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
• GTEx eGene: eQTL in 36 tissues, sQTL in 2 (q < 0.05)
• Drug target: yes — 6 via a complex or family; 8 molecules with ChEMBL bioactivity
• Approved drugs acting on a complex or family including it: 1 — Nirogacestat (Gamma-secretase)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.33 (unconstrained)
• 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: 19 — 9 protein_coding, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000261879

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 4

ENST00000261879, ENST00000380340, ENST00000380343, ENST00000558631, ENST00000559744, ENST00000559823, ENST00000559971, ENST00000560353, ENST00000560716, ENST00000560890, ENST00000940505, ENST00001037297, ENST00001037298, ENST00001103188, ENST00001103189, ENST00001103190, ENST00001103191, ENST00001103192, ENST00001137153

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.

Highest expression (Bgee): testis, sperm, adult organism, male germ cell, islet of Langerhans.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APH1B is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	9.1e-34	+0.56	15:63279621:C:T
Skin Sun Exposed Lower leg	eqtl	7.2e-32	+0.38	15:63277703:C:T
Nerve Tibial	eqtl	1.4e-20	+0.49	15:63277703:C:T
Skin Not Sun Exposed Suprapubic	eqtl	5.6e-17	+0.31	15:63277703:C:T
Esophagus Mucosa	eqtl	9.7e-15	+0.31	15:63277703:C:T
Pancreas	eqtl	1.1e-12	+0.49	15:63279621:C:T
Lung	eqtl	4.3e-12	+0.34	15:63279621:C:T
Adipose Subcutaneous	eqtl	1.3e-11	+0.32	15:63277703:C:T
Artery Tibial	eqtl	1.7e-10	+0.32	15:63279621:C:T
Esophagus Muscularis	eqtl	7.5e-10	+0.32	15:63277703:C:T
Esophagus Gastroesophageal Junction	eqtl	1.2e-09	+0.36	15:63279621:C:T
Stomach	eqtl	1.6e-09	+0.37	15:63279621:C:T
Artery Aorta	eqtl	1.6e-09	+0.34	15:63277703:C:T
Brain Frontal Cortex BA9	eqtl	2.1e-09	+0.32	15:63279621:C:T
Testis	eqtl	3.4e-08	-0.17	15:63279621:C:T
Colon Transverse	eqtl	3.6e-08	+0.23	15:63277703:C:T
Testis	sqtl	2.0e-06	+0.88	15:63280482:CTT:C
Brain Hippocampus	eqtl	3.4e-06	+0.30	15:63277703:C:T
Adipose Visceral Omentum	eqtl	3.5e-06	+0.24	15:63277703:C:T
Muscle Skeletal	eqtl	4.3e-06	+0.23	15:63303679:T:C

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 282 tissues 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
granulocyte	CL:0000094	83.76	gold quality
adrenal cortex	UBERON:0001235	83.76	gold quality
ventricular zone	UBERON:0003053	83.67	gold quality
mucosa of stomach	UBERON:0001199	83.36	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.98	gold quality
gall bladder	UBERON:0002110	82.91	gold quality
left uterine tube	UBERON:0001303	82.58	gold quality
spinal cord	UBERON:0002240	82.53	gold quality
substantia nigra pars compacta	UBERON:0001965	82.52	gold quality
left lobe of thyroid gland	UBERON:0001120	82.37	gold quality
thyroid gland	UBERON:0002046	82.36	gold quality
thoracic aorta	UBERON:0001515	82.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.24	gold quality
ascending aorta	UBERON:0001496	82.17	gold quality
right lobe of thyroid gland	UBERON:0001119	82.09	gold quality
ganglionic eminence	UBERON:0004023	81.93	gold quality
endocervix	UBERON:0000458	81.92	gold quality
left coronary artery	UBERON:0001626	81.88	gold quality
globus pallidus	UBERON:0001875	81.77	gold quality
aorta	UBERON:0000947	81.76	gold quality
corpus callosum	UBERON:0002336	81.65	gold quality
medial globus pallidus	UBERON:0002477	81.55	gold quality
lymph node	UBERON:0000029	81.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.46	gold quality
left ovary	UBERON:0002119	81.45	gold quality
popliteal artery	UBERON:0002250	81.44	gold quality
tibial artery	UBERON:0007610	81.44	gold quality
right ovary	UBERON:0002118	81.41	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.41	gold quality
omental fat pad	UBERON:0010414	81.39	gold quality
peritoneum	UBERON:0002358	81.37	gold quality
ovary	UBERON:0000992	81.35	gold quality
bone marrow cell	CL:0002092	81.26	gold quality
coronary artery	UBERON:0001621	81.25	gold quality
body of uterus	UBERON:0009853	81.19	gold quality
caudate nucleus	UBERON:0001873	81.13	gold quality
right coronary artery	UBERON:0001625	81.06	gold quality
nucleus accumbens	UBERON:0001882	80.83	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.78	gold quality
upper lobe of left lung	UBERON:0008952	80.71	gold quality
decidua	UBERON:0002450	80.63	gold quality
tibial nerve	UBERON:0001323	80.61	gold quality
tendon of biceps brachii	UBERON:0008188	80.58	silver quality
right hemisphere of cerebellum	UBERON:0014890	80.52	gold quality
bone marrow	UBERON:0002371	80.51	gold quality
upper lobe of lung	UBERON:0008948	80.37	gold quality
minor salivary gland	UBERON:0001830	80.30	gold quality
cerebellar hemisphere	UBERON:0002245	80.29	gold quality
cerebellar cortex	UBERON:0002129	80.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.23	gold quality
ectocervix	UBERON:0012249	80.16	gold quality
prostate gland	UBERON:0002367	80.15	gold quality
substantia nigra	UBERON:0002038	80.13	gold quality
tibia	UBERON:0000979	80.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.84	gold quality
lower esophagus	UBERON:0013473	79.78	gold quality
midbrain	UBERON:0001891	79.74	gold quality
lateral nuclear group of thalamus	UBERON:0002736	79.68	gold quality
pancreas	UBERON:0001264	79.65	gold quality
metanephros cortex	UBERON:0010533	79.63	gold quality
prefrontal cortex	UBERON:0000451	79.60	gold quality
hypothalamus	UBERON:0001898	79.58	gold quality
putamen	UBERON:0001874	79.45	gold quality
cerebellum	UBERON:0002037	79.38	gold quality
anatomical system	UBERON:0000467	79.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.18	gold quality
adenohypophysis	UBERON:0002196	79.05	gold quality
caput epididymis	UBERON:0004358	79.04	gold quality
amygdala	UBERON:0001876	79.02	gold quality
material anatomical entity	UBERON:0000465	79.01	gold 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

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Testis	tissue	79.0
Choroid plexus	tissue	18.4
Thyroid gland	tissue	18.3
Locus coeruleus	tissue	17.1
Spinal cord	tissue	16.3
Substantia nigra	tissue	15.3
Fallopian tube	tissue	15.3
Corpus callosum	tissue	15.2
Hippocampal formation	tissue	15.0
Nucleus accumbens	tissue	14.9
Medulla oblongata	tissue	14.1
Superior colliculi	tissue	13.7
Midbrain	tissue	13.4
Periaqueductal gray	tissue	13.4
Pons	tissue	12.7
Thalamus	tissue	12.2
Septum	tissue	12.2
Hypothalamus	tissue	11.9
Spleen	tissue	11.6
Cerebellum	tissue	11.4
Hippocampus	tissue	11.4
Adrenal gland	tissue	11.4
Retina	tissue	11.3
Prostate	tissue	11.0
Epididymis	tissue	10.9
Ovary	tissue	10.8
Postcentral gyrus	tissue	10.8
Ventral forebrain	tissue	10.7
Putamen	tissue	10.6
Olfactory bulb	tissue	10.2
Basal ganglia	tissue	10.1
Breast	tissue	9.9
Amygdala	tissue	9.6
Adipose tissue	tissue	9.5
Lymph node	tissue	9.4
Cerebral cortex	tissue	9.4
Somatosensory cortex	tissue	9.4
Appendix	tissue	9.2
Motor cortex	tissue	9.1
Retrosplenial cortex	tissue	9.1
Thymus	tissue	9.0
Retrosplenial and cingulate cortex	tissue	8.6
Insular cortex	tissue	8.6
Prefrontal cortex	tissue	8.5
Entorhinal cortex	tissue	8.5
Lung	tissue	8.3
Occipital cortex	tissue	8.2
Temporal cortex	tissue	8.0
Placenta	tissue	7.6
Bone marrow	tissue	7.6
Seminal vesicle	tissue	7.5
Tonsil	tissue	7.4
Kidney	tissue	7.2
Parathyroid gland	tissue	7.0
Gallbladder	tissue	7.0
Cervix	tissue	6.7
Pituitary gland	tissue	6.7
Urinary bladder	tissue	6.7
Endometrium 1	tissue	6.5
Vagina	tissue	6.3

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Dorsal funiculus (white matter) (21.6), Periaquaductal grey, anterior (20.7), Cervical spinal cord, central gray (20.1), Lateral funiculus (white matter) (19.7), Cervical spinal cord, ventral horn (19.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting APH1B by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 104 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 2.54e-10, LOEUF 1.33, missense Z 0.343 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000261879 — one region, missense o/e 0.97.

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)

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Pongo abelii	Q5RDM3	98.8%	Diamond
Dictyostelium discoideum	Q55FS3	32.6%	Diamond
Arabidopsis thaliana	Q8L9G7	32.5%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
USP3-AS1	ncRNA	100130855
FBXL22	protein-coding	283807
CA12	protein-coding	771
USP3	protein-coding	9960
RAB8B	protein-coding	51762
LINC02568	ncRNA	102723344
RPS27L	protein-coding	51065
LACTB	protein-coding	114294

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 (25 total): helix 11, transmembrane region 7, sequence conflict 2, strand 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
8OQY	Structure of apo form of human gamma-secretase PSEN1 APH-1B isoform reconstituted into …	ELECTRON MICROSCOPY	3.3
8OQZ	Structure of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc …	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, GPCRHMM predicted membrane proteins

Protein evidence: Evidence at protein level

Function

Pathways and Gene Ontology

Reactome pathways

10 curated (TAS) of 36; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

36 pathways:

ID	Pathway	Evidence
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants ⚕	curated
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants ⚕	curated
R-HSA-977225	Amyloid fiber formation	curated
R-HSA-3928665	EPH-ephrin mediated repulsion of cells	curated
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus	curated
R-HSA-205043	NRIF signals cell death from the nucleus	curated
R-HSA-9017802	Noncanonical activation of NOTCH3	curated
R-HSA-1251985	Nuclear signaling by ERBB4	curated
R-HSA-193692	Regulated proteolysis of p75NTR	curated
R-HSA-9839383	TGFBR3 PTM regulation	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer ⚕	—
R-HSA-2644603	Signaling by NOTCH1 in Cancer ⚕	—
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus	electronic
R-HSA-422475	Axon guidance	—
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE	—
R-HSA-73887	Death Receptor Signaling	—
R-HSA-1266738	Developmental Biology	—
R-HSA-2682334	EPH-Ephrin signaling	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus	electronic
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus	electronic
R-HSA-9675108	Nervous system development	—
R-HSA-162582	Signal Transduction	—
R-HSA-1236394	Signaling by ERBB4	—
R-HSA-157118	Signaling by NOTCH	—
R-HSA-1980143	Signaling by NOTCH1	—
R-HSA-1980145	Signaling by NOTCH2	—
R-HSA-9012852	Signaling by NOTCH3	—
R-HSA-9013694	Signaling by NOTCH4	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-9006936	Signaling by TGFB family members	—
R-HSA-9839373	Signaling by TGFBR3	—
R-HSA-193704	p75 NTR receptor-mediated signalling	—

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 (7): Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), protein processing (GO:0016485), 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 (7): Golgi membrane (GO:0000139), 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

17 top-level categories:

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
Death Receptor Signaling	1
Signaling by NOTCH	1

GO top-level categories

30 GO namespaces:

Category	Terms
protein metabolic process	2
bounding membrane of organelle	2
cell surface receptor signaling pathway	1
proteolysis	1
protein maturation	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
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
endomembrane system	1
cytoplasmic vesicle	1
plasma membrane protein complex	1
catalytic complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
Notch receptor processing	BP	direct assay
amyloid precursor protein catabolic process	BP	direct assay
amyloid-beta formation	BP	direct assay
protein processing	BP	direct assay
gamma-secretase complex	CC	direct assay
membrane	CC	direct assay
transport vesicle	CC	direct assay
endopeptidase activator activity	MF	mutant phenotype
protein-macromolecule adaptor activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 566 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APH1B	NCSTN	Q92542	958
APH1B	PSENEN	Q9NZ42	953
APH1B	PSEN1	P49768	864
APH1B	PSEN2	P49810	829
APH1B	APP	P05067	760
APH1B	APH1A	Q96BI3	579
APH1B	BACE1	P56817	565
APH1B	RYR3	Q15413	552
APH1B	RHBDL2	Q9NX52	495
APH1B	LAMP1	P11279	490
APH1B	ADAM10	O14672	477
APH1B	DLL1	O00548	466
APH1B	JAG2	Q9Y219	460
APH1B	BACE2	Q9Y5Z0	447
APH1B	ECHDC3	Q96DC8	440

IntAct

Human interaction partners of APH1B in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
NOTCH1	association	0.600	4
APP	physical association	0.560	3
BDNF	physical association	0.560	3
TM4SF4	physical association	0.560	3
TUSC5	physical association	0.560	3
VSTM1	physical association	0.560	3
PSEN2	physical association	0.400	1

BioGRID (11 interactions; top human partners by supporting records): FXYD6-FXYD2 (Two-hybrid), HNRNPL (Affinity Capture-RNA), NCSTN (Affinity Capture-Western), PSEN1 (Affinity Capture-Western), PSEN2 (Affinity Capture-Western), PSENEN (Affinity Capture-Western), SLC43A2 (Affinity Capture-MS), SLC6A12 (Affinity Capture-MS), TM4SF4 (Two-hybrid), TUSC5 (Two-hybrid), VSTM1 (Two-hybrid)

SIGNOR signaling

4 signaling 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

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ Gamma-secretase complex (APH1B, PSEN1, PSENEN, NCSTN)	4	PSEN1, PSENEN, APH1B, NCSTN
Gamma-secretase complex (APH1B, PSEN2, PSENEN, NCSTN)	4	PSENEN, APH1B, NCSTN, PSEN2

Disease & clinical

Genetic variants

Variant evidence for APH1B: 46 ClinVar records (1 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

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)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2424797	NC_000015.9:g.(?62146656)(64747263_?)del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore APH1B’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 561):

Position(s)	Effect	Δscore	Sites
15:63279149	acceptor_gain	1.0000
15:63279153	acceptor_gain	1.0000
15:63279159–63279160	acceptor_loss	1.0000	3
15:63279160	acceptor_gain	1.0000	2
15:63279332–63279333	donor_loss	1.0000	5
15:63279337	donor_gain	1.0000
15:63287547–63287548	donor_loss	1.0000	4
15:63302473–63302474	donor_loss	1.0000	5
15:63277711	donor_gain	0.9900
15:63286556–63286557	acceptor_loss	0.9900	6

AlphaMissense

455 missense substitutions predicted likely pathogenic (of 1,663 scored), across 151 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H196	8	0.884	0.955
F40	8	0.816	0.971
F131	8	0.816	0.965
F124	7	0.936	0.988
E84	7	0.910	0.944
F178	7	0.884	0.974
F14	7	0.871	0.964
W42	7	0.857	0.981
W173	7	0.838	0.965
H170	7	0.816	0.920
F156	7	0.790	0.889
Q83	6	0.836	0.962
G142	6	0.821	0.887
G121	6	0.819	0.954
G147	6	0.805	0.914
F228	6	0.805	0.935
N135	6	0.741	0.907
G15	5	0.931	0.966
G125	5	0.907	0.986
F155	5	0.899	0.962

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.67e-08
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000537

Disease associations

OMIM: gene MIM:607630 | disease phenotypes:

GWAS associations

9 associations:

Study	Trait	p-value
GCST010002_224	Refractive error	6e-36
GCST008058_64	Estimated glomerular filtration rate	8e-21
GCST008059_91	Estimated glomerular filtration rate	7e-18
GCST006291_101	Spherical equivalent or myopia (age of diagnosis)	5e-14
GCST003997_21	Myopia	2e-11
GCST007320_62	Alzheimer’s disease or family history of Alzheimer’s disease	3e-8
GCST007321_11	Family history of Alzheimer’s disease	3e-7
GCST009391_588	Metabolite levels	6e-7
GCST003488_4	Response to fenofibrate (triglyceride levels)	8e-6

EFO canonical traits (from GWAS)

4 canonical traits:

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)

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes APH1B — the drug acts on the assembly or class, not necessarily on this subunit alone.

6 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
NIROGACESTAT	Gamma-secretase	6	4
SEMAGACESTAT	Gamma-secretase	6	3
TARENFLURBIL	Gamma-secretase	6	3
AVAGACESTAT	Gamma-secretase	6	2
BEGACESTAT	Gamma-secretase	6	2
RG-4733	Gamma-secretase	6	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,554 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

8 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1770916	NIROGACESTAT	4	781
CHEMBL520733	SEMAGACESTAT	3	731
CHEMBL190083	TARENFLURBIL	3	4,947
CHEMBL1090771	AVAGACESTAT	2	491
CHEMBL463981	BEGACESTAT	2	227
CHEMBL4297422	RG-4733	2	684
CHEMBL2151205	E-2212	1	19
CHEMBL4205422	MK-0752	1	674

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

403 measured of 442 human assays (444 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-1-cyclopropyl-6-(2,5-difluoro-phenyl)-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.04 nM
(4aS,6S,8aR)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-ethyl-octahydro-benzo[c][1,2]thiazine 2,2-dioxide	IC50	0.06 nM
(4aS,6S,8aR)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-methyl-octahydro-benzo[c][1,2]thiazine 2,2-dioxide	IC50	0.08 nM
CHEMBL2096800	IC50	0.14 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-3-cyclopropyl-6-(2,5-difluoro-phenyl)-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.19 nM
(S)-3-(3,4-Difluoro-phenyl)-2-methyl-N-[(S)-1-methyl-2-oxo-5-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide	IC50	0.2 nM
(4aS,6S,8aR)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-propyl-octahydro-benzo[c][1,2]thiazine 2,2-dioxide	IC50	0.24 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-3-cyclobutyl-6-(2,5-difluoro-phenyl)-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.26 nM
(S)-3-(3,4-Difluoro-phenyl)-2-methyl-N-[(S)-1-methyl-2-oxo-5-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide	IC50	0.3 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-ethyl-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.4 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-isopropyl-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.41 nM
4-{3-[(S)-3-(3,4-Difluoro-phenyl)-2-methyl-propionylamino]-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl}-benzamide	IC50	0.49 nM
Cyclic sulfamide	IC50	0.5 nM
(4aS,6S,8aR)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-ethyl-octahydro-isothiochromene 2,2-dioxide	IC50	0.76 nM
(S)-N-[(S)-5-Benzo[1,3]dioxol-5-yl-1-(2-hydroxy-ethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3,4-difluoro-phenyl)-2-methyl-propionamide	IC50	0.9 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-methyl-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	0.9 nM
5-Chloro-thiophene-2-sulfonic acid [5-((E)-3-morpholin-4-yl-propenyl)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-13-yl]-amide	IC50	1 nM
Cyclic sulfamide	IC50	1 nM
CHEMBL58925	IC50	1 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-3-propyl-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	1.17 nM
(S)-3-(3,4-Difluoro-phenyl)-2-methyl-N-[(S)-1-methyl-2-oxo-5-(4-oxo-4H-chromen-7-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide	IC50	1.2 nM
(+/-)-(4aS,6R,8aS)-3-tert-butyl-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	1.39 nM
(S)-N-((S)-5-Benzo[1,3]dioxol-5-yl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3,4-difluoro-phenyl)-2-methyl-propionamide	IC50	1.8 nM
(S)-N-((S)-5-Benzo[1,3]dioxol-5-yl-1-methylcarbamoylmethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3,4-difluoro-phenyl)-2-methyl-propionamide	IC50	1.8 nM
Cyclic sulfamide	IC50	2 nM
(S)-3-(3,4-Difluoro-phenyl)-2-methyl-N-[(S)-1-methyl-2-oxo-5-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide	IC50	2.2 nM
4-(4-(1-(4-chloro-N-(2,5-difluorophenyl)phenylsulfonamido)ethyl)-3-(3-(pyrrolidin-1-yl)propoxy)benzoyl)benzyl 5-(5-((3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)pentylcarbamate	IC50	2.9 nM
cis-methyl 4-(3-(4-chlorophenylsulfonyl)-3-(2,5-difluorophenyl)cyclohexyl)butanoate	IC50	3 nM
Cyclic sulfamide	IC50	3.4 nM
(S)-3-(3,4-Difluoro-phenyl)-2-methyl-N-[(S)-1-methyl-2-oxo-5-(1-oxo-indan-5-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide	IC50	3.6 nM
(S)-N-[(S)-5-Benzo[1,3]dioxol-5-yl-2-oxo-1-(3-oxo-butyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-3-(3,4-difluoro-phenyl)-2-methyl-propionamide	IC50	3.7 nM
Cyclic sulfamide	IC50	4 nM
CHEMBL406322	IC50	4 nM
CHEMBL5196156	IC50	4.5 nM
(S)-3-(3,4-Difluoro-phenyl)-N-[(S)-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-2-methyl-propionamide	IC50	4.7 nM
CHEMBL3353090	IC50	5 nM
CHEMBL3771056	IC50	5 nM
5-Chloro-thiophene-2-sulfonic acid [5-(2-morpholin-4-yl-ethoxy)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-13-yl]-amide	IC50	5 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-5-yl]-2-(4-phenyl-piperazin-1-yl)-acetamide	IC50	5 nM
CHEMBL431679	IC50	5 nM
CHEMBL117978	IC50	5 nM
(S)-N-((S)-5-Benzo[1,3]dioxol-5-yl-1-dimethylcarbamoylmethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-(3,4-difluoro-phenyl)-2-methyl-propionamide	IC50	5.5 nM
CHEMBL3580774	IC50	6 nM
CHEMBL3394946	IC50	6 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-5-yl]-2-piperidin-1-yl-acetamide	IC50	6 nM
CHEMBL417588	IC50	6 nM
4-(4-(1-(4-chloro-N-(2,5-difluorophenyl)phenylsulfonamido)ethyl)-3-(3-(pyrrolidin-1-yl)propoxy)benzoyl)benzyl 8-(5-((3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)octylcarbamate	IC50	6.1 nM
(+/-)-(4aS,6R,8aS)-6-(4-chloro-benzenesulfonyl)-6-(2,5-difluoro-phenyl)-octahydro-benzo[1,2,6]thiadiazine 2,2-dioxide	IC50	6.18 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-5-yl]-2-pyrrolidin-1-yl-acetamide	IC50	7 nM
N-[13-(5-Chloro-thiophene-2-sulfonylamino)-tricyclo[8.2.1.0*3,8*]trideca-3(8),4,6-trien-5-yl]-2-morpholin-4-yl-acetamide	IC50	7 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

3048 with measured affinity, of 4783 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)	affects cotreatment, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, increases 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	increases expression, affects cotreatment	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)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for APH1B across ~30M SureChEMBL compounds — explore on Sugi Predict.