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
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 41 tissues, sQTL in 13 (q < 0.05)
• ChEMBL bioactivity: 6 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.73 (intermediate), LOEUF 0.57 (moderately constrained)
• MANE Select transcript: NM_012105
• Notable: 96 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 26 — 14 protein_coding, 6 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000330333

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 5: 5

ENST00000330333, ENST00000328735, ENST00000347667, ENST00000463674, ENST00000465326, ENST00000466122, ENST00000470864, ENST00000475618, ENST00000487994, ENST00000491838, ENST00000854368, ENST00000854369, ENST00000854370, ENST00000854371, ENST00000854372, ENST00000921490, ENST00000953405, ENST00000953406, ENST00001002623, ENST00001002624, ENST00001002625, ENST00001033631, ENST00001114393, ENST00001114394, ENST00001118596, ENST00001131690

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
ENSE00003645299	41237513	41237729
ENSE00003650610	41250752	41250901
ENSE00003680958	41245962	41246063
ENSE00003844244	41168160	41168575
ENSE00004779197	41275371	41282530

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.

Highest expression (Bgee): parotid gland, gall bladder, pancreatic ductal cell, saliva-secreting gland, minor salivary gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BACE2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 54 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	2.3e-159	-0.94	21:41247822:T:C
Heart Atrial Appendage	eqtl	1.5e-61	-0.48	21:41247822:T:C
Brain Spinal cord cervical c-1	eqtl	5.8e-44	-1.20	21:41148207:T:C
Pancreas	eqtl	6.2e-41	-0.66	21:41247822:T:C
Lung	eqtl	8.2e-40	-0.41	21:41247822:T:C
Artery Coronary	eqtl	2.2e-33	-0.65	21:41247822:T:C
Nerve Tibial	eqtl	2.4e-32	-0.37	21:41247822:T:C
Thyroid	eqtl	1.3e-30	+0.38	21:41160148:C:A
Artery Aorta	eqtl	3.2e-26	-0.38	21:41247822:T:C
Testis	eqtl	2.5e-20	-0.33	21:41244078:C:T
Esophagus Mucosa	eqtl	3.0e-17	+0.32	21:41167642:AC:A
Whole Blood	eqtl	6.2e-16	+0.25	21:41209498:C:T
Testis	sqtl	4.2e-13	+0.69	21:41244078:C:T
Brain Substantia nigra	eqtl	9.6e-13	-0.63	21:41144400:G:T
Brain Putamen basal ganglia	eqtl	2.1e-12	-0.32	21:41247822:T:C
Heart Left Ventricle	eqtl	1.1e-11	-0.18	21:41247327:A:G
Adipose Subcutaneous	eqtl	3.4e-11	-0.15	21:41247327:A:G
Artery Aorta	sqtl	2.1e-10	+0.54	21:41210231:AC:A
Skin Sun Exposed Lower leg	eqtl	1.3e-09	+0.16	21:41173323:T:C
Brain Cerebellar Hemisphere	eqtl	2.9e-09	-0.32	21:41247822:T:C

FANTOM5 promoters

showing 10 of 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

showing 100 of 278 tissues 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
epithelial cell of pancreas	CL:0000083	93.18	gold quality
prostate gland	UBERON:0002367	92.91	gold quality
type B pancreatic cell	CL:0000169	92.67	gold quality
esophagus mucosa	UBERON:0002469	92.57	gold quality
tibial nerve	UBERON:0001323	92.52	gold quality
cardia of stomach	UBERON:0001162	92.47	gold quality
esophagus squamous epithelium	UBERON:0006920	92.27	gold quality
tendon of biceps brachii	UBERON:0008188	92.17	gold quality
rectum	UBERON:0001052	92.16	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.97	gold quality
fundus of stomach	UBERON:0001160	91.86	gold quality
endocervix	UBERON:0000458	91.83	gold quality
metanephros cortex	UBERON:0010533	91.67	gold quality
tonsil	UBERON:0002372	91.66	gold quality
esophagus	UBERON:0001043	91.62	gold quality
epithelium of esophagus	UBERON:0001976	91.57	gold quality
colonic epithelium	UBERON:0000397	91.31	gold quality
body of uterus	UBERON:0009853	91.22	gold quality
pharyngeal mucosa	UBERON:0000355	91.18	gold quality
mucosa of transverse colon	UBERON:0004991	91.12	gold quality
ileal mucosa	UBERON:0000331	91.11	gold quality
ectocervix	UBERON:0012249	91.03	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.89	gold quality
nipple	UBERON:0002030	90.87	gold quality
skin of hip	UBERON:0001554	90.85	gold quality
vena cava	UBERON:0004087	90.82	gold quality
omental fat pad	UBERON:0010414	90.70	gold quality
peritoneum	UBERON:0002358	90.69	gold quality
lower esophagus	UBERON:0013473	90.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.51	gold quality
myometrium	UBERON:0001296	90.50	gold quality
urethra	UBERON:0000057	90.24	gold quality
endometrium	UBERON:0001295	90.24	gold quality
bronchial epithelial cell	CL:0002328	90.17	gold quality
caecum	UBERON:0001153	90.11	gold quality
palpebral conjunctiva	UBERON:0001812	90.09	gold quality
colon	UBERON:0001155	90.07	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.07	gold quality
large intestine	UBERON:0000059	90.06	gold quality
uterus	UBERON:0000995	90.06	gold quality
left uterine tube	UBERON:0001303	90.05	gold quality
vermiform appendix	UBERON:0001154	89.99	gold quality
skin of leg	UBERON:0001511	89.92	gold quality
calcaneal tendon	UBERON:0003701	89.92	gold quality
epithelium of nasopharynx	UBERON:0001951	89.88	gold quality
transverse colon	UBERON:0001157	89.85	gold quality
placenta	UBERON:0001987	89.85	gold quality
adult mammalian kidney	UBERON:0000082	89.81	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.79	gold quality
vagina	UBERON:0000996	89.77	gold quality
bronchus	UBERON:0002185	89.58	gold quality
right atrium auricular region	UBERON:0006631	89.45	gold quality
epithelium of bronchus	UBERON:0002031	89.41	gold quality
intestine	UBERON:0000160	89.25	gold quality
lymph node	UBERON:0000029	89.18	gold quality
mucosa of stomach	UBERON:0001199	89.07	gold quality
squamous epithelium	UBERON:0006914	89.05	gold quality
parietal pleura	UBERON:0002400	88.92	gold quality
tendon	UBERON:0000043	88.88	gold quality
visceral pleura	UBERON:0002401	88.68	gold quality
right uterine tube	UBERON:0001302	88.56	gold quality
adipose tissue	UBERON:0001013	88.48	gold quality
zone of skin	UBERON:0000014	88.26	gold quality
connective tissue	UBERON:0002384	88.26	gold quality
cauda epididymis	UBERON:0004360	88.25	gold quality
cardiac atrium	UBERON:0002081	88.16	gold quality
stromal cell of endometrium	CL:0002255	88.14	gold quality
pleura	UBERON:0000977	88.08	gold quality
colonic mucosa	UBERON:0000317	88.02	gold quality
female reproductive system	UBERON:0000474	87.89	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Stomach 1	tissue	21.6	low
Choroid plexus	tissue	20.1
Spinal cord	tissue	19.2
Superior colliculi	tissue	9.4
Kidney	tissue	9.1	not detected
Salivary gland	tissue	8.9	not detected
Medulla oblongata	tissue	8.9
Midbrain	tissue	7.8
Substantia nigra	tissue	7.7
Gallbladder	tissue	7.7	not detected
Thalamus	tissue	7.1
Colon	tissue	6.8	not detected
Prostate	tissue	6.6	low
Pons	tissue	6.3
Hippocampal formation	tissue	6.3
Entorhinal cortex	tissue	6.3
Cerebral cortex	tissue	6.1	high
Insular cortex	tissue	6.1
Pancreas	tissue	6.0	not detected
Occipital cortex	tissue	5.9
Somatosensory cortex	tissue	5.8
Motor cortex	tissue	5.6
Prefrontal cortex	tissue	5.5
Retrosplenial and cingulate cortex	tissue	5.4
Temporal cortex	tissue	5.4
Putamen	tissue	5.2
Periaqueductal gray	tissue	5.2
Retrosplenial cortex	tissue	5.2
Cervix	tissue	5.0	not detected
Adipose tissue	tissue	5.0	not detected
Amygdala	tissue	4.9
Olfactory bulb	tissue	4.9
Basal ganglia	tissue	4.7	medium
Hypothalamus	tissue	4.6
Spleen	tissue	4.5	not detected
Smooth muscle	tissue	4.4	medium
Corpus callosum	tissue	4.4
Urinary bladder	tissue	4.3	not detected
Rectum	tissue	4.2	not detected
Locus coeruleus	tissue	4.1
Ventral forebrain	tissue	4.1
Appendix	tissue	4.1	not detected
Endometrium 1	tissue	4.0	not detected
Hippocampus	tissue	4.0	low
Fallopian tube	tissue	4.0	not detected
Vagina	tissue	3.8	not detected
Esophagus	tissue	3.6	not detected
Septum	tissue	3.5
Tonsil	tissue	3.4	not detected
Duodenum	tissue	3.3	not detected
Skin 1	tissue	3.1	not detected
Breast	tissue	3.0	not detected
Postcentral gyrus	tissue	3.0
Lymph node	tissue	2.9	not detected
Placenta	tissue	2.8	low
Lung	tissue	2.8	not detected
Small intestine	tissue	2.8	not detected
Seminal vesicle	tissue	2.5	not detected
Thyroid gland	tissue	2.2	not detected
Heart muscle	tissue	2.1	low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Dorsal spinal cord (19.2), Dorsal funiculus (white matter) (18.2), Ventral spinal cord (16.6), Lateral funiculus (white matter) (15.0), Nucleus raphe pallidus (14.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

Targeting BACE2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 153 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.729, LOEUF 0.574, missense Z 0.736 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000330333 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
21:41,168,264–41,237,663	248 / 261.4	0.95	no
21:41,237,664–41,237,709	4 / 17.3	0.23	yes (p 1.4e-03)
21:41,237,710–41,275,621	343 / 419.4	0.82	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860440) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased circulating calcium level	1
diluted coat color	1
abnormal retina morphology	1
abnormal melanosome morphology	1
abnormal melanogenesis	1
abnormal cell physiology	1
abnormal epidermal melanocyte morphology	1
abnormal retina melanin granule morphology	1
increased cornea thickness	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Plasmodium falciparum 3D7	Q8IAS0	100.0%	Diamond
Plasmodium falciparum NF54	W7JWW5	100.0%	Diamond
Bos taurus	Q2HJ40	98.2%	Diamond
Cavia porcellus	Q1KLR6	92.0%	Diamond
Strongylocentrotus purpuratus	W8W138	49.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PLAC4	ncRNA	191585
LINC00323	ncRNA	284835
FAM3B	protein-coding	54097
MIR3197	ncRNA	100423023
MX2	protein-coding	4600
DSCAM	protein-coding	1826
MX1	protein-coding	4599
TMPRSS2	protein-coding	7113

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 (75 total): strand 28, helix 16, sequence conflict 6, splice variant 5, turn 4, 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 by resolution:

PDB	Title	Method	Resolution (Å)
7D5B	BACE2 xaperone complex with …	X-RAY DIFFRACTION	1.31
7N4N	BACE-2 in complex with ligand 36	X-RAY DIFFRACTION	1.41
7F1G	BACE2 xaperone complex with …	X-RAY DIFFRACTION	1.5
3ZKQ	BACE2 XAPERONE COMPLEX	X-RAY DIFFRACTION	1.51
6JSZ	BACE2 xaperone complex with …	X-RAY DIFFRACTION	1.53
3ZKM	BACE2 FAB COMPLEX	X-RAY DIFFRACTION	1.85
4BEL	BACE2 XAPERONE COMPLEX	X-RAY DIFFRACTION	1.85
3ZKG	BACE2 MUTANT APO STRUCTURE	X-RAY DIFFRACTION	1.9
3ZKN	BACE2 FAB INHIBITOR COMPLEX	X-RAY DIFFRACTION	2
7D5U	BACE2 xaperone complex with …	X-RAY DIFFRACTION	2.04
3ZLQ	BACE2 XAPERONE COMPLEX	X-RAY DIFFRACTION	2.1
3ZKS	BACE2 XAPERONE COMPLEX WITH INHIBITOR	X-RAY DIFFRACTION	2.11
6UJ0	Unbound BACE2 mutant structure	X-RAY DIFFRACTION	2.15
4BFB	BACE2 XAPERONE COMPLEX	X-RAY DIFFRACTION	2.21
3ZKX	TERNARY BACE2 XAPERONE COMPLEX	X-RAY DIFFRACTION	2.37
3ZKI	BACE2 MUTANT STRUCTURE WITH LIGAND	X-RAY DIFFRACTION	2.4
6UJ1	BACE2 mutant in complex with a macrocyclic compound	X-RAY DIFFRACTION	3.03
2EWY	Crystal structure of human BACE2 in complex with a hydroxyethylenamine transition-state …	X-RAY DIFFRACTION	3.1
3ZL7	BACE2 FYNOMER COMPLEX	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 antibodies co-crystallized with this protein: 3ZKM, 3ZKN, 3ZKQ, 3ZKS, 3ZKX, 3ZLQ, 4BEL, 4BFB, 6JSZ, 7D5B, 7D5U, 7F1G, 7N4N

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Aspartic-type peptidases, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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)

Position	Role
110
303

Disulfide bonds (3)

Type	Positions
Disulfide bond	233–433, 292–457, 344–393

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	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 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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

30 GO namespaces:

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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
glucose homeostasis	BP	mutant phenotype
melanosome organization	BP	mutant phenotype
membrane protein ectodomain proteolysis	BP	direct assay
negative regulation of amyloid precursor protein biosynthetic process	BP	mutant phenotype
protein processing	BP	direct assay
Golgi apparatus	CC	direct assay
melanosome membrane	CC	direct assay
plasma membrane	CC	direct assay
aspartic-type endopeptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 676 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BACE2	APP	P05067	820
BACE2	PSEN1	P49768	747
BACE2	NCSTN	Q92542	692
BACE2	PSEN2	P49810	679
BACE2	RTN3	O95197	616
BACE2	RTN4	Q9NQC3	585
BACE2	CLTRN	Q9HBJ8	570
BACE2	NRG1	P98202	567
BACE2	NAV1	Q8NEY1	566
BACE2	ADAM10	O14672	562
BACE2	APH1A	Q96BI3	556
BACE2	PLSCR1	O15162	553
BACE2	RTN2	O75298	552
BACE2	SCN2B	O60939	552
BACE2	RTN1	Q16799	544

IntAct

Human interaction partners of BACE2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

24 partners by confidence:

Partner	Interaction type	MIscore	Records
APP	physical association	0.560	3
ARFGAP3	physical association	0.560	3
ASAH1	physical association	0.560	3
CATSPERD	physical association	0.560	3
DUSP10	physical association	0.560	3
KLF3	physical association	0.560	3
KRT19	physical association	0.560	3
LARP4B	physical association	0.560	3
LASP1	physical association	0.560	3
LGALS9C	physical association	0.560	3
MATK	physical association	0.560	3
RFFL	physical association	0.560	3
RHNO1	physical association	0.560	3
SCAPER	physical association	0.560	3
STX11	physical association	0.560	3
TCP10L	physical association	0.560	3
TEX12	physical association	0.560	3
TMTC1	physical association	0.560	3
TPM3	physical association	0.560	3
IAPP	protein cleavage	0.560	2
INS	protein cleavage	0.440	1
FAM171A2	association	0.350	1
PCM1	physical association	0.000	1
SNRNP70	physical association	0.000	1

BioGRID (107 interactions; top human partners by supporting records): ATP1B3 (Affinity Capture-MS; 3 records), HLA-E (Affinity Capture-MS; 3 records), TMEM30A (Affinity Capture-MS; 3 records), CD1E (Affinity Capture-MS; 2 records), CHST6 (Affinity Capture-MS; 2 records), CLEC2D (Affinity Capture-MS; 2 records), GGA1 (Protein-peptide; 2 records), GGA2 (Protein-peptide; 2 records), IFNE (Affinity Capture-MS; 2 records), MPPE1 (Affinity Capture-MS; 2 records), ST8SIA4 (Affinity Capture-MS; 2 records), TCTN2 (Affinity Capture-MS; 2 records), TMPRSS11B (Affinity Capture-MS; 2 records), ABCD1 (Affinity Capture-MS), ABL1 (Affinity Capture-MS)

SIGNOR signaling

showing 1 of 4 signaling interactions:

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

Disease & clinical

Genetic variants

Variant evidence for BACE2: 96 ClinVar records (0 pathogenic / likely pathogenic); 6 GWAS associations.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 24 predictions of 1,260):

Position(s)	Effect	Δscore	Sites
21:41226255	acceptor_gain	1.0000
21:41226260	acceptor_gain	1.0000
21:41245953–41245954	acceptor_gain	1.0000	2
21:41245960	acceptor_gain	1.0000
21:41245964	acceptor_gain	1.0000
21:41250902–41250903	donor_loss	1.0000	5
21:41257134	acceptor_gain	1.0000
21:41257148	acceptor_gain	1.0000
21:41257156–41257157	acceptor_loss	1.0000	6
21:41257327–41257328	donor_loss	1.0000	5

AlphaMissense

1,139 missense substitutions predicted likely pathogenic (of 3,336 scored), across 282 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D110	8	0.999	1.000
D303	8	0.999	1.000
S113	8	0.990	0.999
D161	8	0.974	0.998
F228	8	0.972	0.998
F336	8	0.965	0.998
F186	8	0.960	0.996
F419	8	0.960	0.998
F396	8	0.959	0.994
F355	8	0.957	0.995
F428	8	0.948	0.998
S114	8	0.921	0.999
N115	8	0.918	0.999
F215	8	0.917	0.983
F371	8	0.913	0.989
F116	8	0.903	0.983
D508	8	0.801	0.895
C344	7	0.998	0.999
C393	7	0.996	0.999
C233	7	0.995	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	1.63e-07
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	3.45e-05
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000843

Disease associations

OMIM: gene MIM:605668 | disease phenotypes:

GWAS associations

6 associations:

Study	Trait	p-value
GCST002110_4	Glycemic traits (pregnancy)	6e-16
GCST008595_128	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	6e-9
GCST010988_205	Adult body size	1e-8
GCST002783_611	Body mass index	6e-6
GCST006257_5	Elevated fasting plasma glucose	6e-6
GCST011426_37	Systemic lupus erythematosus	9e-6

EFO canonical traits (from GWAS)

4 canonical traits:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,306 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

6 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3989948	LANABECESTAT	3	348
CHEMBL3301601	VERUBECESTAT	3	615
CHEMBL3916243	ATABECESTAT	2	224
CHEMBL2177913	AZD-3839	1	43
CHEMBL2333941	LY-2811376	1	65
CHEMBL2396989	LY-2886721	1	11

PharmGKB: 1 entry (CPIC guideline: no)

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)

3481 measured of 3515 human assays (3515 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4aR,6R,8aS)-8a-[2,4-difluoro-5-[(2,2,2-trifluoroethylamino)methyl]phenyl]-6-(fluoromethyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine	IC50	0.006 nM	US-9045498: Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
CHEMBL4088234	IC50	0.024 nM
(1S,5S,6S)-3-amino-N-cyclopropyl-5-[2-fluoro-5-[[5-[(2S)-1-methoxypropan-2-yl]oxypyrazine-2-carbonyl]amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.059 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.07 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(2H-triazol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.09 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-(2,2-difluoroethyl)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.09 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide	IC50	0.1 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-[5-[[5-[(2S)-but-3-yn-2-yl]oxypyrazine-2-carbonyl]amino]-2,3-difluorophenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.11 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
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
(1S,5S,6S)-3-amino-5-[2-fluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.14 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide	IC50	0.146 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(4aS,7aR)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine	IC50	0.149 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
CHEMBL4564324	IC50	0.157 nM
CHEMBL2152903	IC50	0.16 nM
(E)-3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylic acid	IC50	0.176 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-1-acetyl-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.178 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine	IC50	0.186 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
(1S,5S,6S)-3-amino-5-[2,3-difluoro-5-[[5-(2,2,3,3-tetrafluoropropoxy)pyrazine-2-carbonyl]amino]phenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.194 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-methyl-1-(trideuteriomethoxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.197 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-[2,3-difluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.199 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(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
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	IC50	0.2 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
CHEMBL4437161	IC50	0.2 nM
(1S,5S,6S)-3-amino-5-[5-[(2-but-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]-2,3-difluorophenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.201 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
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-(1,1-dideuterioprop-2-ynoxy)pyrazine-2-carboxamide	IC50	0.209 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.22 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-1-(difluoromethyl)-5-[2,3-difluoro-5-[(2-prop-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.222 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-5-[5-[(2-but-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]-2-fluorophenyl]-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.236 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
6-[(Z)-2-[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]-1-fluoroethenyl]pyridine-3-carbonitrile	IC50	0.241 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
(1S,5S,6S)-1-(difluoromethyl)-5-[2-fluoro-5-[(2-prop-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.244 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
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-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.249 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
CHEMBL3352906	KI	0.25 nM
N-[3-[(1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluoro-5-methylphenyl]-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide	IC50	0.256 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.264 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.266 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.266 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide	IC50	0.268 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
[(1S,5S,6R)-3-amino-7,7-difluoro-5-[2-fluoro-5-[[7-(1,3-oxazol-2-ylmethoxy)pyrido[3,2-d]pyrimidin-4-yl]amino]-3-pyridinyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]methanol	IC50	0.274 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1R,5S,6S)-3-amino-5-(fluoromethyl)-1-[(Z)-2-methyl-3-morpholin-4-yl-3-oxoprop-1-enyl]-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.274 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.276 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(2,2,2-trifluoroethoxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.28 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[(4aR,7aS)-7a-[5-[(Z)-2-(5-but-2-ynoxypyrazin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide	IC50	0.287 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
N-[3-[(1R,5S,6S)-3-amino-5-methyl-1-methylsulfonyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.29 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,2-oxazol-3-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyridine-2-carboxamide	IC50	0.293 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-tert-butyl-5-[2-fluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.294 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(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)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide	IC50	0.297 nM	US-20160046618: 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
(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	IC50	0.3 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
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-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.3 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-cyclopropyl-5-[2-fluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.3 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of 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	increases expression, affects cotreatment	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	increases methylation, affects cotreatment	1
terbufos	increases methylation	1
benzo(e)pyrene	affects methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
aflatoxin B2	affects methylation	1
methacrylaldehyde	decreases expression, affects cotreatment	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	increases expression, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for BACE2 across ~30M SureChEMBL compounds — explore on Sugi Predict.