PSEN2

Summary

PSEN2 (presenilin 2, HGNC:9509) is a protein-coding gene on chromosome 1q42.13, encoding Presenilin-2 (P49810). Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

Alzheimer’s disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified.

Source: NCBI Gene 5664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alzheimer disease 4 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 363 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 62
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9509
Approved symbol	PSEN2
Name	presenilin 2
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Aliases	AD3L, STM2, PS2, PS-2, E5-1
Ensembl gene	ENSG00000143801
Ensembl biotype	protein_coding
OMIM	600759
Entrez	5664

Gene structure

Transcript identifiers

Ensembl transcripts: 80 — 57 protein_coding, 15 nonsense_mediated_decay, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000366782, ENST00000366783, ENST00000422240, ENST00000460775, ENST00000471728, ENST00000472139, ENST00000485677, ENST00000487450, ENST00000495488, ENST00000521431, ENST00000524196, ENST00000626989, ENST00000676467, ENST00000676616, ENST00000676747, ENST00000676840, ENST00000676888, ENST00000676907, ENST00000676945, ENST00000677065, ENST00000677414, ENST00000677529, ENST00000677596, ENST00000677599, ENST00000677748, ENST00000677880, ENST00000678021, ENST00000678233, ENST00000678320, ENST00000678655, ENST00000678706, ENST00000678776, ENST00000678784, ENST00000678820, ENST00000678835, ENST00000679088, ENST00000679098, ENST00000900065, ENST00000900066, ENST00000900067, ENST00000900068, ENST00000900069, ENST00000900070, ENST00000900071, ENST00000900072, ENST00000900073, ENST00000900074, ENST00000900075, ENST00000900076, ENST00000900077, ENST00000900078, ENST00000940855, ENST00000940856, ENST00000940857, ENST00000940858, ENST00000940859, ENST00000940860, ENST00000940861, ENST00000940862, ENST00000940863, ENST00000940864, ENST00000968761, ENST00000968762, ENST00000968763, ENST00000968764, ENST00000968765, ENST00000968766, ENST00000968767, ENST00000968768, ENST00000968769, ENST00000968770, ENST00000968771, ENST00000968772, ENST00000968773, ENST00000968774, ENST00000968775, ENST00000968776, ENST00000968777, ENST00000968778, ENST00000968779

RefSeq mRNA: 2 — MANE Select: NM_000447 NM_000447, NM_012486

CCDS: CCDS1556, CCDS44324

Canonical transcript exons

ENST00000366783 — 13 exons

Exon	Start	End
ENSE00001071124	226891743	226891844
ENSE00001071125	226883705	226883919
ENSE00001071130	226888829	226889049
ENSE00001071132	226890035	226890133
ENSE00001236977	226875365	226875550
ENSE00001403718	226871262	226871404
ENSE00001442607	226895424	226896098
ENSE00001900559	226870616	226870649
ENSE00003462721	226881888	226882048
ENSE00003464607	226891278	226891361
ENSE00003465186	226885538	226885679
ENSE00003590454	226888091	226888158
ENSE00003626336	226894007	226894125

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.2454 / max 57.4897, expressed in 1532 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8888	4.2454	1532

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	93.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.08	gold quality
pancreas	UBERON:0001264	91.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.34	gold quality
skeletal muscle tissue	UBERON:0001134	88.90	gold quality
adrenal tissue	UBERON:0018303	88.77	gold quality
muscle of leg	UBERON:0001383	88.74	gold quality
gastrocnemius	UBERON:0001388	88.64	gold quality
islet of Langerhans	UBERON:0000006	87.86	gold quality
muscle tissue	UBERON:0002385	87.80	gold quality
adrenal gland	UBERON:0002369	87.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.32	gold quality
lower esophagus	UBERON:0013473	87.31	gold quality
right adrenal gland	UBERON:0001233	87.25	gold quality
left adrenal gland cortex	UBERON:0035825	87.24	gold quality
right adrenal gland cortex	UBERON:0035827	87.24	gold quality
left adrenal gland	UBERON:0001234	87.22	gold quality
sural nerve	UBERON:0015488	86.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.49	gold quality
pituitary gland	UBERON:0000007	86.41	gold quality
adenohypophysis	UBERON:0002196	86.37	gold quality
left uterine tube	UBERON:0001303	86.36	gold quality
prostate gland	UBERON:0002367	86.30	gold quality
cerebellum	UBERON:0002037	86.07	gold quality
cerebellar cortex	UBERON:0002129	86.02	gold quality
cerebellar hemisphere	UBERON:0002245	85.98	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.83	gold quality
apex of heart	UBERON:0002098	85.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.50	gold quality
prefrontal cortex	UBERON:0000451	85.09	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.26
E-GEOD-89232	no	1840.02
E-GEOD-150728	no	1514.44
E-GEOD-98556	no	506.13
E-HCAD-6	no	320.28
E-CURD-112	no	3.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMAL1, CLOCK, EGR1, ESR1, HMGA1, JUN, MYC

miRNA regulators (miRDB)

17 targeting PSEN2, 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-5193	100.00	67.26	1744
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-4509	96.19	65.80	900
HSA-MIR-5002-3P	95.75	67.04	542
HSA-MIR-5586-3P	95.51	67.00	805

Literature-anchored findings (GeneRIF, showing 40)

• enhancement of amyloid beta protein by Herp, and endoplasmic reticulum stress-inducible protein (PMID:11799129)
• interaction with CALP/KChIP4 (PMID:11847232)
• inhibition of endoproteolysis by gamma-secretase inhibitors (PMID:11876645)
• Notch receptor cleavage depends on but is not directly executed by presenilins (PMID:11891288)
• Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons (PMID:11904448)
• PS2 mRNA is present only in lymphocytes, in contrast to PS1 mrna, which is found in both myeloid and lymphoid cells. (PMID:11987239)
• regulation by nicastrin and role in determining amyloid beta-peptide production via complex formation (PMID:12048259)
• interaction with GFAP epsilon (PMID:12058025)
• mutant presenilin 2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells (PMID:12173418)
• PS2/gamma-secretase contains PEN-2 and requires it for presenilin expression (PMID:12198112)
• There is no evidence to suggest that variations in the PSEN2 gene pose as major risk factors for sporadic early-onset Alzheimer disease (PMID:12210343)
• in oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that may play a role in the induction and/or proliferation of an inflammatory response in AD brain. (PMID:12232783)
• Transcriptional synergism on the pS2 gene promoter between a p160 coactivator and estrogen receptor-alpha depends on the coactivator subtype, the type of estrogen response element, and the promoter context. (PMID:12403846)
• presenilin binds to APH-1, which plays a role in the maturation of presenilin-nicastrin complexes (PMID:12471034)
• C-terminal fragment-PS2 could exhibit some of its functions in the absence of the presenilin 2 N-terminal fragment (NTF-PS2) counterpart derived from the presenilinase cleavage. (PMID:12556443)
• Overexpression of either wild type or mutant presenilin 2 in various cell lines does not directly induce apoptosis or increase the susceptibility to apoptosis. (PMID:12605888)
• the current study does not support the notion that the polymorphism in the PS2 gene constitutes a risk factor for either late-onset or early-onset AD (PMID:12770698)
• In vitro characterization of the presenilin-dependent gamma-secretase complex using a novel affinity ligand (PMID:12846562)
• presenilins are multifunctional proteins with catalytic activity as well as roles in the generation, stabilization, and transport of the gamma-secretase complex (PMID:12885769)
• a novel mutation in the PSEN2 gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms that PSEN2 mutations are associated with variable clinical expression. (PMID:12925374)
• identification of two novel spliced presenilin 2 transcripts in lymphocytes and brain under oxidant stress (PMID:14577603)
• IMP1 is a bi-aspartic polytopic protease capable of cleaving transmembrane proteins such as presenilin 2. (PMID:14741365)
• HeLa cells overexpressing both PS2 and ubiquilin-1 had PS2 mRNA levels lower than HeLa cells overexpressing PS2 alone, indicating that ubiquilin-1 overexpression, in fact, decreases PS2 transcription. (PMID:15004330)
• Ca(2+) release from intracellular stores was significantly reduced in fibroblasts from familial Alzheimer patients with presenilin 2 mutations. (PMID:15006697)
• results suggest that the proximal two-thirds of the PEN-2 TMD1 is functionally important for endoproteolysis of PS1 holoproteins and the generation of PS1 fragments, essential components of the gamma-secretase complex (PMID:15537629)
• dimeric (NCSTN/APH-1) and trimeric (NCSTN/APH-1/PS1) intermediates of gamma-secretase complex assembly are retained within the ER and incorporation of the fourth binding partner (PEN-2) also occurs on immature NCSTN. (PMID:15591316)
• knock down of anterior pharynx defective 1 homolog A (APH-1A), but not APH-1b, resulted in impaired maturation of nicastrin and reduced expression of presenilin 1, presenilin 2, and PEN-2 proteins (PMID:15629423)
• Four verified PS2 familial Alzheimer disease(FAD) mutations cause substantial changes in the Abeta 42/40 ratio, like PS1 mutations that cause very-early-onset FAD and may represent partial loss of function mutations (PMID:15663477)
• In fibroblasts from familial Alzheimer’s disease the presenilin 2 mutation Thr122Arg reduces both Ca2+ release from and capacitative Ca2+ entry to intracellular stores, revealing a modulatory role in disease pathogenesis. (PMID:15755689)
• Of the nine pathogenic mutations found in 12 cases, three were in APP, one in PSEN2, and five in PSEN1, including two novel Greek mutations (L113Q and N135S) in Alzheimer disease (PMID:15776278)
• Wild-type PS2 transgenes expressed in the mouse CNS support little Abeta40 or Abeta42 production. (PMID:15951428)
• Presenilin (PS)1 mutations interfere with PS2-mediated activity by reducing PS2 fragments (PMID:16014629)
• endoproteolysis, N and C terminal fragment interactions, and the assembly and activity of gamma-secretase complexes are very conserved between PS1 and PS2 (PMID:16135086)
• identification of genes whose expression is modulated by overexpression of mutant presenilin-2 in transgenic mice (PMID:16258850)
• mechanisms by which presenilin 2 affects the programmed cell death include the role of the proteolytically derived presenilin fragments generated by both presenilinase- and caspases (PMID:16375654)
• in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2) (PMID:16474849)
• Familial Alzheimer’s disease (FAD)-linked Presenilin mutants lower the Ca(2+) content of intracellular stores. (PMID:16620965)
• reduced presenilin proteolytic function leads to increased Abeta42/Abeta40 in Alzheimer disease (Review) (PMID:17268504)
• mutations in Alzheimer disease (Review) (PMID:17268505)
• Presenilin 2 Ser130Leu mutation in a case of late-onset “sporadic” Alzheimer’s disease. (PMID:17345043)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psen2	ENSDARG00000015540
mus_musculus	Psen2	ENSMUSG00000010609
rattus_norvegicus	Psen2	ENSRNOG00000002879
drosophila_melanogaster	Psn	FBGN0284421
caenorhabditis_elegans		WBGENE00004769

Paralogs (1): PSEN1 (ENSG00000080815)

Protein

Protein identifiers

Presenilin-2 — P49810 (reviewed: P49810)

Alternative names: AD3LP, AD5, E5-1, STM-2

All UniProt accessions (19): P49810, A0A7I2V2W1, A0A7I2V355, A0A7I2V3R9, A0A7I2V3Y8, A0A7I2V4D0, A0A7I2V4T4, A0A7I2V4Y6, A0A7I2V551, A0A7I2V5L1, A0A7I2V5Q3, A0A7I2V5S6, A0A7I2V5Y0, A0A7I2YQG9, B1AP22, E5RFW4, E5RG63, E5RHT1, E5RJM5

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular amyloid beta that contains longer amyloid beta. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis. Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria.

Subunit / interactions. Homodimer; predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with DOCK3. Interacts with HERPUD1, FLNA, FLNB and PARL. Interacts with AP1G1; this interaction is phosphorylation dependent and directs PSEN2 via early endosome to late endosome/lysosome.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Late endosome membrane. Lysosome membrane.

Tissue specificity. Expressed in the placenta, skeletal muscle and heart. Expressed in the somatodendritic compartment of hippocampal neurons. Expressed in the heart, brain, placenta, liver, skeletal muscle and kidney.

Post-translational modifications. Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments. Phosphorylated on serine residues. Phosphorylation at Ser-19 affects PSEN2 sorting.

Disease relevance. Alzheimer disease 4 (AD4) [MIM:606889] A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 1V (CMD1V) [MIM:613697] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PAL motif is required for normal active site conformation.

Similarity. Belongs to the peptidase A22A family.

Isoforms (3)

UniProt ID	Names	Canonical?
P49810-1	1	yes
P49810-2	2
P49810-3	3

RefSeq proteins (2): NP_000438, NP_036618 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001108	Peptidase_A22A	Family
IPR001493	Pept_A22A_PS2	Family
IPR006639	Preselin/SPP	Family
IPR042524	Presenilin_C	Homologous_superfamily

Pfam: PF01080

UniProt features (69 total): sequence variant 11, topological domain 10, helix 10, transmembrane region 8, mutagenesis site 5, turn 5, modified residue 4, sequence conflict 4, chain 2, short sequence motif 2, active site 2, splice variant 2, intramembrane region 1, region of interest 1, compositionally biased region 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7Y5X	ELECTRON MICROSCOPY	3
7Y5Z	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49810-F1	71.99	0.38

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): 263; 366

Post-translational modifications (4): 19, 22, 25, 30

Mutagenesis-validated functional residues (5):

Position	Phenotype
16–21	impairs ap1g1 interaction. does not affect aspartic endopeptidase activity, intramembrane cleaving. does not affect gamm
19	does not affect ap1g1 interaction. does not affect aspartic endopeptidase activity, intramembrane cleaving. does not aff
19	impairs ap1g1 interaction. does not affect aspartic endopeptidase activity, intramembrane cleaving. does not affect gamm
263	reduces production of amyloid-beta in app processing.
366	reduces production of amyloid-beta in app processing and of nicd in notch1 processing. increased mitochondrion-endoplasm

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-193692	Regulated proteolysis of p75NTR
R-HSA-205043	NRIF signals cell death from the nucleus
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802	Noncanonical activation of NOTCH3
R-HSA-9839383	TGFBR3 PTM regulation

MSigDB gene sets: 422 (showing top): ELVIDGE_HYPOXIA_DN, REACTOME_SIGNALING_BY_NOTCH, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_NOTCH_RECEPTOR_PROCESSING, USF_C, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MEMBRANE_DOCKING, GOBP_PROTEIN_MATURATION, UEDA_PERIFERAL_CLOCK, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (12): response to hypoxia (GO:0001666), membrane protein ectodomain proteolysis (GO:0006509), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), protein processing (GO:0016485), amyloid-beta formation (GO:0034205), intracellular signal transduction (GO:0035556), amyloid precursor protein catabolic process (GO:0042987), calcium ion homeostasis (GO:0055074), regulation of calcium import into the mitochondrion (GO:0110097), obsolete mitochondrion-endoplasmic reticulum membrane tethering (GO:1990456), proteolysis (GO:0006508)

GO Molecular Function (5): aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), aspartic-type endopeptidase activity (GO:0004190), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (17): Golgi membrane (GO:0000139), kinetochore (GO:0000776), nuclear inner membrane (GO:0005637), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), centrosome (GO:0005813), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), membrane (GO:0016020), protein-containing complex (GO:0032991), presynaptic membrane (GO:0042734), gamma-secretase complex (GO:0070765), endomembrane system (GO:0012505), nuclear membrane (GO:0031965), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Signaling by ERBB4	1
p75 NTR receptor-mediated signalling	1
Cell death signalling via NRAGE, NRIF and NADE	1
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
EPH-Ephrin signaling	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
organelle membrane	2
presynapse	2
cellular anatomical structure	2
response to stress	1
response to decreased oxygen levels	1
membrane protein proteolysis	1
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
intracellular anatomical structure	1
signal transduction	1
amyloid precursor protein metabolic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
calcium import into the mitochondrion	1
regulation of calcium ion transmembrane transport	1
aspartic-type endopeptidase activity	1
endopeptidase activity	1
aspartic-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
condensed chromosome, centromeric region	1
intracellular membraneless organelle	1
supramolecular complex	1
organelle inner membrane	1
nuclear membrane	1
endosome	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
centriole	1

Protein interactions and networks

STRING

2048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSEN2	NCSTN	Q92542	999
PSEN2	PSENEN	Q9NZ42	999
PSEN2	APH1A	Q96BI3	998
PSEN2	APH1B	Q8WW43	997
PSEN2	PSEN1	P49768	983
PSEN2	APOE	P02649	961
PSEN2	APP	P05067	955
PSEN2	KCNIP3	Q9Y2W7	953
PSEN2	CIB1	Q99828	941
PSEN2	SRI	P30626	917
PSEN2	MAPT	P10636	883
PSEN2	BACE1	P56817	851
PSEN2	ABCA7	Q8IZY2	803
PSEN2	ADAM10	O14672	790
PSEN2	FHL2	Q14192	787

IntAct

176 interactions, top by confidence:

A	B	Type	Score
PSEN2	APP	psi-mi:“MI:0915”(physical association)	0.680
APP	PSEN2	psi-mi:“MI:0915”(physical association)	0.680
PSEN2	FHL2	psi-mi:“MI:0915”(physical association)	0.590
FHL2	PSEN2	psi-mi:“MI:0407”(direct interaction)	0.590
PSEN2	AK2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	BAK1	psi-mi:“MI:0915”(physical association)	0.560
CASP1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
COX4I1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	FTL	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	MNDA	psi-mi:“MI:0915”(physical association)	0.560
PIK3R1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	RNF2	psi-mi:“MI:0915”(physical association)	0.560
SLC6A13	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2		psi-mi:“MI:0915”(physical association)	0.560
H3C1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	SOX14	psi-mi:“MI:0915”(physical association)	0.560
	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
MICAL2	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PDZK1IP1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
UBAC1	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	NEBL	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	ELL2	psi-mi:“MI:0915”(physical association)	0.560
RYBP	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	MKL1	psi-mi:“MI:0915”(physical association)	0.560
ZXDC	PSEN2	psi-mi:“MI:0915”(physical association)	0.560
PSEN2	SP6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (114): PSEN2 (Affinity Capture-Western), CIB1 (Affinity Capture-Western), PSEN2 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), CLK1 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), PSEN2 (Affinity Capture-MS), KCNIP3 (Two-hybrid), RNF115 (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS), PSEN2 (FRET), PSEN2 (Affinity Capture-Western)

ESM2 similar proteins: A9RA88, B0CMA4, F1QYC4, G5EBX4, G5ECD6, O02100, O12976, O12977, O13909, O17386, O45876, O59802, O64668, O64761, O88777, P49768, P49769, P49810, P52166, P79801, P79802, P97887, Q01608, Q0MS45, Q18600, Q4JIM4, Q54VP1, Q5F3W2, Q5R687, Q5R780, Q5RCN9, Q5U4Q2, Q61144, Q61ZW5, Q66J27, Q6PQZ3, Q6RH31, Q80UA9, Q8HXW5, Q8R2Y3

Diamond homologs: O02100, O12976, O12977, O88777, P49768, P49769, P49810, P52166, P79801, P79802, P97887, Q0MS45, Q4JIM4, Q5R780, Q5RCN9, Q61144, Q6RH31, Q8HXW5, Q90X07, Q90ZE4, Q9XT96, Q9XT97, O02194, Q54ET2, Q9SIK7, Q9W6T7, O64668, Q54DE8, Q01608

SIGNOR signaling

29 interactions.

A	Effect	B	Mechanism
NCSTN	up-regulates	PSEN2	binding
APH1A	up-regulates	PSEN2	binding
APH1B	up-regulates	PSEN2	binding
CSNK1A1	unknown	PSEN2	phosphorylation
CSNK1D	unknown	PSEN2	phosphorylation
CSNK1D	“up-regulates activity”	PSEN2	phosphorylation
CSNK2A1	unknown	PSEN2	phosphorylation
CSNK2A1	“up-regulates activity”	PSEN2	phosphorylation
CASP3	“up-regulates activity”	PSEN2	cleavage
CASP8	“up-regulates activity”	PSEN2	cleavage
CASP6	“up-regulates activity”	PSEN2	cleavage
CASP7	“up-regulates activity”	PSEN2	cleavage
CASP1	“up-regulates activity”	PSEN2	cleavage
ESR1	“up-regulates quantity by expression”	PSEN2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	5	24.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	164
Likely benign	102
Benign	31

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
3720283	NM_000447.3(PSEN2):c.342_343del (p.Lys115fs)	Pathogenic
4763759	NM_000447.3(PSEN2):c.524C>T (p.Ser175Phe)	Pathogenic
8845	NM_000447.3(PSEN2):c.422A>T (p.Asn141Ile)	Pathogenic
8846	NM_000447.3(PSEN2):c.715A>G (p.Met239Val)	Pathogenic
8850	NM_000447.3(PSEN2):c.717G>A (p.Met239Ile)	Pathogenic
8851	NM_000447.3(PSEN2):c.365C>G (p.Thr122Arg)	Pathogenic
8853	NM_000447.3(PSEN2):c.254C>T (p.Ala85Val)	Pathogenic
465218	NM_000447.3(PSEN2):c.886+2_886+4del	Likely pathogenic
4726843	NM_000447.3(PSEN2):c.356+2T>C	Likely pathogenic

SpliceAI

3003 predictions. Top by Δscore:

Variant	Effect	Δscore
1:226870648:AGG:A	donor_loss	1.0000
1:226883703:A:AG	acceptor_gain	1.0000
1:226883704:G:GG	acceptor_gain	1.0000
1:226883917:GCT:G	donor_gain	1.0000
1:226883920:G:GG	donor_gain	1.0000
1:226885533:CTCAG:C	acceptor_loss	1.0000
1:226885534:TCAGC:T	acceptor_loss	1.0000
1:226885535:CAGC:C	acceptor_loss	1.0000
1:226885536:A:AG	acceptor_gain	1.0000
1:226885537:G:GT	acceptor_gain	1.0000
1:226885537:GC:G	acceptor_gain	1.0000
1:226885537:GCATC:G	acceptor_gain	1.0000
1:226885679:GGTGA:G	donor_loss	1.0000
1:226885680:G:GG	donor_gain	1.0000
1:226885680:GTG:G	donor_loss	1.0000
1:226888089:A:AG	acceptor_gain	1.0000
1:226888090:G:GA	acceptor_gain	1.0000
1:226888090:GTTC:G	acceptor_gain	1.0000
1:226888827:AG:A	acceptor_gain	1.0000
1:226888828:GG:G	acceptor_gain	1.0000
1:226888828:GGGAA:G	acceptor_gain	1.0000
1:226889047:ATG:A	donor_loss	1.0000
1:226889049:GG:G	donor_loss	1.0000
1:226889051:T:A	donor_loss	1.0000
1:226890134:G:GG	donor_gain	1.0000
1:226891274:CCA:C	acceptor_loss	1.0000
1:226891276:A:AC	acceptor_loss	1.0000
1:226891276:A:AG	acceptor_gain	1.0000
1:226891276:AGCT:A	acceptor_gain	1.0000
1:226891277:G:GT	acceptor_gain	1.0000

AlphaMissense

2921 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:226883835:T:A	L91Q	1.000
1:226883835:T:C	L91P	1.000
1:226883844:C:A	P94H	1.000
1:226883844:C:G	P94R	1.000
1:226883847:T:A	V95D	1.000
1:226883855:T:C	C98R	1.000
1:226883856:G:A	C98Y	1.000
1:226883857:C:G	C98W	1.000
1:226888103:T:A	W171R	1.000
1:226888103:T:C	W171R	1.000
1:226888107:T:C	L172S	1.000
1:226888897:G:A	G212E	1.000
1:226888905:G:C	G215R	1.000
1:226888906:G:A	G215D	1.000
1:226888957:T:C	L232P	1.000
1:226888968:A:C	S236R	1.000
1:226888970:T:A	S236R	1.000
1:226888970:T:G	S236R	1.000
1:226889019:T:A	W253R	1.000
1:226889019:T:C	W253R	1.000
1:226890035:A:C	D263A	1.000
1:226890035:A:T	D263V	1.000
1:226890038:T:C	L264P	1.000
1:226890044:C:A	A266D	1.000
1:226890047:T:A	V267E	1.000
1:226890050:T:C	L268P	1.000
1:226890061:G:A	G272R	1.000
1:226890061:G:C	G272R	1.000
1:226890061:G:T	G272W	1.000
1:226890062:G:A	G272E	1.000

dbSNP variants (sampled 300 via entrez): RS1000008471 (1:226871393 A>C), RS1000154846 (1:226874210 G>T), RS1000173454 (1:226880396 A>T), RS1000309274 (1:226880014 C>G), RS1000323122 (1:226882940 C>G), RS1000348059 (1:226902958 TG>T), RS1000483790 (1:226887892 T>C), RS1000507813 (1:226878648 G>T), RS1000546391 (1:226872784 C>T), RS1000606812 (1:226887013 TGGCAGATGGTGGGAAGCA>T), RS1000610040 (1:226873962 G>A), RS1000630071 (1:226893389 C>T), RS1000648476 (1:226878400 G>A,T), RS1000756335 (1:226882662 T>C), RS1000770825 (1:226899057 G>A)

Disease associations

OMIM: gene MIM:600759 | disease phenotypes: MIM:606889, MIM:613697

GenCC curated gene-disease

Disease	Classification	Inheritance
Alzheimer disease 4	Strong	Autosomal dominant
early-onset autosomal dominant Alzheimer disease	Supportive	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy 1V	Limited	AD

Mondo (8): Alzheimer disease 4 (MONDO:0011743), dilated cardiomyopathy 1V (MONDO:0013373), dilated cardiomyopathy (MONDO:0005021), Huntington disease-like syndrome (MONDO:0015548), vascular dementia (MONDO:0004648), Alzheimer disease (MONDO:0004975), early-onset autosomal dominant Alzheimer disease (MONDO:0015140), (MONDO:0015470)

Orphanet (5): Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), Familial isolated dilated cardiomyopathy (Orphanet:154), Dilated cardiomyopathy (Orphanet:217604), Huntington disease-like syndrome (Orphanet:158266), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000504	Abnormality of vision
HP:0000657	Oculomotor apraxia
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0000741	Apathy
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001276	Hypertonia
HP:0001279	Syncope
HP:0001289	Confusion
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0002120	Cerebral cortical atrophy
HP:0002185	Neurofibrillary tangles
HP:0002186	Apraxia
HP:0002197	Generalized-onset seizure
HP:0002354	Memory impairment
HP:0002381	Aphasia
HP:0002463	Language impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_903	Heel bone mineral density	2.000000e-17
GCST010002_355	Refractive error	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
C536596	Alzheimer disease type 4 (supp.)
C566856	Cardiomyopathy, Dilated, 1V (supp.)
C580174	Huntington Disease-Like Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2094135 (PROTEIN COMPLEX), CHEMBL3708 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,401 (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
CHEMBL1770916	NIROGACESTAT	4	756
CHEMBL190083	TARENFLURBIL	3	4,903
CHEMBL520733	SEMAGACESTAT	3	701
CHEMBL1090771	AVAGACESTAT	2	479
CHEMBL4297422	RG-4733	2	668
CHEMBL463981	BEGACESTAT	2	218
CHEMBL2151205	E-2212	1	19
CHEMBL4205422	MK-0752	1	657

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — A22: Presenilin

Binding affinities (BindingDB)

45 measured of 60 human assays (60 total across all organisms); most potent 45 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-morpholin-4-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	5 nM
5-Chloro-thiophene-2-sulfonic acid [5-(2-morpholin-4-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	5 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-(4-phenyl-piperazin-1-yl)-acetamide	IC50	5 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-piperidin-1-yl-acetamide	IC50	6 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-pyrrolidin-1-yl-acetamide	IC50	7 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-morpholin-4-yl-acetamide	IC50	7 nM
Pyridine-2-carboxylic acid [13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-amide	IC50	12 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-imidazol-1-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	15 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 4-chloro-benzyl ester	IC50	16 nM
5-Chloro-thiophene-2-sulfonic acid {5-[(E)-3-(4-phenyl-piperazin-1-yl)-propenyl]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	21 nM
[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-carbamic acid benzyl ester	IC50	23 nM
5-Chloro-thiophene-2-sulfonic acid (5-fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	29 nM
5-Chloro-thiophene-2-sulfonic acid (4-fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	34 nM
5-Chloro-thiophene-2-sulfonic acid {5-[(E)-3-(4-methyl-piperazin-1-yl)-propenyl]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	39 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-diethylamino-acetamide	IC50	41 nM
Thiophene-2-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	50 nM
5-chloro-thiophene-2-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	62 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-2-(4-methyl-piperazin-1-yl)-acetamide	IC50	69 nM
N-(5-Fluoro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-benzenesulfonamide	IC50	70 nM
5-Chloro-thiophene-2-sulfonic acid [5-(2-piperidin-1-yl-ethoxy)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	73 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid benzyl ester	IC50	74 nM
Pyridine-2-carboxylic acid (13-benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-amide	IC50	75 nM
4-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	129 nM
5-Chloro-thiophene-2-sulfonic acid (5-chloro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	146 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-piperidin-1-yl-propenyl)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl]-amide	IC50	152 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 2-chloro-benzyl ester	IC50	153 nM
5-Chloro-thiophene-2-sulfonic acid (4-chloro-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	175 nM
N-Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	190 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	209 nM
2-(Benzyl-methyl-amino)-N-[13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-acetamide	IC50	226 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(2-methyl-piperidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	227 nM
2-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	239 nM
5-Chloro-thiophene-2-sulfonic acid (5-hydroxy-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	269 nM
3-Fluoro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	324 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	335 nM
(13-Benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-carbamic acid 3-chloro-benzyl ester	IC50	412 nM
4-Chloro-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	467 nM
5-Chloro-thiophene-2-sulfonic acid (5-methoxy-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-amide	IC50	490 nM
5-Methyl-hexanoic acid (13-benzenesulfonylamino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl)-amide	IC50	535 nM
Butane-1-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	610 nM
5-Chloro-thiophene-2-sulfonic acid {5-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl}-amide	IC50	623 nM
4-Methyl-N-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl-benzenesulfonamide	IC50	651 nM
Propane-1-sulfonic acid tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylamide	IC50	721 nM
2-Benzylamino-N-[13-(5-chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-5-yl]-acetamide	IC50	3490 nM
N-(5-Amino-tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-yl)-benzenesulfonamide	IC50	6000 nM

ChEMBL bioactivities

3235 potent at pChembl≥5 of 3441 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.99	EC50	0.0103	nM	CHEMBL4456488
10.94	EC50	0.0114	nM	CHEMBL4443026
10.93	EC50	0.0117	nM	CHEMBL4525398
10.89	EC50	0.013	nM	CHEMBL4547187
10.86	EC50	0.0139	nM	CHEMBL4535601
10.82	IC50	0.015	nM	CHEMBL392113
10.70	IC50	0.02	nM	CHEMBL235659
10.62	IC50	0.024	nM	CHEMBL235869
10.52	IC50	0.03	nM	CHEMBL468083
10.43	IC50	0.037	nM	CHEMBL235869
10.40	IC50	0.04	nM	CHEMBL209888
10.38	IC50	0.042	nM	CHEMBL235659
10.30	IC50	0.05	nM	CHEMBL393761
10.22	IC50	0.06	nM	CHEMBL377691
10.22	IC50	0.06	nM	CHEMBL401521
10.22	IC50	0.06	nM	CHEMBL252671
10.22	IC50	0.06	nM	CHEMBL523832
10.22	IC50	0.06	nM	CHEMBL495009
10.22	IC50	0.06	nM	CHEMBL512282
10.22	IC50	0.06	nM	CHEMBL467457
10.15	IC50	0.07	nM	CHEMBL511572
10.12	IC50	0.075	nM	CHEMBL392113
10.10	IC50	0.08	nM	CHEMBL379089
10.10	IC50	0.08	nM	CHEMBL392068
10.10	IC50	0.08	nM	CHEMBL237875
10.10	IC50	0.08	nM	CHEMBL495185
10.09	IC50	0.082	nM	CHEMBL392068
10.05	IC50	0.09	nM	CHEMBL393542
10.00	IC50	0.1	nM	CHEMBL2396772
10.00	IC50	0.1	nM	CHEMBL237850
9.96	IC50	0.11	nM	CHEMBL236597
9.92	EC50	0.119	nM	CHEMBL392068
9.92	IC50	0.12	nM	CHEMBL523883
9.89	IC50	0.13	nM	AVAGACESTAT
9.85	IC50	0.14	nM	CHEMBL2396771
9.85	IC50	0.14	nM	CHEMBL2096800
9.85	IC50	0.14	nM	CHEMBL237666
9.82	IC50	0.15	nM	CHEMBL372085
9.82	IC50	0.15	nM	CHEMBL511928
9.77	IC50	0.17	nM	CHEMBL494588
9.77	IC50	0.17	nM	CHEMBL583904
9.77	IC50	0.17	nM	CHEMBL572032
9.75	IC50	0.178	nM	CHEMBL2059813
9.75	IC50	0.178	nM	CHEMBL5202466
9.74	IC50	0.18	nM	CHEMBL2396770
9.72	IC50	0.19	nM	CHEMBL2164125
9.72	IC50	0.19	nM	CHEMBL210587
9.70	IC50	0.2	nM	CHEMBL392246
9.70	IC50	0.2	nM	CHEMBL571602
9.70	IC50	0.2	nM	CHEMBL133857

PubChem BioAssay actives

3049 with measured affinity, of 4786 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-benzyl-2-methyl-N’-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)propanediamide	301810: Inhibition of human gamma secretase assessed as amyloid-beta40 peptide production in HEK293 cells by ELISA	ic50	<0.0001	uM
2-methyl-N-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)-N’-(3,3,3-trifluoropropyl)propanediamide	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
2-methyl-N-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)-N’-(2,2,2-trifluoroethyl)propanediamide	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
N-[(1R,5S)-3-(5-fluoro-6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
4-(3-fluorophenyl)-N-[(1R,5S)-3-(2-methoxy-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3-fluoro-4-methylphenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-4-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
N-[(1R,5S)-3-(2-chloro-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-4-(3,4-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
4-(3-fluoro-5-methylphenyl)-N-[(1R,5S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
5-N-(3,4-difluorophenyl)-5-N-ethyl-3-N-[(1R,5S)-3-(5-fluoro-6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1,2,4-triazole-3,5-diamine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
5-N-(3,5-difluorophenyl)-5-N-ethyl-3-N-[(1R,5S)-3-(2-methoxy-4-pyridinyl)-3-azabicyclo[3.2.1]octan-8-yl]-1-methyl-1,2,4-triazole-3,5-diamine	1586853: Inhibition of gamma-secretase (unknown origin) assessed as decrease in amyloid beta-42 secretion by cell based AlphaLisa assay	ec50	<0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-fluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	<0.0001	uM
(4aS,6R,8aS)-6-(4-chlorophenyl)sulfonyl-1-cyclopropyl-6-(2,5-difluorophenyl)-4,4a,5,7,8,8a-hexahydro-3H-benzo[c][1,2,6]thiadiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	<0.0001	uM
[1-[[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]amino]-1-oxopropan-2-yl] N-(2,2,3,3,3-pentafluoropropyl)carbamate	301809: Inhibition of human gamma secretase in HEK293 cells by reporter gene assay	ic50	<0.0001	uM
(2S)-2-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide	1628293: Inhibition of gamma secretase in HEK293 cells expressing APP 695 assessed as reduction in amyloid beta levels after 5 hrs by Western blot analysis	ic50	0.0001	uM
methyl 2-methyl-2-[[(2R,3R)-3-methyl-2-[[(2R)-3-methyl-2-[[2-methyl-2-[[(2R)-3-methyl-2-[[(2R,3S)-2-[[2-methyl-2-[[(2R,3R)-3-methyl-2-[[(2R)-3-methyl-2-[[(2R)-3-methyl-2-[[2-methyl-2-[[2-[[(2R)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]acetyl]amino]propanoyl]amino]butanoyl]amino]butanoyl]amino]pentanoyl]amino]propanoyl]amino]-3-phenylmethoxybutanoyl]amino]butanoyl]amino]propanoyl]amino]butanoyl]amino]pentanoyl]amino]propanoate	241010: Inhibitory activity against Gamma-secretase in HeLa cells expressing APP-reporter	ic50	0.0001	uM
N-(cyclopropylmethyl)-2-methyl-N’-(5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl)propanediamide	301810: Inhibition of human gamma secretase assessed as amyloid-beta40 peptide production in HEK293 cells by ELISA	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(4-fluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(2,4-difluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(3,4-difluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-chlorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[1-(4-fluorophenyl)-1,2,4-triazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(2,4-difluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(3,4-difluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
(1’R,4R,10’S)-5’-[5-(4-chlorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0001	uM
N-[4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexyl]azetidine-1-sulfonamide	258050: Inhibition of human gamma-secretase in SHSY5Y neuroblastoma cells	ic50	0.0001	uM
[(2R)-2-[5-chloro-N-(4-chlorophenyl)sulfonyl-2-(hydroxymethyl)anilino]propyl] N-ethyl-N-(3-imidazol-1-ylpropyl)carbamate	314049: Inhibition of gamma secretase in human H4 cells assessed as reduction in amyloid beta40 level by ELISA	ic50	0.0001	uM
[(2R)-2-[5-chloro-N-(4-chlorophenyl)sulfonyl-2-(hydroxymethyl)anilino]propyl] N-(cyclopropylmethyl)-N-(3-imidazol-1-ylpropyl)carbamate	314049: Inhibition of gamma secretase in human H4 cells assessed as reduction in amyloid beta40 level by ELISA	ic50	0.0001	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-methyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0001	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-ethyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-hydroxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]pentanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]pentanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-[(2S)-6-methoxy-6-methylheptan-2-yl]-1,3-thiazol-2-yl]butanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-hydroxy-N-[(2S)-1-[[5-[(2S)-6-methoxy-6-methylheptan-2-yl]-1,3-thiazol-2-yl]amino]-1-oxopentan-2-yl]-3,3-dimethylbutanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]butanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0001	uM
(2R)-2-[(4-chlorophenyl)sulfonyl-[[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]methyl]amino]-5,5,5-trifluoropentanamide	754316: Inhibition of gamma-secretase in human IMR32 cell membrane using APP as substrate after 2 hrs by ELISA	ic50	0.0001	uM
(4R)-4-cyclopropyl-8-fluoro-5-[[6-(trifluoromethyl)-3-pyridinyl]sulfonyl]-1,4-dihydropyrazolo[4,5-c]quinoline	755856: Inhibition of partially purified human gamma-secretase-mediated cleavage of MBP-APPc125Sw fusion protein measured after overnight incubation by ELISA	ic50	0.0001	uM
(4R)-4-cyclopropyl-8-fluoro-5-[4-(trifluoromethyl)phenyl]sulfonyl-1,4-dihydropyrazolo[4,5-c]quinoline	755856: Inhibition of partially purified human gamma-secretase-mediated cleavage of MBP-APPc125Sw fusion protein measured after overnight incubation by ELISA	ic50	0.0001	uM
(1’R,4R,10’S)-2-(2,2,2-trifluoroethyl)-5’-[(E)-3-[4-(trifluoromethyl)piperidin-1-yl]prop-1-enyl]spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
2-[1-(4-chlorophenyl)sulfonyl-2-[2-fluoro-4-(1,2,4-oxadiazol-3-yl)phenyl]ethyl]-5,5,5-trifluoropentanamide	1866066: Inhibition of gamma-secretase (unknown origin) assessed as decrease in Abeta42 levels	ic50	0.0002	uM
2-[1-(4-chlorophenyl)sulfonyl-2-[4-(1,2,4-oxadiazol-3-yl)-2-bicyclo[1.1.1]pentanyl]ethyl]-5,5,5-trifluoropentanamide	1866066: Inhibition of gamma-secretase (unknown origin) assessed as decrease in Abeta42 levels	ic50	0.0002	uM
(2S)-3-(3,4-difluorophenyl)-2-methyl-N-[(3S)-1-methyl-2-oxo-5-(1-oxo-2H-isoquinolin-6-yl)-3H-1,4-benzodiazepin-3-yl]propanamide	71732: In vitro inhibition of gamma secretase.	ic50	0.0002	uM
(1’R,4R,10’S)-5’-[1-(2-fluorophenyl)imidazol-4-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
5’-[5-(2-fluorophenyl)-1-methylpyrazol-3-yl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13’-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene] 1,1-dioxide	375649: Inhibition of gamma secretase in human SH-SY5Y cells by HTRF assay	ic50	0.0002	uM
5-(4-chlorophenyl)sulfonyl-4-cyclopropyl-1,4-dihydropyrazolo[4,5-c]quinoline	448576: Inhibition of Gamma-secretase in human IMR-32 cells after 2 hrs by ELISA assay	ic50	0.0002	uM
5-(4-chlorophenyl)sulfonyl-4-(trifluoromethyl)-1,4-dihydropyrazolo[4,5-c]quinoline	448576: Inhibition of Gamma-secretase in human IMR-32 cells after 2 hrs by ELISA assay	ic50	0.0002	uM
(4aR,6R,8aS)-6-(4-chlorophenyl)sulfonyl-6-(2,5-difluorophenyl)-3-propyl-1,3,4,4a,5,7,8,8a-octahydrobenzo[c]thiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0002	uM
(4aS,6R,8aS)-6-(4-chlorophenyl)sulfonyl-3-cyclopropyl-6-(2,5-difluorophenyl)-4,4a,5,7,8,8a-hexahydro-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide	265340: Inhibition of gamma secretase	ic50	0.0002	uM
(2S)-2-[3-(3,5-difluorophenyl)propanoylamino]-N-[5-(6-methoxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]propanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0002	uM
(2S)-2-hydroxy-N-[(2S)-1-[[5-(6-hydroxy-6-methylheptan-2-yl)-1,3-thiazol-2-yl]amino]-1-oxopentan-2-yl]-3,3-dimethylbutanamide	301212: Inhibition of gamma secretase activity in human H4 cells transfected with APP695 mutant assessed as beta amyloid(1-40) production by whole cell assay	ic50	0.0002	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	decreases expression, increases abundance, affects cotreatment, increases expression	3
Estradiol	increases expression, increases activity, increases phosphorylation	3
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
Lipopolysaccharides	increases expression, decreases expression, affects cotreatment, decreases reaction	2
FR900359	increases phosphorylation	1
oxyphylla A	decreases reaction, increases expression	1
pimagedine	affects cotreatment, decreases reaction, increases expression	1
naringenin	increases activity, increases expression, increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases phosphorylation, increases activity, increases expression	1
sodium arsenate	decreases expression, increases abundance	1
nimesulide	decreases activity	1
cobaltous chloride	decreases expression	1
coumarin	increases phosphorylation	1
benazol P	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
homosalate	increases expression, increases reaction	1
deguelin	decreases expression	1
pifithrin	decreases reaction, increases activity, increases reaction	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
enzalutamide	affects expression	1
picoxystrobin	decreases expression	1
Resveratrol	decreases expression	1
Temozolomide	decreases expression	1
Glyphosate	decreases expression, increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcium Chloride	increases expression	1
Cannabidiol	decreases expression	1
Cycloheximide	affects expression, affects reaction, decreases expression	1

ChEMBL screening assays

479 unique, capped per target: 460 binding, 12 functional, 6 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037933	Binding	Inhibition of gamma secretase in human IMR32 cells assessed as inhibition of Abeta40 site cleavage by ELISA	N-Bridged bicyclic sulfonamides as inhibitors of gamma-secretase. — Bioorg Med Chem Lett
CHEMBL3611640	Unclassified	Selectivity ratio of IC50 for gamma-secretase-mediated cleavage of NotchdeltaE in in human HeLa cells expressing NotchdeltaE to IC50 for gamma-secretase in human SH-SY5Y cells expressing beta-APP C-terminal fragment SPA4CT	Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aβ42 lowering in rodents and rhesus monkeys. — Bioorg Med Chem Lett
CHEMBL4122735	ADMET	Modulation of gamma-secretase in human E6 cells expressing HeLaTetON-NotchdeltaE-NLuc/CLuc-RBP assessed as notch cleavage after 16 hrs by bioluminescence assay	Discovery of tetrahydroindazoles as a novel class of potent and in vivo efficacious gamma secretase modulators. — Bioorg Med Chem

Cellosaurus cell lines

23 cell lines: 15 induced pluripotent stem cell, 4 transformed cell line, 3 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4P89	AG09369	Transformed cell line	Male
CVCL_4P91	AG09905	Transformed cell line	Male
CVCL_A4PF	MUNIi007-A	Induced pluripotent stem cell	Female
CVCL_A8YW	F12448	Induced pluripotent stem cell	Female
CVCL_C0CV	PSEN2-N141I-hiPSC	Induced pluripotent stem cell	Female
CVCL_C0CW	PSEN2-141 N-hiPSC	Induced pluripotent stem cell	Female
CVCL_D0KH	PUMCi006-A	Induced pluripotent stem cell	Female
CVCL_D7YT	Ubigene A-549 PSEN2 KO	Cancer cell line	Male
CVCL_D8U4	Ubigene HCT 116 PSEN2 KO	Cancer cell line	Male
CVCL_D9PY	Ubigene HEK293 PSEN2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00009191	PHASE4	COMPLETED	The Depression in Alzheimer’s Disease Study (DIADS)
NCT00009217	PHASE4	COMPLETED	Treatment of Behavioral Symptoms in Alzheimer’s Disease
NCT00018278	PHASE4	COMPLETED	Electrophysiologic Measures of Treatment Response in Alzheimer Disease
NCT00035204	PHASE4	COMPLETED	A Study of the Effects on Sleep, Attention, and Gastrointestinal Tolerance of Galantamine and Donepezil in Patients With Alzheimer’s Disease
NCT00042172	PHASE4	COMPLETED	Treatment for Early Memory Loss
NCT00046358	PHASE4	COMPLETED	The Effect of Short-Term Statins and NSAIDs on Levels of Beta-Amyloid, a Protein Associated With Alzheimer’s Disease
NCT00104442	PHASE4	COMPLETED	Study of the Effects of Current Drug Treatments on Levels of Certain Brain Chemicals in Alzheimer’s Disease
NCT00120874	PHASE4	COMPLETED	Memantine and Comprehensive, Individualized Management of Alzheimer’s Disease and Caregiver Training
NCT00142324	PHASE4	UNKNOWN	CALM-AD
NCT00165724	PHASE4	COMPLETED	Alzheimer’s Disease Long-term Follow-up Study (ALF Study)
NCT00165750	PHASE4	TERMINATED	Correlation Between Regional Brain Volume and Response to Donepezil Treatment in AD Patients
NCT00202124	PHASE4	COMPLETED	Double Blind Study of Trp01 in Patients With Alzheimer’s Disease
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00216515	PHASE4	COMPLETED	The Efficacy of Galantamine on the Attention and the Frontal Function of the Patients With Dementia of Alzheimer Type
NCT00230568	PHASE4	COMPLETED	EARTH 413: A Study of Aricept in Hispanic Patients With Mild to Moderate Alzheimer’s Disease (AD)
NCT00234637	PHASE4	COMPLETED	Rivastigmine Monotherapy and Combination Therapy With Memantine in Patients With Moderately Severe Alzheimer’s Disease Who Failed to Benefit From Previous Cholinesterase Inhibitor Treatment
NCT00245206	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00260624	PHASE4	COMPLETED	Escitalopram Treatment of Patients With Agitated Dementia
NCT00303277	PHASE4	COMPLETED	Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
NCT00305903	PHASE4	COMPLETED	Safety and Tolerability of Rivastigmine With Add-on Memantine in Patients With Probable Alzheimer’s Disease
NCT00306124	PHASE4	UNKNOWN	Dopaminergic Enhancement of Learning and Memory in Healthy Adults and Patients With Dementia/Mild Cognitive Impairment
NCT00334906	PHASE4	COMPLETED	Study of Memantine in Assessment of Selected Measures of Volumetric Magnetic Resonance Imaging (MRI) and Cognition in Moderate AD (Alzheimer’s Disease)
NCT00369603	PHASE4	TERMINATED	Functional Brain Imaging of Medication Treatment Response in Mild Alzheimer’s Disease Patients
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00381381	PHASE4	COMPLETED	The Clinical Response of Choline Acetyltransferase and Apolipoprotein Epsilon Gene Polymorphisms to Donepezil in Alzheimer’s Disease
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00401167	PHASE4	COMPLETED	Memantine for Agitation and Aggression in Severe Alzheimer’s Disease
NCT00403520	PHASE4	COMPLETED	Hippocampus Study: Comparative Effect of Donepezil 10mg/d and Placebo on Clinical and Radiological Markers
NCT00417482	PHASE4	COMPLETED	Antipsychotic Discontinuation in Alzheimer’s Disease