NCSTN

Summary

NCSTN (nicastrin, HGNC:17091) is a protein-coding gene on chromosome 1q23.2, encoding Nicastrin (Q92542). 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).

This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer’s disease; however, the nature of the encoded protein’s role in Alzheimer’s disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Source: NCBI Gene 23385 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acne inversa, familial, 1 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 574 total — 15 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015331

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17091
Approved symbol	NCSTN
Name	nicastrin
Location	1q23.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0253, APH2
Ensembl gene	ENSG00000162736
Ensembl biotype	protein_coding
OMIM	605254
Entrez	23385

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 27 protein_coding, 22 retained_intron, 11 nonsense_mediated_decay

ENST00000294785, ENST00000368063, ENST00000421914, ENST00000424645, ENST00000424754, ENST00000435149, ENST00000437169, ENST00000438008, ENST00000459963, ENST00000465223, ENST00000467837, ENST00000491332, ENST00000491390, ENST00000699526, ENST00000699527, ENST00000699528, ENST00000699529, ENST00000699530, ENST00000699531, ENST00000699532, ENST00000699533, ENST00000699534, ENST00000699535, ENST00000699536, ENST00000699537, ENST00000699538, ENST00000699539, ENST00000699540, ENST00000699541, ENST00000699542, ENST00000699543, ENST00000699544, ENST00000699545, ENST00000699546, ENST00000699547, ENST00000699548, ENST00000699549, ENST00000699550, ENST00000699551, ENST00000699552, ENST00000699553, ENST00000699554, ENST00000699555, ENST00000699556, ENST00000699557, ENST00000874126, ENST00000874129, ENST00000874132, ENST00000874133, ENST00000874134, ENST00000874135, ENST00000874136, ENST00000874137, ENST00000874138, ENST00000913594, ENST00000913595, ENST00000913596, ENST00000913597, ENST00000913598, ENST00000913599

RefSeq mRNA: 4 — MANE Select: NM_015331 NM_001290184, NM_001290186, NM_001349729, NM_015331

CCDS: CCDS1203, CCDS91084

Canonical transcript exons

ENST00000294785 — 17 exons

Exon	Start	End
ENSE00002341633	160357041	160357253
ENSE00002410422	160351222	160351372
ENSE00003505604	160352054	160352206
ENSE00003552543	160350105	160350250
ENSE00003587603	160351696	160351805
ENSE00003605596	160344722	160344826
ENSE00003622506	160348999	160349122
ENSE00003663647	160349549	160349670
ENSE00003689425	160352887	160352991
ENSE00003786380	160353160	160353237
ENSE00003976861	160343383	160343481
ENSE00003976872	160354118	160354290
ENSE00003976891	160356260	160356347
ENSE00003976898	160358149	160358949
ENSE00003976906	160356600	160356754
ENSE00003976907	160355655	160355757
ENSE00003976909	160355863	160355958

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.6795 / max 329.9391, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6109	59.8995	1822
6108	6.2808	1775
6110	0.8965	379
6114	0.3625	158
6113	0.1614	62
6112	0.0786	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	97.90	gold quality
monocyte	CL:0000576	97.35	gold quality
mononuclear cell	CL:0000842	97.27	gold quality
leukocyte	CL:0000738	97.24	gold quality
body of pancreas	UBERON:0001150	97.02	gold quality
granulocyte	CL:0000094	96.87	gold quality
rectum	UBERON:0001052	96.84	gold quality
islet of Langerhans	UBERON:0000006	96.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.65	gold quality
olfactory bulb	UBERON:0002264	96.64	gold quality
right lung	UBERON:0002167	96.57	gold quality
minor salivary gland	UBERON:0001830	96.48	gold quality
ventricular zone	UBERON:0003053	96.48	gold quality
smooth muscle tissue	UBERON:0001135	96.26	gold quality
gall bladder	UBERON:0002110	96.26	gold quality
right lobe of thyroid gland	UBERON:0001119	96.21	gold quality
right uterine tube	UBERON:0001302	96.19	gold quality
right ovary	UBERON:0002118	96.17	gold quality
body of stomach	UBERON:0001161	96.16	gold quality
left lobe of thyroid gland	UBERON:0001120	96.14	gold quality
upper lobe of left lung	UBERON:0008952	96.12	gold quality
right coronary artery	UBERON:0001625	96.10	gold quality
spleen	UBERON:0002106	96.07	gold quality
left ovary	UBERON:0002119	96.06	gold quality
pancreas	UBERON:0001264	96.02	gold quality
small intestine	UBERON:0002108	95.95	gold quality
saliva-secreting gland	UBERON:0001044	95.94	gold quality
transverse colon	UBERON:0001157	95.93	gold quality
metanephros cortex	UBERON:0010533	95.88	gold quality
mucosa of transverse colon	UBERON:0004991	95.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-2983	no	1499.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting NCSTN, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6766-5P	99.68	67.70	2325

Literature-anchored findings (GeneRIF, showing 40)

• nicastrin does not display aminopeptidase M- and B-like activities (PMID:11726200)
• cell surface accumulation caused by presenilin 1 (PMID:11943765)
• The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample (PMID:11992262)
• regulation by presenilin and role in determining amyloid beta-peptide production via complex formation (PMID:12048259)
• BACE1 interacts with nicastrin (PMID:12054507)
• associates with active-gamma secretase and undergoes tight cellular regulation (PMID:12130643)
• These data indicate that mammalian APH-1 (mAPH-1) along with presenilin 1 and nicastrin is probably a functional component of the gamma-secretase complex required for the intramembrane proteolysis of APP and Notch (PMID:12297508)
• nicastrin binds to APH-1, which plays a role in the maturation of presenilin-nicastrin complexes (PMID:12471034)
• nicastrin undergoes a major conformational change during the assembly of the gamma-secretase complex (PMID:12644462)
• Co-expression of Drosophila Pen-2 with Aph-1 and nicastrin increases the formation of Psn fragments as well as gamma-secretase activity (PMID:12660785)
• Overexpression of nicastrin increases amyloid beta-peptide production. (PMID:12692078)
• Expression of nicastrin increases amyloid beta peptide levels and gamma-secretase activity. (PMID:12763021)
• Nicastrin is essential for the gamma-secretase cleavage of APP and Notch in mammalian cells and has both positive and negative functions in the regulation of gamma-secretase activity (PMID:12815056)
• the transmembrane domain region of nicastrin mediates direct interactions with APH-1 and the gamma-secretase complex (PMID:12917438)
• nicastrin has a role in the cleavage of APH-1 and generates a stable C-terminal fragment that associates with it (PMID:14593096)
• NCT interacts with gamma-secretase complex components via its transmembrane domain (PMID:14602727)
• The scanning of the nicastrin gene identified a missense mutation (N417Y) in two patients with sporadic AD, in an early-onset familial AD and in a young control subject. (PMID:14642438)
• Immature nicastrin can stably interact with APH-1 to form a potential scaffold for binding of presenilin and PEN-2. Moreover, binding of the latter two complex partners critically depends on the integrity of the nicastrin ectodomain (PMID:15189355)
• role of co-expression with presenilin in rescuing loss of function mutant of APH-1 (PMID:15210705)
• 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)
• 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)
• knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels (PMID:15975090)
• we have identified a novel alternatively spliced transcript of nicastrin in human brain tissue (PMID:16303145)
• Here, we have observed that NCT N-linked oligosaccharides mediated specific interactions with the secretory pathway lectins calnexin and ERGIC-53 (PMID:16938437)
• Compartmental microenvironments play a role in gamma-secretase complex (composed by presenilin, nicastrin, APH-1 and PEN-2)activity and specificity. (PMID:18201567)
• necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin (PMID:18667537)
• S-palmitoylation plays a role in stability and raft localization of nicastrin and APH-1, but does not directly modulate gamma-secretase processing of APP and other substrates. (PMID:19028695)
• Nicastrin controls cell death via phosphoinositide 3-kinase/Akt and p53-dependent pathways. (PMID:19187441)
• -1216C/A and -796T/G single nucleotide polymorphims in the nicastrin gene may be related to the development of sporadic Alzheimer disease in a Chinese population. (PMID:19394408)
• scFv disrupted proper folding & glycosyl maturation of the endogenous NCT, which are required for stability of gamma-secretase complex & intrinsic proteolytic activity, respectively, implicating dual role of NCT in the gamma-secretase complex (PMID:19684016)
• Glu-333 of nicastrin directly participates in gamma-secretase activity. (PMID:19729449)
• Results indicate that the rs10752637 single-nucleotide polymorphism can likely influence the expression of nicastrin, and that this may be an influencing factor during the pathogenesis of Alzheimer’s disease. (PMID:19840113)
• Nicastrin can function to maintain epithelial to mesenchymal transition during breast cancer progression. (PMID:20224929)
• 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)
• Reduction in amyloid deposits is found in the forebrain of transgenic mice expressing S-palmitoylation-deficient nicastrin. (PMID:21123562)
• Deep sequencing of the Nicastrin gene in pooled DNA, the identification of genetic variants that affect risk of Alzheimer’s disease. (PMID:21364883)
• NCSTN and PSENEN, are involved in the pathogenesis of some familial hidradenitis suppurativa (Acne Inversa). (PMID:21412258)
• confirmed the gene NCSTN is responsible for acne inversa by combining exome sequencing with previous genome-wide linkage analysis (PMID:21430701)
• The pathogenic nature of these two mutations provides further evidence that the NCSTN gene is the disease gene of acne inversa (PMID:21495993)
• Data suggest that nicastrin (NCT) is a molecular target for the mechanism-based inhibition of gamma-secretase. (PMID:21725355)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000103284
mus_musculus	Ncstn	ENSMUSG00000003458
rattus_norvegicus	Ncstn	ENSRNOG00000005355
drosophila_melanogaster	Nct	FBGN0039234
caenorhabditis_elegans	aph-2	WBGENE00000148

Protein

Protein identifiers

Nicastrin — Q92542 (reviewed: Q92542)

All UniProt accessions (20): A0A2R8YCK1, A0A2R8YE20, A0A2U3TZL9, A0A8V8TNC8, A0A8V8TNI3, A0A8V8TNI9, Q92542, A0A8V8TNU8, A0A8V8TNV3, A0A8V8TNV7, A0A8V8TPQ8, A0A8V8TPR8, A0A8V8TQ51, A0A8V8TQ61, H0Y3Z4, H0Y6T7, Q5T205, Q5T209, Q5T210, Q5T211

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.

Subunit / interactions. Component of the gamma-secretase complex. 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/PEN2. Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Interacts with PSEN1 and PSEN2.

Subcellular location. Membrane. Cytoplasmic vesicle membrane. Melanosome.

Tissue specificity. Detected in brain (at protein level). Widely expressed.

Post-translational modifications. N-glycosylated.

Disease relevance. Acne inversa, familial, 1 (ACNINV1) [MIM:142690] 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. The disease is caused by variants affecting the gene represented in this entry.

Induction. Constitutively expressed in neural cells.

Similarity. Belongs to the nicastrin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92542-1	1	yes
Q92542-2	2

RefSeq proteins (4): NP_001277113, NP_001277115, NP_001336658, NP_056146* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008710	Nicastrin	Family
IPR041084	Ncstrn_small	Domain

Pfam: PF05450, PF18266

UniProt features (112 total): strand 44, helix 28, glycosylation site 16, turn 6, disulfide bond 5, sequence variant 3, topological domain 2, splice variant 2, mutagenesis site 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

30 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
4UIS	ELECTRON MICROSCOPY	4.4
2N7Q	SOLUTION NMR
2N7R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92542-F1	89.73	0.69

Functional residue map

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

Disulfide bonds (5): 50–62, 140–159, 195–213, 230–248, 586–620

Glycosylation sites (16): 264, 387, 417, 435, 464, 506, 530, 562, 573, 580, 612, 45, 55, 187, 200, 204

Mutagenesis-validated functional residues (2):

Position	Phenotype
336–337	increases production of amyloid-beta (beta-app40 and beta-app42) in app processing.
653	no effect on gamma-secretase activity.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1474228	Degradation of the extracellular matrix
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-6798695	Neutrophil degranulation
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: 269 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_METENCEPHALON_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, GOBP_NOTCH_RECEPTOR_PROCESSING, GOBP_GLIAL_CELL_DEVELOPMENT, HSIAO_HOUSEKEEPING_GENES, GOBP_NEUROGENESIS

GO Biological Process (25): myeloid cell homeostasis (GO:0002262), proteolysis (GO:0006508), membrane protein ectodomain proteolysis (GO:0006509), G protein-coupled dopamine receptor signaling pathway (GO:0007212), glutamate receptor signaling pathway (GO:0007215), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), learning or memory (GO:0007611), protein processing (GO:0016485), cerebellum development (GO:0021549), central nervous system myelination (GO:0022010), adult behavior (GO:0030534), membrane protein intracellular domain proteolysis (GO:0031293), amyloid-beta formation (GO:0034205), T cell proliferation (GO:0042098), amyloid precursor protein metabolic process (GO:0042982), amyloid precursor protein biosynthetic process (GO:0042983), positive regulation of amyloid precursor protein biosynthetic process (GO:0042986), amyloid precursor protein catabolic process (GO:0042987), epithelial cell proliferation (GO:0050673), neuron apoptotic process (GO:0051402), cellular response to calcium ion (GO:0071277), regulation of long-term synaptic potentiation (GO:1900271), short-term synaptic potentiation (GO:1990926), amyloid-beta metabolic process (GO:0050435)

GO Molecular Function (8): protein-macromolecule adaptor activity (GO:0030674), aspartic endopeptidase activity, intramembrane cleaving (GO:0042500), ATPase binding (GO:0051117), endopeptidase activator activity (GO:0061133), growth factor receptor binding (GO:0070851), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233)

GO Cellular Component (24): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), focal adhesion (GO:0005925), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), membrane (GO:0016020), azurophil granule membrane (GO:0035577), sarcolemma (GO:0042383), melanosome (GO:0042470), presynaptic membrane (GO:0042734), extracellular exosome (GO:0070062), gamma-secretase complex (GO:0070765), lysosome (GO:0005764), endomembrane system (GO:0012505), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), synaptic membrane (GO:0097060), secretory vesicle (GO:0099503)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by ERBB4	1
Extracellular matrix organization	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
Innate Immune System	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
protein metabolic process	3
membrane protein proteolysis	2
cell surface receptor signaling pathway	2
behavior	2
amyloid precursor protein metabolic process	2
bounding membrane of organelle	2
endosome	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
presynapse	2
cellular anatomical structure	2
plasma membrane	2
immune system process	1
homeostasis of number of cells	1
synaptic transmission, dopaminergic	1
G protein-coupled receptor signaling pathway	1
cellular response to dopamine	1
glutamate receptor activity	1
cognition	1
proteolysis	1
protein maturation	1
metencephalon development	1
anatomical structure development	1
oligodendrocyte development	1
axon ensheathment in central nervous system	1
myelination	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
T cell activation	1
lymphocyte proliferation	1
macromolecule biosynthetic process	1
positive regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
regulation of amyloid precursor protein biosynthetic process	1
cell population proliferation	1
protein binding	1
molecular adaptor activity	1
aspartic-type endopeptidase activity	1
enzyme binding	1

Protein interactions and networks

STRING

1630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NCSTN	APH1B	Q8WW43	999
NCSTN	PSEN1	P49768	999
NCSTN	PSEN2	P49810	999
NCSTN	APH1A	Q96BI3	999
NCSTN	PSENEN	Q9NZ42	999
NCSTN	TMED10	P49755	966
NCSTN	APP	P05067	941
NCSTN	APEH	P13798	902
NCSTN	RHBDL2	Q9NX52	886
NCSTN	BACE1	P56817	835
NCSTN	ADAM10	O14672	807
NCSTN	TNF	P01375	780
NCSTN	MMEL1	Q495T6	767
NCSTN	GSAP	A4D1B5	762
NCSTN	ADAM17	P78536	692

IntAct

96 interactions, top by confidence:

A	B	Type	Score
PSEN1	NCSTN	psi-mi:“MI:0914”(association)	0.790
PSEN1	NCSTN	psi-mi:“MI:0915”(physical association)	0.790
APH1A	NCSTN	psi-mi:“MI:0915”(physical association)	0.760
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
TMED10	PSEN1	psi-mi:“MI:0914”(association)	0.620
NCSTN	TMED10	psi-mi:“MI:0915”(physical association)	0.620
TMED10	NCSTN	psi-mi:“MI:0915”(physical association)	0.620
APH1B	NOTCH1	psi-mi:“MI:0914”(association)	0.600
BSG	NCSTN	psi-mi:“MI:0407”(direct interaction)	0.590
BSG	PSEN1	psi-mi:“MI:0914”(association)	0.590
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
NOTCH1	PSEN1	psi-mi:“MI:0914”(association)	0.460
NCSTN	PSEN1	psi-mi:“MI:0407”(direct interaction)	0.440
FLOT2	PSEN1	psi-mi:“MI:0914”(association)	0.420
STXBP1	PSEN1	psi-mi:“MI:0914”(association)	0.420
GAP43	PSEN1	psi-mi:“MI:0914”(association)	0.420
SLC2A3	PSEN1	psi-mi:“MI:0914”(association)	0.420
BSG	PSEN1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (250): NCSTN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), NCSTN (Co-fractionation), NCSTN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), NCSTN (Affinity Capture-Western), NCSTN (Affinity Capture-MS), HNRNPF (Co-fractionation), NCSTN (Co-fractionation), NCSTN (Affinity Capture-MS), NCSTN (Proximity Label-MS), ALDOA (Affinity Capture-MS), SLC25A5 (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NGV2, A2VE47, A4IG72, A7E2V1, D3Z2R5, F1PCT7, O43909, P02786, P04844, P25235, P57716, Q07891, Q0VCN6, Q28120, Q28DV7, Q2V905, Q5R9Q9, Q5RBM1, Q5RDH6, Q5XIA1, Q5ZJH2, Q5ZL00, Q62351, Q64255, Q6DDX8, Q6NZ07, Q7TMC8, Q8BXQ2, Q8C7X2, Q8CGU6, Q8K224, Q8N766, Q8N961, Q8R553, Q8VCM8, Q8VDL4, Q92542, Q969N2, Q969V3, Q99JH7

Diamond homologs: P57716, Q8CGU6, Q92542, Q9VC27

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
NCSTN	up-regulates	APH1A	binding
NCSTN	up-regulates	PSEN1	binding
NCSTN	“form complex”	gamma-secretase	binding
SGK1	“down-regulates quantity by destabilization”	NCSTN	phosphorylation
SGK1	“down-regulates quantity”	NCSTN	phosphorylation
NCSTN	up-regulates	PSEN2	binding
APH1A	up-regulates	NCSTN	binding
APH1B	up-regulates	NCSTN	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Activated NOTCH1 Transmits Signal to the Nucleus	8	48.4×	1e-09
NOTCH3 Activation and Transmission of Signal to the Nucleus	5	40.3×	1e-05
NOTCH2 Activation and Transmission of Signal to the Nucleus	5	37.2×	1e-05
Constitutive Signaling by NOTCH1 PEST Domain Mutants	6	20.0×	2e-05
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	6	20.0×	2e-05
EPH-ephrin mediated repulsion of cells	5	18.6×	2e-04
ER-Phagosome pathway	5	11.0×	2e-03
Neutrophil degranulation	10	3.9×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
membrane protein ectodomain proteolysis	5	46.3×	1e-05
Notch signaling pathway	7	14.2×	1e-04
ERAD pathway	5	12.9×	4e-03
protein processing	5	12.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	9
Uncertain significance	280
Likely benign	209
Benign	32

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1179000	NM_015331.3(NCSTN):c.97G>A (p.Gly33Arg)	Pathogenic
1179001	NM_015331.3(NCSTN):c.1285C>T (p.Arg429Ter)	Pathogenic
1180810	NM_015331.3(NCSTN):c.1635C>G (p.Tyr545Ter)	Pathogenic
1403303	NM_015331.3(NCSTN):c.1290del (p.Leu431fs)	Pathogenic
2105450	NM_015331.3(NCSTN):c.1118C>G (p.Ser373Ter)	Pathogenic
225419	NM_015331.3(NCSTN):c.1300C>T (p.Arg434Ter)	Pathogenic
2430258	NM_015331.3(NCSTN):c.1101_1101+17delinsTGTCCA	Pathogenic
30452	NM_015331.3(NCSTN):c.1752del (p.Glu584fs)	Pathogenic
30453	NM_015331.3(NCSTN):c.1551+1G>A	Pathogenic
30454	NM_015331.3(NCSTN):c.349C>T (p.Arg117Ter)	Pathogenic
3342377	NM_015331.3(NCSTN):c.1294C>T (p.Arg432Ter)	Pathogenic
3677004	NM_015331.3(NCSTN):c.751_752del (p.Leu251fs)	Pathogenic
446481	NM_015331.3(NCSTN):c.1101+1G>A	Pathogenic
4536224	NM_015331.3(NCSTN):c.1258C>T (p.Gln420Ter)	Pathogenic
504025	NM_015331.3(NCSTN):c.17del (p.Gly6fs)	Pathogenic
1492943	NM_015331.3(NCSTN):c.436+1G>C	Likely pathogenic
2096665	NM_015331.3(NCSTN):c.1352+1G>C	Likely pathogenic
3247993	NC_000001.10:g.(?160323012)(160326377_?)del	Likely pathogenic
3377655	NM_015331.3(NCSTN):c.278dup (p.Tyr94fs)	Likely pathogenic
4082100	NM_015331.3(NCSTN):c.579del (p.Lys193fs)	Likely pathogenic
4292514	NM_015331.3(NCSTN):c.1654del (p.Gln552fs)	Likely pathogenic
4725617	NM_015331.3(NCSTN):c.436+1G>A	Likely pathogenic
4735809	NM_015331.3(NCSTN):c.996+1G>A	Likely pathogenic
806257	NM_015331.3(NCSTN):c.214del (p.Val72fs)	Likely pathogenic

SpliceAI

2808 predictions. Top by Δscore:

Variant	Effect	Δscore
1:160344825:GT:G	donor_gain	1.0000
1:160351220:A:AG	acceptor_gain	1.0000
1:160351221:G:GG	acceptor_gain	1.0000
1:160351221:GT:G	acceptor_gain	1.0000
1:160351221:GTGCT:G	acceptor_gain	1.0000
1:160352204:GGG:G	donor_gain	1.0000
1:160352205:GGG:G	donor_gain	1.0000
1:160352868:A:AG	acceptor_gain	1.0000
1:160352869:C:G	acceptor_gain	1.0000
1:160352872:A:AG	acceptor_gain	1.0000
1:160352873:C:G	acceptor_gain	1.0000
1:160352988:ACAG:A	donor_loss	1.0000
1:160352989:CAGGT:C	donor_loss	1.0000
1:160352990:AGGTA:A	donor_loss	1.0000
1:160352991:GGT:G	donor_loss	1.0000
1:160352992:G:C	donor_loss	1.0000
1:160352993:T:A	donor_loss	1.0000
1:160353155:CCCA:C	acceptor_loss	1.0000
1:160353156:CCAGG:C	acceptor_loss	1.0000
1:160353157:CAG:C	acceptor_loss	1.0000
1:160353158:AGGT:A	acceptor_gain	1.0000
1:160353159:GGTG:G	acceptor_gain	1.0000
1:160354114:CCAG:C	acceptor_loss	1.0000
1:160354116:A:G	acceptor_loss	1.0000
1:160354287:ACAA:A	donor_gain	1.0000
1:160354287:ACAAG:A	donor_loss	1.0000
1:160354289:AA:A	donor_gain	1.0000
1:160354289:AAGT:A	donor_loss	1.0000
1:160354290:AGTAA:A	donor_loss	1.0000
1:160354291:G:GG	donor_gain	1.0000

AlphaMissense

4625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:160357188:T:A	W648R	1.000
1:160357188:T:C	W648R	1.000
1:160357190:G:C	W648C	1.000
1:160357190:G:T	W648C	1.000
1:160357203:T:A	W653R	1.000
1:160357203:T:C	W653R	1.000
1:160357205:G:C	W653C	1.000
1:160357205:G:T	W653C	1.000
1:160344784:T:C	C50R	0.999
1:160344785:G:A	C50Y	0.999
1:160344786:T:G	C50W	0.999
1:160344820:T:C	C62R	0.999
1:160351327:T:A	C230S	0.999
1:160351327:T:C	C230R	0.999
1:160351328:G:A	C230Y	0.999
1:160351328:G:C	C230S	0.999
1:160351328:G:T	C230F	0.999
1:160351329:C:G	C230W	0.999
1:160351337:G:C	R233P	0.999
1:160351704:T:A	C248S	0.999
1:160351704:T:C	C248R	0.999
1:160351705:G:A	C248Y	0.999
1:160351705:G:C	C248S	0.999
1:160351706:T:G	C248W	0.999
1:160352204:G:T	G332W	0.999
1:160352888:A:T	E333V	0.999
1:160352908:A:C	S340R	0.999
1:160352910:C:A	S340R	0.999
1:160352910:C:G	S340R	0.999
1:160357197:A:C	S651R	0.999

dbSNP variants (sampled 300 via entrez): RS1000113597 (1:160348757 T>A), RS1000449872 (1:160345014 C>G,T), RS1000460714 (1:160353066 A>C,G), RS1000580525 (1:160353342 G>A), RS1000586547 (1:160344476 T>G), RS1000591680 (1:160345737 C>T), RS1000729968 (1:160358410 T>C), RS1000782123 (1:160358725 G>T), RS1001183786 (1:160354823 A>G), RS1001569279 (1:160341863 C>T), RS1002190249 (1:160353863 G>A), RS1002371578 (1:160347909 C>T), RS1002394618 (1:160348116 T>C), RS1002497894 (1:160342385 A>G), RS1002861542 (1:160350959 T>C)

Disease associations

OMIM: gene MIM:605254 | disease phenotypes: MIM:142690

GenCC curated gene-disease

Disease	Classification	Inheritance
acne inversa, familial, 1	Strong	Autosomal dominant

Mondo (1): acne inversa, familial, 1 (MONDO:0007728)

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000987	Atypical scarring of skin
HP:0040154	Acne inversa

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003263_116	Post bronchodilator FEV1 in COPD	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2094135 (PROTEIN COMPLEX), CHEMBL3418 (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

3229 potent at pChembl≥5 of 3435 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

3042 with measured affinity, of 4780 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
enzalutamide	affects expression	1
bisphenol S	decreases methylation	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Irinotecan	affects response to substance	1
Oxaliplatin	affects response to substance, increases expression	1
Glyphosate	decreases expression	1
Cannabidiol	decreases expression	1
Cisplatin	increases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Disulfiram	affects binding, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Isoflurane	increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

480 unique, capped per target: 461 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

6 cell lines: 4 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3BY	Abcam HEK293T NCSTN KO	Transformed cell line	Female
CVCL_D1TN	Abcam U-87MG NCSTN KO	Cancer cell line	Male
CVCL_D7VK	Ubigene A-549 NCSTN KO	Cancer cell line	Male
CVCL_D8R3	Ubigene HCT 116 NCSTN KO	Cancer cell line	Male
CVCL_D9L1	Ubigene HEK293 NCSTN KO	Transformed cell line	Female
CVCL_E0IU	Ubigene HeLa NCSTN KO	Cancer cell line	Female

Clinical trials (associated diseases)

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