BACE2

Summary

BACE2 (beta-secretase 2, HGNC:934) is a protein-coding gene on chromosome 21q22.2-q22.3, encoding Beta-secretase 2 (Q9Y5Z0). Responsible for the proteolytic processing of the amyloid precursor protein (APP).

This gene encodes an integral membrane glycoprotein that functions as an aspartic protease. The encoded protein cleaves amyloid precursor protein into amyloid beta peptide, which is a critical step in the etiology of Alzheimer’s disease and Down syndrome. The protein precursor is further processed into an active mature peptide. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 25825 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 96 total
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012105

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:934
Approved symbol	BACE2
Name	beta-secretase 2
Location	21q22.2-q22.3
Locus type	gene with protein product
Status	Approved
Aliases	ASP1, DRAP, ALP56, CEAP1
Ensembl gene	ENSG00000182240
Ensembl biotype	protein_coding
OMIM	605668
Entrez	25825

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 6 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000328735, ENST00000330333, ENST00000347667, ENST00000463674, ENST00000465326, ENST00000466122, ENST00000470864, ENST00000475618, ENST00000487994, ENST00000491838, ENST00000854368, ENST00000854369, ENST00000854370, ENST00000854371, ENST00000854372, ENST00000921490, ENST00000953405, ENST00000953406

RefSeq mRNA: 3 — MANE Select: NM_012105 NM_012105, NM_138991, NM_138992

CCDS: CCDS13668, CCDS13669, CCDS13670

Canonical transcript exons

ENST00000330333 — 9 exons

Exon	Start	End
ENSE00003469846	41226266	41226354
ENSE00003499814	41243376	41243510
ENSE00003571071	41241819	41241947
ENSE00003625781	41257158	41257326
ENSE00003637712	41275371	41282530
ENSE00003645299	41237513	41237729
ENSE00003650610	41250752	41250901
ENSE00003680958	41245962	41246063
ENSE00003844244	41168160	41168575

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 98.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2760 / max 615.8619, expressed in 1496 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
189214	18.5852	1349
189213	5.2138	1225
189215	4.4525	854
189210	0.9781	677
189212	0.6621	423
189221	0.3155	29
209326	0.2572	119
189211	0.2061	73
189224	0.1836	25
189220	0.1370	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.49	gold quality
gall bladder	UBERON:0002110	97.17	gold quality
pancreatic ductal cell	CL:0002079	97.11	silver quality
saliva-secreting gland	UBERON:0001044	96.69	gold quality
minor salivary gland	UBERON:0001830	96.43	gold quality
renal medulla	UBERON:0000362	96.36	gold quality
islet of Langerhans	UBERON:0000006	96.16	gold quality
pylorus	UBERON:0001166	96.11	gold quality
ascending aorta	UBERON:0001496	96.04	gold quality
thoracic aorta	UBERON:0001515	96.02	gold quality
descending thoracic aorta	UBERON:0002345	95.57	gold quality
aorta	UBERON:0000947	95.41	gold quality
saphenous vein	UBERON:0007318	95.37	gold quality
mouth mucosa	UBERON:0003729	95.20	gold quality
pericardium	UBERON:0002407	95.19	gold quality
popliteal artery	UBERON:0002250	95.02	gold quality
tibial artery	UBERON:0007610	95.00	gold quality
body of stomach	UBERON:0001161	94.92	gold quality
nasal cavity epithelium	UBERON:0005384	94.68	gold quality
lower esophagus mucosa	UBERON:0035834	94.65	gold quality
stomach	UBERON:0000945	94.64	gold quality
pancreas	UBERON:0001264	94.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.00	gold quality
body of pancreas	UBERON:0001150	93.95	gold quality
left coronary artery	UBERON:0001626	93.78	gold quality
right coronary artery	UBERON:0001625	93.70	gold quality
coronary artery	UBERON:0001621	93.68	gold quality
trachea	UBERON:0003126	93.40	gold quality
smooth muscle tissue	UBERON:0001135	93.21	gold quality
nasal cavity mucosa	UBERON:0001826	93.20	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	42.06
E-MTAB-5061	yes	25.74
E-MTAB-9067	yes	16.61
E-CURD-122	yes	15.21
E-CURD-112	yes	13.25
E-GEOD-83139	yes	10.89
E-HCAD-1	yes	9.38
E-ENAD-27	yes	6.05
E-CURD-11	no	62.31
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

153 targeting BACE2, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-659-3P	99.85	70.69	1620

Literature-anchored findings (GeneRIF, showing 39)

• BACE has a loose substrate specificity and that the substrate recognition site in BACE extends over several amino acids (PMID:11741910)
• Specificity and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity (PMID:12093293)
• the enzymatic properties of BACE2 were analyzed, including substrate specificity and pH range (PMID:12423367)
• A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer. ALP56 may be a useful target molecule in breast cancer treatment. (PMID:12611455)
• 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)
• antagonistic effect with beta-site amyloid precursor protein-cleaving enzyme 1 on beta-amyloid peptide production in cells (PMID:12801932)
• Analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in Down syndrome brains compared to the control group; increased secretion of BACE-2 by cultured fibroblasts and neural stem cells from Down syndrome patients was noted (PMID:12895444)
• data indicate that despite being homologous in amino acid sequence, beta-site beta amyloid precursor protein cleaving enzyme 2(BACE2) and BACE1 have distinct functions and transcriptional regulation (PMID:15857888)
• Chromosome 21 BACE2 haplotype associates with Alzheimer’s disease (PMID:16023140)
• the crystal structure of mature BACE2 in complex with a hydroxyethylamine transition-state mimetic inhibitor at 3.1 angstroms resolution was presented. (PMID:16305800)
• Results describe the functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells. (PMID:16757811)
• Data characterize the human beta-secretase 2 (BACE2) 5’-flanking region. (PMID:16757812)
• BACE2is not involved in the Alzheimer dissease(AD)pathogenesis of Down syndrome (DS) patients; instead, therapeutic interventions that potentiate BACE2 may prevent AD pathogenesis. (PMID:16816112)
• These results indicate that increased V(max) for beta-secretase is a feature of AD pathogenesis and this increase does not correlate directly with levels of BACE1, the principal beta-secretase in brain. (PMID:17113083)
• BACE1 and BACE2 may act as alternative alpha-secretase-like proteases in proteolytic processing of IL-1R2 and APP (PMID:17307738)
• The expression levels of BACE2 was comparable between DS and controls in fetal brain and in adult brain. (PMID:18163181)
• study found no association between three BACE2 polymorphisms and sporadic Alzheimer’s disease in the Chinese Han population even after statistical adjustment for age, gender and APOE epsilon 4 status (PMID:19124009)
• Trransgenic BACE2 mice show increased anxiety-like behaviour along with increased numbers of noradrenergic neurones in the locus coeruleus. (PMID:19840121)
• BACE1 likely accounts for most of the Abeta produced in the human brain, and that BACE2 activity is not a likely contributor (PMID:19968762)
• The BACE2 distal promoter contains an activating cis-regulatory element that is responsive to Trichostatin A (TSA) treatment according to promoter reporter assays in HEK 293 cells. (PMID:20494980)
• All these data point to a role for BACE2 in the IRbeta trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in beta-cell function. (PMID:20943756)
• BACE2 overexpression in cultured cells was found to lower net amyloid ss-protein levels. (PMID:22986058)
• Inhibiting Chrna7 expression markedly stimulated the production of Abeta through the mechanism of increased expression of BACE1 and inhibited expression of BACE2 in SH-SY5Y cells. (PMID:23324234)
• BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. (PMID:23754390)
• Data identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. (PMID:23903356)
• Data suggest that the amino acid residues would be essential for selectivity of beta-amyloid precursor protein cleavage enzymes BACE1 and BACE2 functions and could be sites for the design of selective inhibitors targeting either BACE1 or BACE2. (PMID:25254246)
• Studies suggest that beta-Secretases BACE1/2 plays an important role in retinal homeostasis and that BACE upregulation in response to stress is a protective measure. (PMID:26427429)
• the behavior of the flap tips during simulations is different between BACE1 and BACE2. The BACE1 active site cavity is more spacious as compared to that of BACE2. The analysis of 10S loop and 113S loop showed a similar trend to that of flaps, with the BACE1 loops being more flexible and less stable than those of BACE2 (PMID:26804314)
• RNA-seq evidence of biallelic expression of BACE2 and 10 neighboring genes in at least one primary human tissue tested indicates that the expression of BACE2 is uncoupled from the control of the maternally inherited 5mCpG imprints at the WRB differentially methylated region (DMR) in disomic controls or trisomy (Down syndrome) individuals. (PMID:27100087)
• Common BACE2 Polymorphisms are Associated with Altered Risk for Alzheimer’s Disease and CSF Amyloid Biomarkers in APOE epsilon4 Non-Carriers. (PMID:31270419)
• TGFbeta1-induced beta-site APP-cleaving enzyme 2 upregulation promotes tumorigenesis through the NF-kappaB signalling pathway in human gliomas. (PMID:31856384)
• BACE2 degradation is mediated by both the proteasome and lysosome pathways. (PMID:32160867)
• RCAN1 Inhibits BACE2 Turnover by Attenuating Proteasome-Mediated BACE2 Degradation. (PMID:32566665)
• Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. (PMID:32647257)
• Cell surface GRP78 regulates BACE2 via lysosome-dependent manner to maintain mesenchymal phenotype of glioma stem cells. (PMID:33413577)
• m(6)A RNA hypermethylation-induced BACE2 boosts intracellular calcium release and accelerates tumorigenesis of ocular melanoma. (PMID:33601055)
• BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells. (PMID:37547981)
• The Alzheimer’s disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling. (PMID:38888964)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	bace2	ENSDARG00000044781
mus_musculus	Bace2	ENSMUSG00000040605
rattus_norvegicus	Bace2	ENSRNOG00000001953
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), BACE1 (ENSG00000186318), CTSE (ENSG00000196188), PGA4 (ENSG00000229183), PGA3 (ENSG00000229859), PGA5 (ENSG00000256713)

Protein

Protein identifiers

Beta-secretase 2 — Q9Y5Z0 (reviewed: Q9Y5Z0)

Alternative names: Aspartic-like protease 56 kDa, Aspartyl protease 1, Beta-site amyloid precursor protein cleaving enzyme 2, Down region aspartic protease, Memapsin-1, Membrane-associated aspartic protease 1, Theta-secretase

All UniProt accessions (1): Q9Y5Z0

UniProt curated annotations — full annotation on UniProt →

Function. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading 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. It has also been shown that it can cleave APP between residues 671 and 672. Involved in the proteolytic shedding of PMEL at early stages of melanosome biogenesis. Cleaves PMEL within the M-beta fragment to release the amyloidogenic PMEL luminal fragment containing M-alpha and a small portion of M-beta N-terminus. This is a prerequisite step for subsequent processing and assembly of PMEL fibrils into amyloid sheets. Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells.

Subunit / interactions. Monomer. Interacts with RTN3 and RTN4.

Subcellular location. Cell membrane. Golgi apparatus. Endoplasmic reticulum. Endosome. Melanosome.

Tissue specificity. Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate.

Post-translational modifications. Undergoes autoproteolytic cleavage. Glycosylated.

Induction. Up-regulated in primary breast and colon tumors and liver metastasis.

Similarity. Belongs to the peptidase A1 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y5Z0-1	1, Isoform A	yes
Q9Y5Z0-2	2, Isoform C
Q9Y5Z0-3	3, Isoform B
Q9Y5Z0-4	4
Q9Y5Z0-5	5

RefSeq proteins (3): NP_036237, NP_620476, NP_620477 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001461	Aspartic_peptidase_A1	Family
IPR001969	Aspartic_peptidase_AS	Active_site
IPR009119	BACE	Family
IPR009121	BACE2	Family
IPR021109	Peptidase_aspartic_dom_sf	Homologous_superfamily
IPR033121	PEPTIDASE_A1	Domain
IPR033874	Memapsin-like	Domain

Pfam: PF00026

Enzyme classification (BRENDA):

• EC 3.4.23.45 — memapsin 1 (BRENDA: 4 organisms, 48 substrates, 57 inhibitors, 1 Km, 0 kcat entries)
• EC 3.4.24.56 — insulysin (BRENDA: 12 organisms, 277 substrates, 293 inhibitors, 87 Km, 99 kcat entries)

Substrate kinetics (BRENDA)

36 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ABZ-GGFLRKHGQ-EDDNP	0.0066–21.3	25
INSULIN	—	15
2-AMINOBENZOYL-GGFLRKHGQ-(N-(2,4-DINITROPHENYL)E	0.014–0.204	7
ABZ-GGFLRKHGQEDDNP	0.0059–0.0254	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-KLVFFAEDK(DNP)-OH	0.0056–0.0076	2
7-METHOXYCOUMARIN-4-YL-ACETYL-RPPGFSAFK-2,4-DINI	0.0047–0.0049	2
AMYLOID BETA-PEPTIDE1-40	0.025–0.027	2
AMYLOID BETA-PROTEIN	0.0012–0.0025	2
DABCYL-TYR-GLU-VAL-HIS-HIS-GLN-LYS-LEU-VAL-PHE-P	1.2–2.3	2
PROINSULIN	0.0002–0.0009	2
GAMMA-SECRETASE CLEAVAGE SITE OF NOTCH	0.2	1
(7-METHOXYCOUMARIN-4-YL)ACETYL-RPPGFSAFK(2,4-DIN	0.0099	1
ABZ-GLY-GLY-LEU-ARG-LYS-HIS-GLY-GLN-EDDNP	0.0111	1
ABZ-SEKKDNYIIKGV-NITROY-OH	0.219	1
AMYLOID BETA	0.08	1

UniProt features (74 total): strand 27, helix 15, sequence conflict 6, splice variant 5, turn 5, disulfide bond 3, glycosylation site 2, mutagenesis site 2, topological domain 2, active site 2, signal peptide 1, propeptide 1, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
7D5B	X-RAY DIFFRACTION	1.31
7N4N	X-RAY DIFFRACTION	1.41
7F1G	X-RAY DIFFRACTION	1.5
3ZKQ	X-RAY DIFFRACTION	1.51
6JSZ	X-RAY DIFFRACTION	1.53
3ZKM	X-RAY DIFFRACTION	1.85
4BEL	X-RAY DIFFRACTION	1.85
3ZKG	X-RAY DIFFRACTION	1.9
3ZKN	X-RAY DIFFRACTION	2
7D5U	X-RAY DIFFRACTION	2.04
3ZLQ	X-RAY DIFFRACTION	2.1
3ZKS	X-RAY DIFFRACTION	2.11
6UJ0	X-RAY DIFFRACTION	2.15
4BFB	X-RAY DIFFRACTION	2.21
3ZKX	X-RAY DIFFRACTION	2.37
3ZKI	X-RAY DIFFRACTION	2.4
6UJ1	X-RAY DIFFRACTION	3.03
2EWY	X-RAY DIFFRACTION	3.1
3ZL7	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5Z0-F1	83.31	0.69

Antibody-complex structures (SAbDab): 13 — 3ZKM, 3ZKN, 3ZKQ, 3ZKS, 3ZKX, 3ZLQ, 4BEL, 4BFB, 6JSZ, 7D5B, 7D5U, 7F1G, 7N4N

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): 110; 303

Disulfide bonds (3): 233–433, 292–457, 344–393

Glycosylation sites (2): 366, 170

Mutagenesis-validated functional residues (2):

Position	Phenotype
110	loss of autoproteolytic cleavage.
303	loss of autoproteolytic cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 237 (showing top): TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_VESICLE_ORGANIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_CELLULAR_PIGMENTATION, CHX10_01, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PIGMENTATION, EVI1_05, KANG_FLUOROURACIL_RESISTANCE_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS, NKX62_Q2, GOBP_PROTEIN_MATURATION, GOCC_TRANS_GOLGI_NETWORK

GO Biological Process (8): proteolysis (GO:0006508), membrane protein ectodomain proteolysis (GO:0006509), protein processing (GO:0016485), peptide hormone processing (GO:0016486), melanosome organization (GO:0032438), glucose homeostasis (GO:0042593), negative regulation of amyloid precursor protein biosynthetic process (GO:0042985), amyloid-beta metabolic process (GO:0050435)

GO Molecular Function (4): aspartic-type endopeptidase activity (GO:0004190), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (8): endosome (GO:0005768), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), membrane (GO:0016020), melanosome membrane (GO:0033162), melanosome (GO:0042470)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
cytoplasm	2
intracellular membrane-bounded organelle	2
protein metabolic process	1
membrane protein proteolysis	1
proteolysis	1
protein maturation	1
hormone metabolic process	1
signaling receptor ligand precursor processing	1
pigment granule organization	1
carbohydrate homeostasis	1
negative regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
regulation of amyloid precursor protein biosynthetic process	1
metabolic process	1
endopeptidase activity	1
aspartic-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasmic vesicle	1
Golgi apparatus subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
melanosome	1
chitosome	1
pigment granule membrane	1
pigment granule	1

Protein interactions and networks

STRING

1038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BACE2	APP	P05067	830
BACE2	PSEN1	P49768	769
BACE2	NCSTN	Q92542	634
BACE2	RTN3	O95197	634
BACE2	CLTRN	Q9HBJ8	627
BACE2	PSEN2	P49810	603
BACE2	APH1A	Q96BI3	600
BACE2	SEZ6L	Q9BYH1	598
BACE2	SEZ6L2	Q6UXD5	589
BACE2	PSENEN	Q9NZ42	589
BACE2	NRG1	P98202	588
BACE2	ADAM10	O14672	581
BACE2	RTN4	Q9NQC3	574
BACE2	NAV1	Q8NEY1	573
BACE2	SCN2B	O60939	555

IntAct

98 interactions, top by confidence:

A	B	Type	Score
IAPP	BACE2	psi-mi:“MI:0570”(protein cleavage)	0.560
BACE2	IAPP	psi-mi:“MI:0407”(direct interaction)	0.560
ASAH1	BACE2	psi-mi:“MI:0915”(physical association)	0.560
KRT19	BACE2	psi-mi:“MI:0915”(physical association)	0.560
LASP1	BACE2	psi-mi:“MI:0915”(physical association)	0.560
MATK	BACE2	psi-mi:“MI:0915”(physical association)	0.560
TPM3	BACE2	psi-mi:“MI:0915”(physical association)	0.560
STX11	BACE2	psi-mi:“MI:0915”(physical association)	0.560
DUSP10	BACE2	psi-mi:“MI:0915”(physical association)	0.560
LARP4B	BACE2	psi-mi:“MI:0915”(physical association)	0.560
ARFGAP3	BACE2	psi-mi:“MI:0915”(physical association)	0.560
SCAPER	BACE2	psi-mi:“MI:0915”(physical association)	0.560
KLF3	BACE2	psi-mi:“MI:0915”(physical association)	0.560
TEX12	BACE2	psi-mi:“MI:0915”(physical association)	0.560
RHNO1	BACE2	psi-mi:“MI:0915”(physical association)	0.560
TMTC1	BACE2	psi-mi:“MI:0915”(physical association)	0.560
RFFL	BACE2	psi-mi:“MI:0915”(physical association)	0.560
TCP10L	BACE2	psi-mi:“MI:0915”(physical association)	0.560
	BACE2	psi-mi:“MI:0915”(physical association)	0.560
CATSPERD	BACE2	psi-mi:“MI:0915”(physical association)	0.560
LGALS9C	BACE2	psi-mi:“MI:0915”(physical association)	0.560
APP	BACE2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (106): BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS), BACE2 (Affinity Capture-MS)

ESM2 similar proteins: A2ZC67, C5FZ57, D4AIC4, D4AT39, D4DE18, D4DGR1, F5B8W7, O04057, O04496, O65390, P00797, P06281, P08424, P0DO21, P13917, P18242, P42210, P42211, P60016, P82952, Q0IU52, Q18DC8, Q18DC9, Q3EBM5, Q42369, Q42456, Q4V3D2, Q6DLS0, Q6DLW5, Q6IE75, Q8RVH5, Q8VYL3, Q8VYV9, Q9FEX1, Q9FSH9, Q9JL18, Q9LEW3, Q9LHE3, Q9LS40, Q9LTW4

Diamond homologs: C5FS55, P42211, P43231, P56817, P56818, P56819, Q01294, Q03168, Q1KLR6, Q2HJ40, Q6IE75, Q9JL18, Q9MZS8, Q9Y5Z0, W8W138, P43095, Q5AC08, Q29079, P00795, P20142, P27821, P28713, P85136, P85137, Q05744, Q4LAL9, Q689Z7, Q9N2D3, A0A2I0C265, C5FZ57, P00791, P00792, P00793, P00794, P03954, P03955, P04073, P0DJD7, P0DJD8, P0DJD9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
BACE2	“up-regulates activity”	APP	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2309 predictions. Top by Δscore:

Variant	Effect	Δscore
21:41226254:A:AG	acceptor_gain	1.0000
21:41226255:A:G	acceptor_gain	1.0000
21:41226260:T:G	acceptor_gain	1.0000
21:41245953:C:A	acceptor_gain	1.0000
21:41245954:G:A	acceptor_gain	1.0000
21:41245959:A:AG	acceptor_gain	1.0000
21:41245960:A:G	acceptor_gain	1.0000
21:41245961:G:GG	acceptor_gain	1.0000
21:41245961:GT:G	acceptor_gain	1.0000
21:41245961:GTAT:G	acceptor_gain	1.0000
21:41245964:T:G	acceptor_gain	1.0000
21:41250748:CTAGA:C	acceptor_gain	1.0000
21:41250749:TAGAT:T	acceptor_gain	1.0000
21:41250899:CAGG:C	donor_loss	1.0000
21:41250900:AGGT:A	donor_loss	1.0000
21:41250901:GGTAT:G	donor_loss	1.0000
21:41250902:G:GC	donor_loss	1.0000
21:41257134:T:A	acceptor_gain	1.0000
21:41257148:C:A	acceptor_gain	1.0000
21:41257154:ACAG:A	acceptor_loss	1.0000
21:41257155:CA:C	acceptor_loss	1.0000
21:41257156:A:AG	acceptor_gain	1.0000
21:41257156:AG:A	acceptor_loss	1.0000
21:41257157:G:GT	acceptor_gain	1.0000
21:41257157:GCT:G	acceptor_gain	1.0000
21:41257157:GCTTT:G	acceptor_gain	1.0000
21:41257324:CAGGT:C	donor_loss	1.0000
21:41257325:AGGT:A	donor_loss	1.0000
21:41257326:GG:G	donor_loss	1.0000
21:41257327:G:GC	donor_loss	1.0000

AlphaMissense

3336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:41168558:G:T	G99W	1.000
21:41226282:A:C	D110A	1.000
21:41226282:A:G	D110G	1.000
21:41226282:A:T	D110V	1.000
21:41226283:C:A	D110E	1.000
21:41226283:C:G	D110E	1.000
21:41237556:T:C	Y149H	1.000
21:41245988:C:A	D303E	1.000
21:41245988:C:G	D303E	1.000
21:41245989:A:C	S304R	1.000
21:41245991:T:A	S304R	1.000
21:41245991:T:G	S304R	1.000
21:41168514:T:C	L84P	0.999
21:41168519:G:T	G86W	0.999
21:41168559:G:A	G99E	0.999
21:41226281:G:C	D110H	0.999
21:41226281:G:T	D110Y	0.999
21:41226285:C:T	T111I	0.999
21:41226288:G:A	G112E	0.999
21:41226290:A:C	S113R	0.999
21:41226292:C:A	S113R	0.999
21:41226292:C:G	S113R	0.999
21:41226293:A:C	S114R	0.999
21:41226295:T:A	S114R	0.999
21:41226295:T:G	S114R	0.999
21:41226298:C:A	N115K	0.999
21:41226298:C:G	N115K	0.999
21:41226303:C:A	A117D	0.999
21:41237557:A:G	Y149C	0.999
21:41237565:G:A	G152R	0.999

dbSNP variants (sampled 300 via entrez): RS1000008001 (21:41265954 C>G), RS1000019718 (21:41174752 T>C), RS1000036431 (21:41168999 C>T), RS1000053403 (21:41239379 T>A,C), RS1000053781 (21:41172131 G>GA), RS1000057774 (21:41273360 G>A), RS1000068380 (21:41277880 A>G), RS1000086214 (21:41233958 C>T), RS1000089000 (21:41197176 G>A,T), RS1000173717 (21:41216966 C>G), RS1000180947 (21:41253934 G>A,C), RS1000206207 (21:41216759 G>A,T), RS1000287178 (21:41249803 G>A), RS1000336634 (21:41239204 C>A), RS1000340323 (21:41184954 C>T)

Disease associations

OMIM: gene MIM:605668 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002110_4	Glycemic traits (pregnancy)	6.000000e-16
GCST002783_236	Body mass index	6.000000e-06
GCST006257_5	Elevated fasting plasma glucose	6.000000e-06
GCST008595_228	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	6.000000e-09
GCST010988_510	Adult body size	1.000000e-08
GCST011426_37	Systemic lupus erythematosus	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005187	C-peptide measurement
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111390 (PROTEIN FAMILY), CHEMBL2525 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,261 (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
CHEMBL3301601	VERUBECESTAT	3	590
CHEMBL3989948	LANABECESTAT	3	338
CHEMBL3916243	ATABECESTAT	2	216
CHEMBL2177913	AZD-3839	1	42
CHEMBL2333941	LY-2811376	1	64
CHEMBL2396989	LY-2886721	1	11

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 (18 total), top 18:

Ligand	Action	Affinity	Parameter
compound 3 [PMID: 27347366]	Inhibition	10.51	pKi
example 41 [WO2012028563]	Inhibition	10.0	pIC50
verubecestat	Inhibition	9.43	pKi
example 98 [WO2011020806]	Inhibition	9.0	pIC50
compound 3l [PMID: 30637955]	Inhibition	8.8	pKi
example 2 [WO2013004676]	Inhibition	8.7	pIC50
example 92 [WO2012095521]	Inhibition	8.4	pIC50
NB-360	Inhibition	8.3	pIC50
example 20 [WO2010128058]	Inhibition	8.22	pIC50
compound J [PMID: 21907142]	Inhibition	8.22	pIC50
atabecestat	Inhibition	8.02	pKi
AM-6494	Inhibition	7.73	pIC50
umibecestat	Inhibition	7.52	pIC50
RO5508887	Inhibition	7.4	pIC50
compound 6 [PMID: 34553947]	Inhibitor	6.73	pKi
JNJ-67569762	Inhibition	6.71	pIC50
β-secretase inhibitor IV	Inhibition	6.62	pKi
hydroxyethylamine transition-state inhibitor 1	Inhibition	6.15	pIC50

Binding affinities (BindingDB)

1840 measured of 1979 human assays (1979 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
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
(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
(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-[(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
(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
(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
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
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((R)-3-fluoropyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.518 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((4aS,8aR)-decahydroisoquinoline-2-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.527 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-hydroxypyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.592 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-3,5-dichloropyridine-2-carboxamide	IC50	0.6 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-1-(difluoromethyl)pyrazole-3-carboxamide	KI	0.6 nM	US-9499502: 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use
(1R,5S,6S)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.6 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)((R)-3-methylmorpholino)methanone	IC50	0.6 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-hydroxy-3-methylpyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.6 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(3R,6S)-5-amino-3-(5-((2-(but- 2-yn-1-yloxy)pyrido[3,4- b]pyrazin-5-yl)amino)-2- fluoropyridin-3-yl)-6- cyclopropyl-6-(fluoromethyl)- 3-methyl-3,6-dihydro-2H-1,4- thiazine 1,1-dioxide	KI	0.65 nM	US-9732088: C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(pyrrolidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.673 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-(trifluoromethyl)piperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.744 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(3R,6S)-5-amino-3-(2-((3-(but- 2-yn-1-yloxy)-1,7-naphthyridin- 8-yl)amino)-5-fluoropyridin-4- yl)-6-cyclopropyl-3,6-dimethyl- 3,6-dihydro-2H-1,4-thiazine 1,1-dioxide	KI	0.79 nM	US-9732088: C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-methylpiperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.793 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-fluoropyridin-3-yl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.8 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)pyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)((R)-3-fluoropyrrolidin-1-yl)methanone	IC50	0.8 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-oxa-6-azaspiro[3.4]octane-6-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.8 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((R)-3-hydroxypyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.8 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-(cyclopropylethynyl)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.856 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(piperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.863 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(3-methylpiperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.867 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(5S)-5-[3-fluoro-5-[3-(1,2,4-oxadiazol-5-yl)phenyl]thiophen-2-yl]-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-3-amine	KI	0.87 nM	US-9416129: Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use
(3R,6S)-5-amino-6- cyclopropyl-3-(5-fluoro-2-((3- hydroxy-1,7-naphthyridin-8- yl)amino)pyridin-4-yl)-3,6- dimethyl-3,6-dihydro-2H-1,4- thiazine 1,1-dioxide	KI	0.89 nM	US-9732088: C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their 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)((R)-3-fluoropyrrolidin-1-yl)methanone	IC50	0.9 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(3R,6S)-5-amino-3-(5-((3-(but- 2-yn-1-yloxy)-1,7-naphthyridin- 8-yl)amino)-2-fluoropyridin-3- yl)-6-cyclopropyl-6- (fluoromethyl)-3-methyl-3,6- dihydro-2H-1,4-thiazine 1,1- dioxide	KI	0.91 nM	US-9732088: C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their use
N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	KI	0.949 nM	US-9029362: Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(3-phenylpiperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.958 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-3,5-difluoropyridine-2-carboxamide	IC50	1 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
N-[3-[(4R,5R)-2-amino-5-fluoro-4-methyl-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyridine-2-carboxamide	IC50	1 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
N-[3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	1 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
N-[3-[(4R,5R)-2-amino-4-methyl-5-(2,2,2-trifluoroethoxy)-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	1 nM	US-8754075: 1,3-oxazines as BACE1 and/or BACE2 inhibitors
(1-hydroxycyclopropyl)methyl 4-[4-carbamoyl-3-(4-fluoroanilino)pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate	KI	1 nM	US-10047098
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-cyano-3-methylpyridine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-prop-2-ynoxypyridine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-1-(difluoromethyl)pyrazole-3-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(4aS,7aS)-3-amino-7-(fluoromethyl)-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(2R,4aS,7aS)-3-amino-2-(4-fluorophenyl)-2-methyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide	KI	1 nM	US-9365589: C5, C6 oxacyclic-fused thiazine dioxide compounds as BACE inhibitors, compositions, and their use
N-[3-[(5R)-3-amino-1-hydroxy-2,5-dimethyl-1-(methylamino)-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	KI	1 nM	US-9428476: S-imino-S-oxo-iminothiadiazine compounds as BACE inhibitors, compositions, and their use

ChEMBL bioactivities

3139 potent at pChembl≥5 of 3224 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL3664019
9.92	Ki	0.12	nM	CHEMBL4557670
9.72	IC50	0.19	nM	CHEMBL4438526
9.66	Ki	0.22	nM	CHEMBL3672916
9.66	Ki	0.22	nM	CHEMBL5933242
9.62	Ki	0.24	nM	CHEMBL3952769
9.62	Ki	0.24	nM	CHEMBL5931532
9.55	Ki	0.28	nM	CHEMBL3942915
9.54	Ki	0.29	nM	CHEMBL5093195
9.52	Ki	0.3	nM	CHEMBL3938241
9.52	Ki	0.3	nM	CHEMBL3936864
9.51	Ki	0.31	nM	CHEMBL3962846
9.49	Ki	0.32	nM	CHEMBL3917788
9.47	Ki	0.34	nM	CHEMBL3908329
9.46	Ki	0.35	nM	CHEMBL3933178
9.46	Ki	0.35	nM	CHEMBL3892420
9.46	Ki	0.35	nM	CHEMBL5992471
9.43	Ki	0.37	nM	VERUBECESTAT
9.43	Ki	0.37	nM	CHEMBL3259832
9.42	IC50	0.38	nM	VERUBECESTAT
9.42	Ki	0.38	nM	CHEMBL5777236
9.41	IC50	0.388	nM	CHEMBL3667410
9.40	Ki	0.4	nM	CHEMBL3973607
9.40	Ki	0.4	nM	CHEMBL3903468
9.39	Ki	0.41	nM	CHEMBL3939857
9.39	Ki	0.41	nM	CHEMBL5810724
9.35	Ki	0.45	nM	CHEMBL3672920
9.34	Ki	0.46	nM	CHEMBL5977232
9.33	Ki	0.47	nM	VERUBECESTAT
9.33	Ki	0.47	nM	CHEMBL3702860
9.30	Ki	0.5	nM	CHEMBL3973232
9.30	Ki	0.5	nM	CHEMBL3925463
9.30	Ki	0.5	nM	CHEMBL4128375
9.30	IC50	0.5	nM	CHEMBL4475802
9.30	Ki	0.5	nM	CHEMBL5787833
9.26	IC50	0.555	nM	CHEMBL3667415
9.24	Ki	0.57	nM	CHEMBL5873781
9.23	Ki	0.59	nM	CHEMBL5845101
9.22	Ki	0.6	nM	CHEMBL3942552
9.22	Ki	0.6	nM	CHEMBL3905233
9.22	Ki	0.6	nM	CHEMBL5995955
9.20	Ki	0.63	nM	CHEMBL3910228
9.19	Ki	0.64	nM	CHEMBL5940085
9.19	Ki	0.64	nM	CHEMBL5847694
9.16	Ki	0.69	nM	CHEMBL3951262
9.14	Ki	0.73	nM	CHEMBL3949563
9.14	Ki	0.73	nM	CHEMBL6059041
9.12	Ki	0.76	nM	CHEMBL5950378
9.10	Ki	0.8	nM	CHEMBL3985208
9.10	Ki	0.8	nM	CHEMBL3895721

PubChem BioAssay actives

895 with measured affinity, of 1126 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-[3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyrazine-2-carboxamide	1809563: Displacement of [3H] JNJ-962 from BACE2 (unknown origin) expressed in HEK293 cell membranes assessed as inhibition constant at pH 6.2 by scintillation counting analysis	ki	0.0001	uM
N-[3-[(4S,6S)-2-amino-6-(difluoromethyl)-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyrazine-2-carboxamide	1545222: Inhibition of BACE2 (unknown origin)	ic50	0.0002	uM
N-[3-[(6R)-4-amino-2-cyano-6-methyl-7H-pyrazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl]-2-methyl-1,3-oxazole-4-carboxamide	1809572: Binding affinity to BACE2 (unknown origin)	ki	0.0003	uM
N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide	1369274: Inhibition of human BACE2	ic50	0.0004	uM
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-fluoropyridine-2-carboxamide	1811787: Inhibition of recombinant human BACE2 using (MCA)-S-E-V-N-L-D-A-E-F-R-K(dinitrophenol)-R-R-R-R-NH2 as substrate by FRET assay	ic50	0.0004	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-3-bromo-1,7-naphthyridine-8-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0005	uM
N-[3-[(4S,6S)-2-amino-6-(1,1-difluoroethyl)-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyridine-2-carboxamide	1545222: Inhibition of BACE2 (unknown origin)	ic50	0.0005	uM
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]-3,5-difluoropyridine-2-carboxamide	1811787: Inhibition of recombinant human BACE2 using (MCA)-S-E-V-N-L-D-A-E-F-R-K(dinitrophenol)-R-R-R-R-NH2 as substrate by FRET assay	ic50	0.0006	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	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0008	uM
(4S)-3’-(3,6-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	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0008	uM
(3S)-3-[2-(difluoromethyl)-4-pyridinyl]-7-fluoro-3-(3-pyrimidin-5-ylphenyl)isoindol-1-amine	1480282: Inhibition of human BACE2 (1 to 473 residues) using CEVNLDAEFK as substrate preincubated for 10 mins followed by substrate addition measured after 6.5 hrs by TR-FRET assay	ic50	0.0009	uM
67979346	1369274: Inhibition of human BACE2	ic50	0.0009	uM
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-methoxypyrazine-2-carboxamide	1811787: Inhibition of recombinant human BACE2 using (MCA)-S-E-V-N-L-D-A-E-F-R-K(dinitrophenol)-R-R-R-R-NH2 as substrate by FRET assay	ic50	0.0009	uM
cis-(1R,3S)-5-[[(2S)-2-[[(3S,4S)-5-(3,5-difluorophenyl)-4-[[3-(dipropylcarbamoyl)benzoyl]amino]-3-hydroxypentanoyl]amino]-3-methylbutanoyl]amino]cyclohexane-1,3-dicarboxylic acid	44242: Inhibition of human beta secretase in MBP-C125 assay.	ic50	0.0010	uM
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(methoxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1720474: Inhibition of recombinant human BACE2 using fluorescence substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins by FRET assay	ic50	0.0010	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-5-chloro-3-fluoropyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0010	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-5-fluoro-3-methylpyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0010	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0010	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-3,5-difluoropyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0010	uM
N-[3-[(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-1,3-thiazin-4-yl]-4-fluorophenyl]-5-(fluoromethoxy)pyridine-2-carboxamide	1545222: Inhibition of BACE2 (unknown origin)	ic50	0.0010	uM
N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-cyanopyridine-2-carbothioamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0010	uM
N-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0010	uM
(6S)-2-amino-6-[3-chloro-5-(5-prop-1-ynyl-3-pyridinyl)thiophen-2-yl]-3,6-dimethyl-5H-pyrimidin-4-one	692562: Inhibition of human recombinant BACE2 by FRET assay	ki	0.0010	uM
N-[3-[(4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxo-7,7a-dihydro-5H-furo[3,4-b][1,4]thiazin-4a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0010	uM
N-[3-[(1S,5R)-3-amino-2,5-dimethyl-1-methylimino-1-oxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0010	uM
N-[6-[(3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-5-fluoro-2-pyridinyl]-3,5-dichloropyridine-2-carboxamide	1830696: Inhibition of human recombinant BACE2 catalytic domain using FRET substrate with BACE-cleavable sequence	ic50	0.0010	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-chloropyridine-2-carboxamide	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0011	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(4S,5S,7R)-8-[[(2S)-1-(benzylamino)-3-methyl-1-oxobutan-2-yl]amino]-5-hydroxy-2,7-dimethyl-8-oxooctan-4-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-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	0.0012	uM
N-[3-[(7R)-9-amino-2,7-dimethyl-5,5-dioxo-5lambda6-thia-2,8-diazaspiro[3.5]non-8-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0012	uM
N-[3-[(1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-chloropyridine-2-carboxamide	1546010: Inhibition of recombinant human C-terminal His6-tagged BACE2 expressed in mammalian expression system using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0018	uM
N-[3-[(1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-chloropyridine-2-carboxamide	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	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	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	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-chloropyridine-2-carboxamide	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	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	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	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-chloropyridine-2-carboxamide	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	uM
N-[3-[(1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-chloropyridine-2-carboxamide	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	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	1546016: Inhibition of BACE2 (unknown origin) using FRET peptide substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0020	uM
N-[3-[(3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-3,5-dichloropyridine-2-carboxamide	1831879: Inhibition of human recombinant BACE2 catalytic domain using FRET substrate	ic50	0.0020	uM
(4S)-7’-(2-fluoro-3-pyridinyl)-3’-(3-methoxy-3-methylbut-1-ynyl)spiro[5H-1,3-oxazole-4,5’-chromeno[2,3-b]pyridine]-2-amine	2141517: Inhibition of BACE2 (unknown origin)	ic50	0.0028	uM
1-N-[(2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-[(3-iodophenyl)methylamino]butan-2-yl]-5-methyl-3-N,3-N-dipropylbenzene-1,3-dicarboxamide	277842: Inhibition of beta amyloid production in human HEK293 cells	ec50	0.0030	uM
N-[3-[(7S)-5-amino-7-methyl-8H-pyrido[4,3-d]pyrimidin-7-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0030	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-5-methylpyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0030	uM
N-[3-[(4aR,7aR)-3-amino-2-methyl-1,1-dioxo-5,6,7,7a-tetrahydrocyclopenta[e][1,2,4]thiadiazin-4a-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	1491562: Binding affinity to human autoBACE2 using QSY7-APPswe-Eu as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by HTRF assay	ki	0.0030	uM
N-[3-[(1R,5S,6R)-3-amino-7,7-difluoro-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-chloropyrazine-2-carboxamide	1545218: Inhibition of C-terminal His6-tagged human BACE2 expressed in mammalian expression system preincubated for 1 hr followed by substrate addition and measured after 1 hr by FRET assay	ic50	0.0030	uM
(4S)-4-amino-5-[[(2S)-1-[[(2S)-3-carboxy-1-[[(4S,5S,7R)-8-[[(2S)-1-[[(2S)-4-carboxy-1-[[(1S)-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	1233535: Apparent inhibition of human recombinant BACE2 using Mca-SEVNLDAEFK-DNP substrate assessed as substrate hydrolysis after 1 hr by HPLC-FLU analysis	ki	0.0030	uM
N-[3-[(3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-bromopyridine-2-carboxamide	1831879: Inhibition of human recombinant BACE2 catalytic domain using FRET substrate	ic50	0.0030	uM
N-[3-[(3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-bromopyrimidine-2-carboxamide	1831879: Inhibition of human recombinant BACE2 catalytic domain using FRET substrate	ic50	0.0030	uM
N-[3-[(2S,5R)-6-amino-2-(fluoromethyl)-5-methyl-5-methylsulfonyl-3,4-dihydropyridin-2-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide	1807508: Inhibition of BACE2 (unknown origin) using APP harboring Swedish Lys-Met/Asn-Leu mutant-derived peptide as substrate incubated for 2 hrs by FRET assay	ic50	0.0031	uM
N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	1369237: Displacement of [3H]-PF-6475886 from recombinant human full length Myc-DDK-tagged BACE2 expressed in HEK293 cell membranes after 30 mins by parallel scintillation proximity assay	ic50	0.0033	uM
2-[3-[(4aS,7R,8aR)-3-amino-7-(methoxymethyl)-2-methyl-1,1-dioxo-5,7,8,8a-tetrahydropyrano[3,4-e][1,2,4]thiadiazin-4a-yl]-4-fluorophenoxy]pyridine-4-carbonitrile	1545241: Inhibition of human BACE2 preincubated for 30 mins followed by QSY7- EISEVNLDAEFC-Eu-amide substrate addition and measured after 1.5 hrs by HTRF assay	ki	0.0034	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
trichostatin A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
terbufos	increases methylation	1
benzo(e)pyrene	affects methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	affects methylation	1
methacrylaldehyde	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aluminum Chloride	affects cotreatment, decreases expression, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1

ChEMBL screening assays

208 unique, capped per target: 172 binding, 33 admet, 3 functional

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
CHEMBL4042702	ADMET	Inhibition of BACE2 (unknown origin) by cell free assay	Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1RQ	Abcam U-87MG BACE2 KO	Cancer cell line	Male
CVCL_E1GG	Abcam SW480 BACE2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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