APH1B

Summary

APH1B (aph-1B gamma-secretase subunit, HGNC:24080) is a protein-coding gene on chromosome 15q22.2, encoding Gamma-secretase subunit APH-1B (Q8WW43). Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein).

This gene encodes a multi-pass transmembrane protein that is a functional component of the gamma-secretase complex, which also contains presenilin and nicastrin. This protein represents a stabilizing cofactor for the presenilin holoprotein in the complex. The gamma-secretase complex catalyzes the cleavage of integral proteins such as notch receptors and beta-amyloid precursor protein.

Source: NCBI Gene 83464 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 46 total — 1 pathogenic
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_031301

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24080
Approved symbol	APH1B
Name	aph-1B gamma-secretase subunit
Location	15q22.2
Locus type	gene with protein product
Status	Approved
Aliases	PSFL, APH-1B, DKFZp564D0372
Ensembl gene	ENSG00000138613
Ensembl biotype	protein_coding
OMIM	607630
Entrez	83464

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000261879, ENST00000380340, ENST00000380343, ENST00000558631, ENST00000559744, ENST00000559823, ENST00000559971, ENST00000560353, ENST00000560716, ENST00000560890, ENST00000940505

RefSeq mRNA: 2 — MANE Select: NM_031301 NM_001145646, NM_031301

CCDS: CCDS10184, CCDS45276

Canonical transcript exons

ENST00000261879 — 6 exons

Exon	Start	End
ENSE00001814585	63305614	63309126
ENSE00001910352	63277605	63277736
ENSE00003484714	63279161	63279331
ENSE00003529800	63302345	63302472
ENSE00003596537	63286558	63286628
ENSE00003680121	63287424	63287546

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8516 / max 413.6449, expressed in 1731 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147121	8.3205	1664
147120	5.5311	1636

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.74	gold quality
right testis	UBERON:0004534	98.35	gold quality
sperm	CL:0000019	97.45	gold quality
adult organism	UBERON:0007023	97.12	gold quality
testis	UBERON:0000473	96.94	gold quality
male germ cell	CL:0000015	96.38	gold quality
islet of Langerhans	UBERON:0000006	90.45	gold quality
adrenal tissue	UBERON:0018303	90.09	gold quality
right uterine tube	UBERON:0001302	89.45	gold quality
calcaneal tendon	UBERON:0003701	89.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.25	gold quality
monocyte	CL:0000576	88.18	gold quality
mononuclear cell	CL:0000842	88.14	gold quality
leukocyte	CL:0000738	88.08	gold quality
blood	UBERON:0000178	87.30	gold quality
buccal mucosa cell	CL:0002336	86.79	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.61	gold quality
tendon	UBERON:0000043	85.31	gold quality
lateral globus pallidus	UBERON:0002476	84.85	gold quality
right adrenal gland cortex	UBERON:0035827	84.79	gold quality
endothelial cell	CL:0000115	84.72	gold quality
right adrenal gland	UBERON:0001233	84.69	gold quality
stromal cell of endometrium	CL:0002255	84.60	gold quality
right lung	UBERON:0002167	84.58	gold quality
left adrenal gland	UBERON:0001234	84.55	gold quality
adrenal gland	UBERON:0002369	84.37	gold quality
left adrenal gland cortex	UBERON:0035825	84.18	gold quality
descending thoracic aorta	UBERON:0002345	83.99	gold quality
spleen	UBERON:0002106	83.98	gold quality
pancreatic ductal cell	CL:0002079	83.89	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	29.06
E-ANND-3	yes	4.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting APH1B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4420	99.82	70.08	1624

Literature-anchored findings (GeneRIF, showing 13)

• Expression of APH-1b increases amyloid beta peptide levels and gamma-secretase activity. (PMID:12763021)
• both APH-1a splice forms and APH-1b are expressed in peripheral and neuronal cells. APH-1aS, APH-1aL, and APH-1b form separate, proteolytically active gamma-secretase complexes containing either one of the two presenilins. (PMID:15286082)
• 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 (APH-1) (PMID:15591316)
• knock down of APH-1a, but not APH-1b, resulted in impaired maturation of nicastrin and reduced expression of presenilin 1, presenilin 2, and PEN-2 proteins (PMID:15629423)
• APH-1b variant protein is destabilized, and the fourth transmembrane domain plays an important role in the protein stability and function of APH-1. (PMID:15823552)
• These results collectively indicate that the three forms of APH-1 can replace each other in presenilin (PS) complexes and that the transmembrane GxxxG region is essential for the stability of the APH-1 protein as well as the assembly of PS complexes. (PMID:16757808)
• These data suggest that a cooperative mechanism involving APOE and APH-1b plays a role in the susceptibility to develop AD. (PMID:17466415)
• A non-synonymous SNP in the gamma-secretase component APH1B (Phe217Leu; rs1047552)is significantly associated with premature coronary atherosclerosis in Dutch males. (PMID:18987747)
• The single-nucleotide polymorphism (Phe217Leu; rs1047552) showed a tendency for association with HIV-1 infection in a Xhosa indigenous South African Bantu study (P = 0.087), and associated significantly in a Caucasian Dutch study (P = 0.049). (PMID:19774691)
• gamma-Secretase inhibition during repeated peripheral inflammation blocks central amyloid-beta accumulation and prevents cognitive dysfunction. (PMID:23665252)
• Data show that presenilin 1 (PS1)/anterior-pharynx-defective protein 1 (Aph1b), presenilin 2 (PS2)/Aph1aL, PS2/Aph1aS and PS2/anterior pharynx defective 1 homolog B (Aph1b) gamma-secretase produced amyloid beta peptide (Abeta) with a higher Abeta42+Abeta43-to-Abeta40 (Abeta42(43)/Abeta40) ratio than the other gamma-secretases. (PMID:27608597)
• Negative evidence for a role of APH1B T27I variant in Alzheimer’s disease. (PMID:31995180)
• Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-beta deposition in Alzheimer’s disease. (PMID:34732252)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	aph1b	ENSDARG00000005612
mus_musculus	Aph1b	ENSMUSG00000032375
mus_musculus	Aph1c	ENSMUSG00000053040
rattus_norvegicus	Aph1b	ENSRNOG00000027295
rattus_norvegicus	Aph1bl2	ENSRNOG00000063302
drosophila_melanogaster	aph-1	FBGN0031458
caenorhabditis_elegans	aph-1	WBGENE00000147

Paralogs (1): APH1A (ENSG00000117362)

Protein

Protein identifiers

Gamma-secretase subunit APH-1B — Q8WW43 (reviewed: Q8WW43)

Alternative names: Aph-1beta, Presenilin-stabilization factor-like

All UniProt accessions (5): Q8WW43, H0YKZ9, H0YLT0, H0YM95, Q4R1J8

UniProt curated annotations — full annotation on UniProt →

Function. Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.

Subunit / interactions. Probable component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with PSEN1 and PSEN2.

Subcellular location. Membrane.

Tissue specificity. Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.

Miscellaneous. Expressed at low levels in most tissues.

Similarity. Belongs to the APH-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WW43-1	1	yes
Q8WW43-2	2

RefSeq proteins (2): NP_001139118, NP_112591* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009294	Aph-1	Family

Pfam: PF06105

UniProt features (24 total): helix 10, transmembrane region 7, sequence conflict 2, strand 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8OQY	ELECTRON MICROSCOPY	3.3
8OQZ	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WW43-F1	90.51	0.73

Function

Pathways and Gene Ontology

Reactome pathways

36 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
R-HSA-1236394	Signaling by ERBB4
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73887	Death Receptor Signaling

MSigDB gene sets: 173 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GSE45365_NK_CELL_VS_CD11B_DC_UP, REACTOME_SIGNALING_BY_NOTCH, GOBP_NOTCH_RECEPTOR_PROCESSING, GOBP_PROTEIN_MATURATION, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_MEMBRANE_PROTEIN_INTRACELLULAR_DOMAIN_PROTEOLYSIS, GNF2_CCNA1, GOBP_AMYLOID_PRECURSOR_PROTEIN_METABOLIC_PROCESS, GOBP_MEMBRANE_PROTEIN_PROTEOLYSIS, PID_P75_NTR_PATHWAY, ALCALA_APOPTOSIS, COWLING_MYCN_TARGETS, PID_NOTCH_PATHWAY, GOCC_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (8): Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), protein processing (GO:0016485), membrane protein intracellular domain proteolysis (GO:0031293), amyloid-beta formation (GO:0034205), amyloid precursor protein catabolic process (GO:0042987), proteolysis (GO:0006508), positive regulation of catalytic activity (GO:0043085)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), endopeptidase activator activity (GO:0061133), protein binding (GO:0005515)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), transport vesicle (GO:0030133), gamma-secretase complex (GO:0070765)

Reactome top-level categories

Rollup of top-17 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
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
bounding membrane of organelle	2
endomembrane system	2
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	1
membrane protein proteolysis	1
amyloid precursor protein catabolic process	1
amyloid-beta metabolic process	1
amyloid precursor protein metabolic process	1
catalytic activity	1
positive regulation of molecular function	1
regulation of catalytic activity	1
protein binding	1
molecular adaptor activity	1
endopeptidase activity	1
peptidase activator activity	1
endopeptidase regulator activity	1
binding	1
Golgi apparatus	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle membrane	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
cytoplasmic vesicle	1
plasma membrane protein complex	1
catalytic complex	1

Protein interactions and networks

STRING

576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APH1B	NCSTN	Q92542	999
APH1B	PSENEN	Q9NZ42	999
APH1B	PSEN1	P49768	998
APH1B	PSEN2	P49810	997
APH1B	APP	P05067	778
APH1B	APH1A	Q96BI3	755
APH1B	BACE1	P56817	590
APH1B	RYR3	Q15413	549
APH1B	ADAM10	O14672	522
APH1B	BACE2	Q9Y5Z0	519
APH1B	RHBDL2	Q9NX52	515
APH1B	LAMP1	P11279	490
APH1B	TMED10	P49755	482
APH1B	JAG2	Q9Y219	465
APH1B	CEBPZ	Q03701	435

IntAct

29 interactions, top by confidence:

A	B	Type	Score
APH1B	NOTCH1	psi-mi:“MI:0914”(association)	0.600
APH1B	NOTCH1	psi-mi:“MI:0915”(physical association)	0.600
NOTCH1	APH1B	psi-mi:“MI:0915”(physical association)	0.600
TM4SF4	APH1B	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	APH1B	psi-mi:“MI:0915”(physical association)	0.560
VSTM1	APH1B	psi-mi:“MI:0915”(physical association)	0.560
	APH1B	psi-mi:“MI:0915”(physical association)	0.560
APH1B	BDNF	psi-mi:“MI:0915”(physical association)	0.560
APP	APH1B	psi-mi:“MI:0915”(physical association)	0.560
NOTCH1	PSEN1	psi-mi:“MI:0914”(association)	0.460
PSEN2	APH1B	psi-mi:“MI:0915”(physical association)	0.400
APH1B		psi-mi:“MI:0915”(physical association)	0.370
SLC43A2	PIK3R2	psi-mi:“MI:0914”(association)	0.350
SLC6A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
TUSC5	APH1B	psi-mi:“MI:0915”(physical association)	0.000
VSTM1	APH1B	psi-mi:“MI:0915”(physical association)	0.000
	APH1B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): APH1B (Affinity Capture-RNA), TM4SF4 (Two-hybrid), TUSC5 (Two-hybrid), VSTM1 (Two-hybrid), FXYD6-FXYD2 (Two-hybrid), APH1B (Affinity Capture-MS), APH1B (Affinity Capture-MS), NCSTN (Affinity Capture-Western), PSENEN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSEN2 (Affinity Capture-Western)

ESM2 similar proteins: A0JNC3, A9RA88, B0CMA4, B0YA61, F1RAX4, G5EBX4, O02100, O13909, O13989, O45876, O59802, O74520, O74949, P38837, P52166, Q0V9G6, Q20123, Q298S5, Q3B8H0, Q4WCL2, Q53FV1, Q55FS3, Q5EBF8, Q5F3W2, Q5R687, Q5RDM3, Q5U4Q2, Q5ZIU0, Q5ZMT9, Q66J27, Q6C741, Q6DF80, Q6FSD1, Q6NZZ4, Q6PQZ3, Q75EY7, Q80UA9, Q8AV61, Q8BVF7, Q8C7N7

Diamond homologs: O45876, Q5RDM3, Q8BVF7, Q8C7N7, Q8WW43, Q96BI3, Q9DCZ9, Q55FS3, Q8JHE9, Q8L9G7, Q9VQG2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
APH1B	up-regulates	NCSTN	binding
APH1B	up-regulates	PSEN2	binding
APH1B	up-regulates	PSEN1	binding
APH1B	up-regulates	PSENEN	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	29
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2424797	NC_000015.9:g.(?62146656)(64747263_?)del	Pathogenic

SpliceAI

1052 predictions. Top by Δscore:

Variant	Effect	Δscore
15:63279149:C:A	acceptor_gain	1.0000
15:63279153:T:G	acceptor_gain	1.0000
15:63279156:TTCA:T	acceptor_loss	1.0000
15:63279157:TCAGA:T	acceptor_loss	1.0000
15:63279158:CAG:C	acceptor_gain	1.0000
15:63279159:A:AC	acceptor_loss	1.0000
15:63279159:A:AG	acceptor_gain	1.0000
15:63279159:AGA:A	acceptor_gain	1.0000
15:63279160:G:GA	acceptor_gain	1.0000
15:63279160:G:GC	acceptor_loss	1.0000
15:63279160:GA:G	acceptor_gain	1.0000
15:63279160:GAG:G	acceptor_gain	1.0000
15:63279160:GAGC:G	acceptor_gain	1.0000
15:63279160:GAGCT:G	acceptor_gain	1.0000
15:63279327:TTAAA:T	donor_gain	1.0000
15:63279329:AAAG:A	donor_loss	1.0000
15:63279330:AA:A	donor_gain	1.0000
15:63279331:AG:A	donor_loss	1.0000
15:63279332:G:GG	donor_gain	1.0000
15:63279333:TAA:T	donor_loss	1.0000
15:63279337:T:G	donor_gain	1.0000
15:63286556:A:AG	acceptor_gain	1.0000
15:63286557:G:GA	acceptor_gain	1.0000
15:63286557:GAAAA:G	acceptor_gain	1.0000
15:63287422:A:AG	acceptor_gain	1.0000
15:63287423:G:GA	acceptor_gain	1.0000
15:63287542:TTCAG:T	donor_loss	1.0000
15:63287543:TCAGG:T	donor_loss	1.0000
15:63287544:CAGGT:C	donor_loss	1.0000
15:63287545:AGGTA:A	donor_loss	1.0000

AlphaMissense

1663 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:63287438:T:C	F124L	0.988
15:63287440:T:A	F124L	0.988
15:63287440:T:G	F124L	0.988
15:63287442:G:A	G125E	0.986
15:63279171:T:A	W42R	0.981
15:63279171:T:C	W42R	0.981
15:63287450:A:C	S128R	0.980
15:63287452:T:A	S128R	0.980
15:63287452:T:G	S128R	0.980
15:63287441:G:A	G125R	0.978
15:63287441:G:C	G125R	0.978
15:63279307:G:C	R87P	0.974
15:63302398:T:C	F178L	0.974
15:63302400:T:A	F178L	0.974
15:63302400:T:G	F178L	0.974
15:63277661:C:A	A13D	0.972
15:63279165:T:C	F40L	0.971
15:63279167:C:A	F40L	0.971
15:63279167:C:G	F40L	0.971
15:63277646:G:A	G8D	0.970
15:63287454:G:A	G129E	0.969
15:63287453:G:A	G129R	0.967
15:63287453:G:C	G129R	0.967
15:63277666:G:A	G15R	0.966
15:63277666:G:C	G15R	0.966
15:63277667:G:A	G15E	0.965
15:63287459:T:C	F131L	0.965
15:63287461:T:A	F131L	0.965
15:63287461:T:G	F131L	0.965
15:63302383:T:A	W173R	0.965

dbSNP variants (sampled 300 via entrez): RS1000048311 (15:63291365 C>G,T), RS1000154624 (15:63298110 G>T), RS1000232087 (15:63285091 C>T), RS1000397668 (15:63277808 G>A), RS1000427478 (15:63293465 C>T), RS1000523791 (15:63296421 T>A,C), RS1000545756 (15:63302680 T>C), RS1000598637 (15:63280182 C>T), RS1000784988 (15:63305244 A>G), RS1000835547 (15:63283186 A>G), RS1001053594 (15:63289936 G>A), RS1001092209 (15:63297030 G>A,T), RS1001236014 (15:63304441 C>A,G), RS1001286054 (15:63282969 G>A,C,T), RS1001530379 (15:63281950 T>C,G)

Disease associations

OMIM: gene MIM:607630 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003488_2	Response to fenofibrate (triglyceride levels)	8.000000e-06
GCST003997_46	Myopia	2.000000e-11
GCST006291_126	Spherical equivalent or myopia (age of diagnosis)	5.000000e-14
GCST007320_63	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-08
GCST007321_2	Family history of Alzheimer’s disease	3.000000e-07
GCST008058_89	Estimated glomerular filtration rate	8.000000e-21
GCST008059_97	Estimated glomerular filtration rate	7.000000e-18
GCST009391_563	Metabolite levels	6.000000e-07
GCST010002_172	Refractive error	6.000000e-36

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement
EFO:0004847	age at onset
EFO:0009268	family history of Alzheimer’s disease
EFO:0010498	hydroxyproline measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2094135 (PROTEIN COMPLEX)

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

3227 potent at pChembl≥5 of 3433 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

3041 with measured affinity, of 4776 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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
sodium arsenite	affects expression, increases expression	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, increases expression, affects expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
methylparaben	decreases expression	1
diallyl trisulfide	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	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	affects expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
enzalutamide	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	increases expression	1
Calcitriol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1

ChEMBL screening assays

478 unique, capped per target: 459 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

Clinical trials (associated diseases)

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