-oxo-1lambda6-thia-2,9-diazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-4-fluorophenyl]-5-cyano-3-methylpyridine-2-carboxamide	1545230: Inhibition of BACE1 in HEK293 cells harboring APP assessed as reduction in amyloidbeta 40 level incubated for 18 to 20 hrs by AlphaLISA Assay	ic50	0.0002	uM
N-[3-[(2S,5R)-6-amino-5-ethylsulfonyl-2-(fluoromethyl)-5-methyl-3,4-dihydropyridin-2-yl]-4-fluorophenyl]-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine-6-carboxamide	1807509: Displacement of [3H]-JNJ962 from BACE1 (unknown origin) expressed in HEK293 cell membrane assessed as inhibition constant by scintillation counting analysis	ki	0.0002	uM
2-methoxy-4-[(E)-2-[5-[4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]ethenyl]phenol	1938216: Inhibition of BACE1 (unknown origin)	ic50	0.0002	uM
(4S)-1’-fluoro-7’-(2-fluoro-3-pyridinyl)-3’-(6-fluoro-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1191077: Inhibition of human recombinant BACE1 pre-incubated with enzyme for 60 mins before fluorescent substrate addition FRET method	ic50	0.0003	uM
(4S)-1’-fluoro-7’-(2-fluoro-3-pyridinyl)-3’-(3-methyl-1,2-oxazol-5-yl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1191077: Inhibition of human recombinant BACE1 pre-incubated with enzyme for 60 mins before fluorescent substrate addition FRET method	ic50	0.0003	uM
(1S,5S,6S)-3-amino-5-[2,3-difluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0003	uM
(4S)-3’-(3,6-dihydro-2H-pyran-4-yl)-7’-(5-prop-1-ynyl-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0003	uM
2-methoxy-4-[(E)-2-[5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl]ethenyl]phenol	1938216: Inhibition of BACE1 (unknown origin)	ic50	0.0003	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-3-carboxy-1-[[(4S,5S,7R)-8-[[(2S)-1-[[(2S)-4-carboxy-1-[(1-carboxy-2-phenylethyl)amino]-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-hydroxy-2,7-dimethyl-8-oxooctan-4-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	42091: Binding affinity for human brain memapsin 2 beta-Secretase (BACE)	ki	0.0003	uM
(2R,5S)-5-[[(2S)-2-[[(2R,4S,5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-hydroxy-2,7-dimethyloctanoyl]amino]-3-methylbutanoyl]amino]-2-benzyl-4-oxooctanedioic acid	238396: Binding affinity against Beta-secretase	ki	0.0003	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-3-carboxy-1-[[(4S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-hydroxy-6-methyl-3-oxoheptan-4-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	239175: Binding affinity towards Beta-secretase determined using continuum electrostatics solvation	ki	0.0003	uM
N-[3-[(4R,4aR,7aS)-2-amino-7,7-difluoro-4-methyl-6,7a-dihydro-4aH-furo[2,3-e][1,3]oxazin-4-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1545221: Inhibition of BACE1 in human SH-SY5Y cells expressing betaAPP assessed as reduction in amyloidbeta (1 to 40 residues) level incubated for 24 hrs by HTRF assay	ic50	0.0004	uM
(4S)-1’-fluoro-7’-(2-fluoro-3-pyridinyl)-3’-pyridin-4-ylspiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1191077: Inhibition of human recombinant BACE1 pre-incubated with enzyme for 60 mins before fluorescent substrate addition FRET method	ic50	0.0004	uM
(4S)-3’-(3,4-dihydro-2H-pyran-6-yl)-1’-fluoro-7’-(2-fluoro-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1191077: Inhibition of human recombinant BACE1 pre-incubated with enzyme for 60 mins before fluorescent substrate addition FRET method	ic50	0.0004	uM
N-[6-[2-[2-[2-amino-3-[3-(3,3-dimethylbutylamino)-3-oxopropyl]quinolin-6-yl]phenyl]ethyl]-3-pyridinyl]-4-fluorobenzamide	1301518: Binding affinity to BACE1 (unknown origin) by surface plasmon resonance spectroscopic analysis	kd	0.0004	uM
N-[3-[(1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0004	uM
(1S,5S,6S)-3-amino-5-[5-[(5-chloropyridine-2-carbonyl)amino]-2,3-difluorophenyl]-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0004	uM
N-[3-[(4aS,5S,7aS)-2-amino-5-(1,1-difluoroethyl)-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-(1,2,4-triazol-1-yl)pyrazine-2-carboxamide	1545213: Inhibition of BACE1 in human SH-SY5Y cells transfected with APP695 assessed as reduction in amyloidbeta (1 to 40 residues) incubated for 24 hrs by sandwich ELlSA	ic50	0.0004	uM
(4S)-3’-(2-fluoro-4-pyridinyl)-7’-(5-prop-1-ynyl-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0004	uM
(1S,5S,6S)-3-amino-5-[5-[(5-chloropyridine-2-carbonyl)amino]-2,3-difluorophenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0004	uM
N-[3-[(3S)-1-amino-5-fluoro-3-methyl-4H-2,6-naphthyridin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1758845: Inhibition of BACE1 in human SH-SY5Y cells expressing APP assessed as reduction in Abeta40 by HTRF assay	ic50	0.0004	uM
N-[3-[(1S,5S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	1807507: Inhibition of BACE1 (1 to 454 residues) (unknown origin) using APP harboring Swedish Lys-Met/Asn-Leu mutant-derived peptide as substrate by FRET assay	ic50	0.0004	uM
3-N-[(2S,3R)-3-hydroxy-4-[(3-methoxyphenyl)methylamino]-1-phenylbutan-2-yl]-5-[methyl(methylsulfonyl)amino]-1-N-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide	778924: Inhibition of BACE1 (unknown origin) assessed as inhibition of cellular amyloid beta level	ic50	0.0004	uM
(4S)-7’-(2-fluoro-3-pyridinyl)-3’-[(3R)-3-fluoropyrrolidin-1-yl]spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1190882: Inhibition of BACE1 (unknown origin) by fluorescence assay	ic50	0.0005	uM
(4S)-3’-(3,6-dihydro-2H-pyran-5-yl)-7’-(5-prop-1-ynyl-3-pyridinyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-2-amine	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0005	uM
4-[(E)-2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethenyl]-2-methoxyphenol	1938216: Inhibition of BACE1 (unknown origin)	ic50	0.0005	uM
pyridin-3-ylmethyl N-[(2S)-3-butylsulfonyl-1-[[(2S,3R)-1-(3,5-difluorophenyl)-4-[(3-ethylphenyl)methylamino]-3-hydroxybutan-2-yl]amino]-1-oxopropan-2-yl]carbamate	292707: Inhibition of BACE expressed in HEK293 cells	ec50	0.0006	uM
N-[2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-1,3-thiazol-4-yl]-1-(difluoromethyl)pyrazole-3-carboxamide	1369218: Inhibition of BACE1 in human H4 cells transfected with wild type APP assessed as reduction in soluble portion of APPbeta level in cells incubated for overnight by ELISA	ic50	0.0006	uM
N-[3-[(9S)-7-amino-2,2-difluoro-9-methyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1545221: Inhibition of BACE1 in human SH-SY5Y cells expressing betaAPP assessed as reduction in amyloidbeta (1 to 40 residues) level incubated for 24 hrs by HTRF assay	ic50	0.0006	uM
(1S,5S,6S)-3-amino-5-[5-[(5-chloropyridine-2-carbonyl)amino]-2,3-difluorophenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	1546012: Inhibition of BACE1 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0006	uM
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	1545217: Inhibition of C-terminal His6-tagged human BACE1 expressed in mammalian expression system preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0006	uM
N-[6-[(1R,5R,6S)-3-amino-2,2,5-trimethyl-1-oxo-1lambda6-thia-4,9-diazabicyclo[4.3.0]nona-1(9),3-dien-5-yl]-5-fluoro-2-pyridinyl]-5-cyano-3-methylpyridine-2-carboxamide	1545230: Inhibition of BACE1 in HEK293 cells harboring APP assessed as reduction in amyloidbeta 40 level incubated for 18 to 20 hrs by AlphaLISA Assay	ic50	0.0006	uM
N-[2-amino-7’-(3,6-dihydro-2H-pyran-5-yl)spiro[5H-1,3-oxazole-4,9’-xanthene]-2’-yl]-5-chloropyridine-2-carboxamide	1301518: Binding affinity to BACE1 (unknown origin) by surface plasmon resonance spectroscopic analysis	kd	0.0006	uM
N-[(4S)-2-amino-3’-(3,6-dihydro-2H-pyran-5-yl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-chloropyridine-2-carboxamide	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0006	uM
3-[5-[(4S)-2-amino-3’-(3,6-dihydro-2H-pyran-4-yl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-3-pyridinyl]prop-2-yn-1-ol	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0006	uM
N-[(4S)-2-amino-3’-(oxan-4-yl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-chloropyridine-2-carboxamide	1416139: Inhibition of recombinant human BACE1 using fluorophore/quencher-tagged peptide as substrate pretreated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0006	uM
N-[3-[(1S,5R)-3-amino-5-methyl-1-methylimino-1-oxo-2-(2,2,2-trifluoroethyl)-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-cyano-3-methylpyridine-2-carboxamide	1704650: Inhibition of BACE1 in HEK293 cells harboring APP assessed as reduction in amyloidbeta 40 level measured after 18 to 20 hrs by AlphaLISA Assay	ic50	0.0006	uM

CTD chemical–gene interactions

85 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	5
Tretinoin	affects localization, decreases expression, increases expression	4
Lead	affects cotreatment, decreases reaction, increases abundance, increases expression, increases reaction	3
methylmercuric chloride	decreases expression	2
bisphenol A	affects binding, decreases methylation	2
potassium chromate(VI)	increases expression, decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Curcumin	increases expression, decreases reaction	2
DDT	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases expression, increases expression, increases methylation	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
4-((alpha-L-rhamnosyloxy)benzyl)isothiocyanate	decreases reaction, increases expression	1
oxyphylla A	decreases reaction, increases expression	1
PF-06840003	affects expression, affects reaction	1
pimagedine	affects cotreatment, decreases reaction, increases expression	1
ferulic acid	decreases reaction, increases expression	1
naringenin	decreases activity	1
triphenyl phosphate	affects expression	1
lead acetate	increases abundance, increases expression, increases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
Azure B	decreases activity	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
dinophysistoxin 1	decreases expression	1
chromium hexavalent ion	affects expression	1
27-hydroxycholesterol	increases expression	1
Go 6976	affects localization, decreases reaction	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

1237 unique, capped per target: 1230 binding, 6 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2388914	Binding	Inhibition of BACE1/BACE2 (unknown origin) transfected in CHO cells assessed as release of amyloid beta (1 to 40) after 24 hrs by immunoassay	Dihydrooxazines As Inhibitors of BACE-1 or BACE-2. — ACS Med Chem Lett
CHEMBL832508	Functional	Beta-secretase inhibitory activity as inhibition of secreted alkaline phosphatase in HEK293 cells expressing SEAP-APP fusion protein	Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations. — J Med Chem
CHEMBL4727125	ADMET	Inhibition human BACE1 expressed in baculovirus expression system at 5 uM using Panvera peptide as substrate measured after 60 mins by fluorescence assay relative to control	Centrally Active Multitarget Anti-Alzheimer Agents Derived from the Antioxidant Lead CR-6. — J Med Chem

Cellosaurus cell lines

6 cell lines: 3 transformed cell line, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8ZX	Ubigene HEK293 BACE1 KO	Transformed cell line	Female
CVCL_D9YE	Ubigene HeLa BACE1 KO	Cancer cell line	Female
CVCL_SE58	HAP1 BACE1 (-) 1	Cancer cell line	Male
CVCL_XB48	FC33	Transformed cell line	Female
CVCL_XL92	HAP1 BACE1 (-) 2	Cancer cell line	Male
CVCL_YK22	HEK293 tGFP-BACE1	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.