PSENEN

Summary

PSENEN (presenilin enhancer, gamma-secretase subunit, HGNC:30100) is a protein-coding gene on chromosome 19q13.12, encoding Gamma-secretase subunit PEN-2 (Q9NZ42). Essential 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).

Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer’s disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55851 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acne inversa, familial, 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 70 total — 8 pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_172341

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30100
Approved symbol	PSENEN
Name	presenilin enhancer, gamma-secretase subunit
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	PEN2
Ensembl gene	ENSG00000205155
Ensembl biotype	protein_coding
OMIM	607632
Entrez	55851

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000222266, ENST00000587708, ENST00000591949, ENST00000856485, ENST00000856486, ENST00000931699, ENST00000931700, ENST00000931701, ENST00000931702, ENST00000931703

RefSeq mRNA: 2 — MANE Select: NM_172341 NM_001281532, NM_172341

CCDS: CCDS12474

Canonical transcript exons

ENST00000587708 — 4 exons

Exon	Start	End
ENSE00001182037	35746708	35747519
ENSE00002951984	35745651	35745700
ENSE00003473718	35746419	35746523
ENSE00003625678	35745835	35745991

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 99.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.4958 / max 481.1660, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175381	54.7653	1823
175380	3.6834	1524
175379	3.0470	1442

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.55	gold quality
right testis	UBERON:0004534	98.52	gold quality
left testis	UBERON:0004533	98.51	gold quality
testis	UBERON:0000473	98.13	gold quality
fallopian tube	UBERON:0003889	97.08	gold quality
granulocyte	CL:0000094	97.07	gold quality
mucosa of transverse colon	UBERON:0004991	96.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.22	gold quality
blood	UBERON:0000178	96.09	gold quality
spinal cord	UBERON:0002240	96.07	gold quality
hypothalamus	UBERON:0001898	96.05	gold quality
leukocyte	CL:0000738	95.90	gold quality
apex of heart	UBERON:0002098	95.82	gold quality
rectum	UBERON:0001052	95.80	gold quality
monocyte	CL:0000576	95.76	gold quality
lower esophagus mucosa	UBERON:0035834	95.76	gold quality
right adrenal gland	UBERON:0001233	95.75	gold quality
amygdala	UBERON:0001876	95.70	gold quality
substantia nigra	UBERON:0002038	95.70	gold quality
adenohypophysis	UBERON:0002196	95.61	gold quality
temporal lobe	UBERON:0001871	95.59	gold quality
prefrontal cortex	UBERON:0000451	95.56	gold quality
caudate nucleus	UBERON:0001873	95.56	gold quality
Ammon’s horn	UBERON:0001954	95.45	gold quality
putamen	UBERON:0001874	95.43	gold quality
cortex of kidney	UBERON:0001225	95.42	gold quality
right lobe of thyroid gland	UBERON:0001119	95.38	gold quality
metanephros cortex	UBERON:0010533	95.38	gold quality
pituitary gland	UBERON:0000007	95.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10283	yes	2525.74
E-CURD-114	yes	62.42
E-HCAD-1	yes	31.66
E-MTAB-10287	yes	25.98
E-GEOD-130148	yes	12.75
E-ANND-3	yes	12.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, TP53

miRNA regulators (miRDB)

26 targeting PSENEN, 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-493-5P	99.96	72.47	2382
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-5000-5P	97.40	66.11	1055
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-7975	95.04	66.76	516

Literature-anchored findings (GeneRIF, showing 40)

• a component of the gamma-secretase complex (PMID:12198112)
• role in regulating proteolytic processing of presenilin 1 in conjunction with APH-1 (PMID:12522139)
• examination of membrane topology (PMID:12639958)
• APH-1 stabilizes the presenilin holoprotein in the complex, whereas PEN-2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex. (PMID:12660785)
• Expression of PEN2 increases amyloid beta peptide levels and gamma-secretase activity. (PMID:12763021)
• presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, associate with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons (PMID:15322084)
• the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes (PMID:15322109)
• The presenilin-subunit stabilizing function of PEN-2 depends on length and overall sequence of its carboxyl-terminal domain. (PMID:15953349)
• knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels (PMID:15975090)
• mutational analyses revealed that the “NF” sequence within the TMD4 of PS1 is the minimal motif that is required for binding with PEN-2, promoting PS1 endoproteolysis and gamma-secretase activity (PMID:16234243)
• Pen-2 may contribute to the activation of the gamma-secretase complex by directly binding to the TMD4 of PS1 (PMID:16234244)
• COX-2 may be a downstream effector of mutant N141I PS2-mediated apoptotic cell death and that inhibition of COX-2 may neuroprotect in AD through modulation of a GSK-3beta-beta-catenin-mediated response. (PMID:16331303)
• expression of PEN-2 is regulated by CREB, and the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2 (PMID:16449647)
• The results of this study suggest that there is an association between rs3817622 and the development of LOAD in APOE epsilon4 carriers within the northern Chinese population. It is possible allele A of the Pen2 gene increases the risk for LOAD. (PMID:17280645)
• Direct binding of unassembled Pen2 to Rer1 is mediated by the first transmembrane domain of Pen2, and a conserved asparagine in this domain is required. (PMID:17668005)
• equilibrium of PS1- and PS2-containing active complexes is dynamic and altered by overexpression of Pen2 or PS1 mutants and that formation of PS2 complexes is positively correlated with increased Abeta42:Abeta40 ratios (PMID:19036728)
• Transactivation of the Pen2 promoter by presenilin 1/2 is p53-dependent. (PMID:19889971)
• Hematopoietic gamma-secretase has reduced activity for APP and Notch1 processing compared to epithelial gamma-secretase. (PMID:20178366)
• Data show that intramembranous cleavage by gamma-secretase and related intramembrane-cleaving proteases may generally occur via stepwise endoproteolysis. (PMID:20534834)
• This study support a gamma-secretase-independent role of presenilin-1 in modulation of filamin-mediated actin cytoskeleton. (PMID:20847418)
• study found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN in 6 Chinese acne inversa (AI) families; results identify the gamma-secretase component genes as culprits for a subset of familial AI (PMID:20929727)
• NCSTN and PSENEN, are involved in the pathogenesis of some familial hidradenitis suppurativa (Acne Inversa). (PMID:21412258)
• structural analysis of PEN-2 conformation by single-particle electron microscopy (PMID:21454611)
• expression of calsenilin leads to a disruption of presenilin 1/gamma-secretase-mediated epsilon-cleavage of N-cadherin, which results in the significant accumulation of N-cadherin C-terminal fragment 1 (PMID:21852538)
• Studies indicate that gradual saturation of gamma-secretase with its substrate can be the pathogenic process in different alleged causes of Alzheimer’s disease (AD). (PMID:22479317)
• Mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). (PMID:22622421)
• secretase subunits restrict the arrangement of the transmembrane domains of presenilin during the formation of the functional structure of the catalytic pore. (PMID:22689582)
• The molecular state of gamma-secretase and its enzymological characteristics are described. (PMID:22787762)
• A review of mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 and the role of gamma-secretase in cutaneous biology and, more specifically in hidradenitis suppurativa. (PMID:23096707)
• Allele A of Pen 2 gene may increase the risk of late onset Alzheimer’s disease. (PMID:23134962)
• a 269 bp region located between the PSENEN and U2AF1L4 human genes is a genuine bidirectional promoter regulating a concerted divergent transcription of these genes. (PMID:23246698)
• Together, our results suggest that iron can increase gamma-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2/ (PMID:23685131)
• Recombinant human Pen-2 fusion protein was purified from bacteria to >95% purity. (PMID:24865334)
• Mutation of on PS1 and PS2 AXXXAXXXG motifs strongly impacts gamma-secretase activity. (PMID:25614624)
• The catalytic subunit of gamma-secretase is presenilin 1 (PS1), which contains an initial substrate-binding site that is distinct from the catalytic site (PMID:25673856)
• Both human PS2V and zebrafish PS1IV can stimulate gamma-secretase activity despite extreme structural divergence (PMID:25814654)
• Brain proteins showing neuron-specific interactions with gamma-secretase (PMID:25893612)
• analysis of how the conformation of presenilin, Pen-2, Aph-1, and nicastrin affect the function and mechanism of gamma-secretase (PMID:25918421)
• A complete inhibition of PS1-induced apoptosis was achieved by knockdown of PS1-associated protein (PSAP), a mitochondrial proapoptotic protein that forms a complex with Bax upon induction of apoptosis, in the presence of gamma-secretase inhibitor. (PMID:26025363)
• We for the first time identify PEN-2 as the causative gene of familial comedones. (PMID:26044244)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psenen	ENSDARG00000068698
mus_musculus	Psenen	ENSMUSG00000036835
rattus_norvegicus	Psenen	ENSRNOG00000020941
drosophila_melanogaster	pen-2	FBGN0053198
caenorhabditis_elegans		WBGENE00003975

Protein

Protein identifiers

Gamma-secretase subunit PEN-2 — Q9NZ42 (reviewed: Q9NZ42)

Alternative names: Presenilin enhancer protein 2

All UniProt accessions (2): Q9NZ42, K7ES79

UniProt curated annotations — full annotation on UniProt →

Function. Essential 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). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity.

Subunit / interactions. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. Golgi stack membrane. Cell membrane. Membrane.

Tissue specificity. Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.

Disease relevance. Acne inversa, familial, 2, with or without Dowling-Degos disease (ACNINV2) [MIM:613736] An autosomal dominant form of acne inversa, a chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. Some ACNINV2 patients also exhibit reticulate hyperpigmentation consistent with Dowling-Degos disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the PEN-2 family.

RefSeq proteins (2): NP_001268461, NP_758844* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019379	Gamma_Secretase_Asp_P_PEN2	Family

Pfam: PF10251

UniProt features (28 total): mutagenesis site 12, helix 5, topological domain 3, strand 3, turn 2, chain 1, intramembrane region 1, transmembrane region 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
8KCS	ELECTRON MICROSCOPY	2.4
6IYC	ELECTRON MICROSCOPY	2.6
7D8X	ELECTRON MICROSCOPY	2.6
8K8E	ELECTRON MICROSCOPY	2.6
8KCT	ELECTRON MICROSCOPY	2.6
6IDF	ELECTRON MICROSCOPY	2.7
8KCU	ELECTRON MICROSCOPY	2.7
8KCO	ELECTRON MICROSCOPY	2.8
7Y5T	ELECTRON MICROSCOPY	2.9
8X52	ELECTRON MICROSCOPY	2.9
8X54	ELECTRON MICROSCOPY	2.9
9K95	ELECTRON MICROSCOPY	2.9
6LR4	ELECTRON MICROSCOPY	3
7Y5X	ELECTRON MICROSCOPY	3
8KCP	ELECTRON MICROSCOPY	3
8X53	ELECTRON MICROSCOPY	3
6LQG	ELECTRON MICROSCOPY	3.1
7C9I	ELECTRON MICROSCOPY	3.1
8OQY	ELECTRON MICROSCOPY	3.3
5A63	ELECTRON MICROSCOPY	3.4
7Y5Z	ELECTRON MICROSCOPY	3.4
8IM7	ELECTRON MICROSCOPY	3.4
8OQZ	ELECTRON MICROSCOPY	3.4
5FN4	ELECTRON MICROSCOPY	4
5FN3	ELECTRON MICROSCOPY	4.1
5FN2	ELECTRON MICROSCOPY	4.2
5FN5	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ42-F1	92.84	0.87

Functional residue map

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

Mutagenesis-validated functional residues (12):

Position	Phenotype
26	decreased app processing by the gamma-secretase complex.
30	decreased expression levels, and decreased stimulation of presenilin endoproteolysis.
33	increased expression at the cell membrane.
36	decreased app processing by the gamma-secretase complex.
46	no effect.
54	decreased app processing by the gamma-secretase complex.
93	induces a n-linked glycosylation.
94	decreased app processing by the gamma-secretase complex.
10	induces a n-linked glycosylation on n-8.
15	decreased app processing by the gamma-secretase complex.
15	no effect on app processing by the gamma-secretase complex.
25	decreased app processing by the gamma-secretase complex.

Function

Pathways and Gene Ontology

Reactome pathways

13 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-977225	Amyloid fiber formation
R-HSA-9839383	TGFBR3 PTM regulation

MSigDB gene sets: 284 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOBP_NOTCH_RECEPTOR_PROCESSING, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, AACYNNNNTTCCS_UNKNOWN, CREBP1_Q2, CREB_Q4, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_PROTEIN_MATURATION, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GATA3_01, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, ATF1_Q6, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (9): membrane protein ectodomain proteolysis (GO:0006509), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), positive regulation of endopeptidase activity (GO:0010950), protein processing (GO:0016485), membrane protein intracellular domain proteolysis (GO:0031293), amyloid-beta formation (GO:0034205), amyloid precursor protein metabolic process (GO:0042982), amyloid precursor protein catabolic process (GO:0042987)

GO Molecular Function (3): enzyme binding (GO:0019899), endopeptidase activator activity (GO:0061133), protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), Golgi cisterna membrane (GO:0032580), presynaptic membrane (GO:0042734), gamma-secretase complex (GO:0070765)

Reactome top-level categories

Rollup of top-13 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
Metabolism of proteins	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane protein proteolysis	2
protein metabolic process	2
endopeptidase activity	2
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cell surface receptor signaling pathway	1
positive regulation of peptidase activity	1
regulation of endopeptidase activity	1
proteolysis	1
protein maturation	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
amyloid precursor protein metabolic process	1
protein binding	1
peptidase activator activity	1
endopeptidase regulator activity	1
binding	1
Golgi apparatus	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
cellular anatomical structure	1
Golgi cisterna	1
synaptic membrane	1
presynapse	1
plasma membrane protein complex	1
catalytic complex	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSENEN	APH1B	Q8WW43	999
PSENEN	NCSTN	Q92542	999
PSENEN	PSEN1	P49768	999
PSENEN	PSEN2	P49810	999
PSENEN	APH1A	Q96BI3	999
PSENEN	TMED10	P49755	899
PSENEN	APP	P05067	896
PSENEN	BACE1	P56817	875
PSENEN	TNF	P01375	875
PSENEN	RHBDL2	Q9NX52	845
PSENEN	APEH	P13798	821
PSENEN	TRIM13	O60858	790
PSENEN	RER1	O15258	775
PSENEN	GSAP	A4D1B5	770
PSENEN	ADAM10	O14672	745

IntAct

49 interactions, top by confidence:

A	B	Type	Score
PSENEN	NCSTN	psi-mi:“MI:0915”(physical association)	0.740
NCSTN	PSENEN	psi-mi:“MI:0915”(physical association)	0.740
APH1A	PSEN1	psi-mi:“MI:0915”(physical association)	0.670
PSEN1	TMBIM6	psi-mi:“MI:0914”(association)	0.660
PSENEN	PSEN1	psi-mi:“MI:0915”(physical association)	0.640
PSEN1	PSENEN	psi-mi:“MI:0915”(physical association)	0.640
TMED10	PSEN1	psi-mi:“MI:0914”(association)	0.620
NCSTN	TMED10	psi-mi:“MI:0915”(physical association)	0.620
APH1B	NOTCH1	psi-mi:“MI:0914”(association)	0.600
PSEN1	PSENEN	psi-mi:“MI:0915”(physical association)	0.560
CRB3	PSENEN	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	PSENEN	psi-mi:“MI:0915”(physical association)	0.560
SLC10A2	PSENEN	psi-mi:“MI:0915”(physical association)	0.560
PSENEN	FYN	psi-mi:“MI:0915”(physical association)	0.560
PSENEN	CYTH1	psi-mi:“MI:0915”(physical association)	0.560
APP	PSENEN	psi-mi:“MI:0915”(physical association)	0.560
PSENEN	FTL	psi-mi:“MI:0915”(physical association)	0.510
FTL	PSENEN	psi-mi:“MI:0915”(physical association)	0.510
TMED10	PSENEN	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (101): PSENEN (Affinity Capture-Western), PSENEN (Affinity Capture-Western), APH1A (Affinity Capture-Western), NCSTN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSEN2 (Affinity Capture-Western), PSENEN (Affinity Capture-Western), PSENEN (Two-hybrid), PSENEN (Affinity Capture-Western), PSENEN (Affinity Capture-Western), PSENEN (Affinity Capture-Western), PSENEN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), APH1A (Affinity Capture-Western), PSEN1 (Affinity Capture-Western)

ESM2 similar proteins: A2QHC2, A2XSY1, A4R2N5, A6QLC6, A6SSM3, A7E7N1, B8K1V7, C4B8E3, D4B5N6, E9QT42, O22252, O22622, O65085, P0DO17, P40046, P49283, Q0JDK9, Q1E8Z0, Q28677, Q28CH8, Q2UVJ5, Q39080, Q5G235, Q63632, Q657W3, Q6MWE5, Q6QI68, Q6Z0E2, Q70LL3, Q75D26, Q8BH79, Q8BR70, Q8JHF0, Q924N4, Q9CQR7, Q9JIS8, Q9M3T9, Q9NZ42, Q9SA71, Q9SKT3

Diamond homologs: Q54BR1, Q5G235, Q6QI68, Q86BE9, Q8JHF0, Q9CQR7, Q9NZ42, Q9FY84, Q9U357

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PSENEN	up-regulates	RYK	cleavage
PSENEN	“form complex”	gamma-secretase	binding
APH1A	up-regulates	PSENEN	binding
APH1B	up-regulates	PSENEN	binding
PSENEN	up-regulates	PSEN1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NOTCH3 Activation and Transmission of Signal to the Nucleus	5	119.0×	1e-08
NOTCH2 Activation and Transmission of Signal to the Nucleus	5	109.8×	2e-08
Activated NOTCH1 Transmits Signal to the Nucleus	6	107.1×	1e-09
EPH-ephrin mediated repulsion of cells	6	65.9×	1e-08
Constitutive Signaling by NOTCH1 PEST Domain Mutants	6	59.1×	1e-08
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	6	59.1×	1e-08
Amyloid fiber formation	5	25.7×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
Notch signaling pathway	7	47.2×	2e-08
protein processing	5	40.5×	9e-06
negative regulation of gene expression	5	16.4×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	0
Uncertain significance	30
Likely benign	28
Benign	2

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
30681	NM_172341.4(PSENEN):c.66del	Pathogenic
30682	NM_172341.4(PSENEN):c.279del (p.Phe94fs)	Pathogenic
3390321	GRCh37/hg19 19q13.12(chr19:36237320-36237748)x1	Pathogenic
446482	NC_000019.10:g.35746423dup	Pathogenic
446483	NM_172341.4(PSENEN):c.35T>A (p.Leu12Ter)	Pathogenic
446484	NM_172341.4(PSENEN):c.194T>G (p.Leu65Arg)	Pathogenic
446485	NM_172341.4(PSENEN):c.167-2A>G	Pathogenic
446486	NM_172341.4(PSENEN):c.62-1G>C	Pathogenic

SpliceAI

998 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35745120:CTCA:C	donor_loss	1.0000
19:35745121:TCAC:T	donor_loss	1.0000
19:35745122:CA:C	donor_loss	1.0000
19:35745123:ACCTG:A	donor_loss	1.0000
19:35745124:C:A	donor_loss	1.0000
19:35745124:CCTGG:C	donor_gain	1.0000
19:35745330:C:CA	donor_gain	1.0000
19:35745346:A:AC	donor_gain	1.0000
19:35745347:C:CC	donor_gain	1.0000
19:35746520:GGCT:G	donor_gain	1.0000
19:35746521:GCT:G	donor_gain	1.0000
19:35746521:GCTG:G	donor_gain	1.0000
19:35745123:A:AC	donor_gain	0.9900
19:35745124:C:CC	donor_gain	0.9900
19:35745685:G:GT	donor_gain	0.9900
19:35745978:G:GT	donor_gain	0.9900
19:35745988:CTGGG:C	donor_loss	0.9900
19:35745989:TGGG:T	donor_loss	0.9900
19:35745990:GG:G	donor_gain	0.9900
19:35745991:GG:G	donor_gain	0.9900
19:35745992:G:GA	donor_loss	0.9900
19:35745992:G:GG	donor_gain	0.9900
19:35745993:TAA:T	donor_loss	0.9900
19:35746417:AGGGG:A	acceptor_gain	0.9900
19:35746418:GGGGG:G	acceptor_gain	0.9900
19:35746519:AGGCT:A	donor_gain	0.9900
19:35746520:GGCTG:G	donor_gain	0.9900
19:35746524:G:GG	donor_gain	0.9900
19:35745331:C:A	donor_gain	0.9800
19:35745337:C:CA	donor_gain	0.9800

AlphaMissense

646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35746445:T:A	W30R	0.998
19:35746445:T:C	W30R	0.998
19:35746466:T:C	F37L	0.998
19:35746468:C:A	F37L	0.998
19:35746468:C:G	F37L	0.998
19:35745974:G:A	C15Y	0.997
19:35745975:C:G	C15W	0.997
19:35745977:G:C	R16P	0.997
19:35746422:G:A	G22E	0.997
19:35746456:C:A	N33K	0.997
19:35746456:C:G	N33K	0.997
19:35746761:T:A	W74R	0.997
19:35746761:T:C	W74R	0.997
19:35745973:T:C	C15R	0.995
19:35746421:G:A	G22R	0.995
19:35746421:G:C	G22R	0.995
19:35746711:T:A	V57D	0.995
19:35746740:T:A	W67R	0.995
19:35746740:T:C	W67R	0.995
19:35746437:C:A	P27H	0.994
19:35746728:G:C	G63R	0.994
19:35746729:G:A	G63D	0.994
19:35746773:T:C	F78L	0.994
19:35746775:C:A	F78L	0.994
19:35746775:C:G	F78L	0.994
19:35745982:T:C	Y18H	0.993
19:35746437:C:G	P27R	0.993
19:35746794:T:A	W85R	0.993
19:35746794:T:C	W85R	0.993
19:35745971:T:C	L14P	0.992

dbSNP variants (sampled 300 via entrez): RS1001123270 (19:35746666 C>A), RS1001532039 (19:35746250 C>T), RS1002437820 (19:35746106 G>A), RS1003120808 (19:35744197 G>A,T), RS1003447402 (19:35744976 A>T), RS1003974626 (19:35745396 A>G), RS1004089174 (19:35745518 C>A,T), RS1005034610 (19:35744258 C>T), RS1006262926 (19:35746051 G>A), RS1006642892 (19:35747461 G>A), RS1007028135 (19:35744616 C>T), RS1007528852 (19:35745561 G>A,C,T), RS1008057979 (19:35745761 C>T), RS1008951236 (19:35744642 A>C), RS1009599540 (19:35746182 A>G)

Disease associations

OMIM: gene MIM:607632 | disease phenotypes: MIM:612838, MIM:613736

GenCC curated gene-disease

Disease	Classification	Inheritance
acne inversa, familial, 2	Strong	Autosomal dominant
Dowling-Degos disease	Supportive	Autosomal dominant

Mondo (3): Brugada syndrome 5 (MONDO:0013015), acne inversa, familial, 2 (MONDO:0013397), Dowling-Degos disease (MONDO:0008371)

Orphanet (2): Brugada syndrome (Orphanet:130), Hereditary progressive cardiac conduction defect (Orphanet:871)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000464	Abnormality of the neck
HP:0000962	Hyperkeratosis
HP:0000989	Pruritus
HP:0001034	Hypermelanotic macule
HP:0001155	Abnormality of the hand
HP:0001231	Abnormal fingernail morphology
HP:0001369	Arthritis
HP:0002046	Heat intolerance
HP:0002860	Squamous cell carcinoma
HP:0003621	Juvenile onset
HP:0007456	Progressive reticulate hyperpigmentation
HP:0007502	Follicular hyperkeratosis
HP:0009123	Mixed hypo- and hyperpigmentation of the skin
HP:0010610	Palmar pits
HP:0011132	Chronic furunculosis
HP:0011354	Generalized abnormality of skin
HP:0012322	Perifolliculitis
HP:0012855	Scrotal hyperpigmentation
HP:0020073	Hypopigmented macule
HP:0025473	Hyperpigmented papule
HP:0030052	Inguinal freckling
HP:0030350	Erythematous papule
HP:0030442	Anal margin squamous cell carcinoma
HP:0031293	Digital pitting scar
HP:0031447	Penile freckling
HP:0031525	Keratoacanthoma
HP:0040154	Acne inversa
HP:0045059	Hyperkeratotic papule
HP:0100838	Recurrent cutaneous abscess formation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010002_54	Refractive error	1.000000e-10
GCST010703_277	Brain morphology (MOSTest)	2.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562924	Dowling-Degos Disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2094135 (PROTEIN COMPLEX), CHEMBL2374 (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)

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

3231 potent at pChembl≥5 of 3438 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

3043 with measured affinity, of 4814 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

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
arsenite	increases reaction, affects binding	1
cobaltous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
azoxystrobin	increases expression	1
CGP 52608	affects binding, increases reaction	1
pyrimidifen	increases expression	1
enzalutamide	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	decreases expression	1
Doxorubicin	increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Smoke	increases abundance, increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

487 unique, capped per target: 464 binding, 16 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

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2CD	Abcam HeLa PSENEN KO	Cancer cell line	Female
CVCL_B9W0	Abcam HEK293 PSENEN KO	Transformed cell line	Female
CVCL_E2I3	HAP1 PSENEN (-) 2	Cancer cell line	Male
CVCL_XS00	HAP1 PSENEN (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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