CTSD

Summary

CTSD (cathepsin D, HGNC:2529) is a protein-coding gene on chromosome 11p15.5, encoding Cathepsin D (P07339). Acid protease active in intracellular protein breakdown.

This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer’s disease.

Source: NCBI Gene 1509 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 776 total — 33 pathogenic, 19 likely-pathogenic (top 4% of genes corpus-wide)
• GTEx eGene: eQTL in 19 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 31
• ChEMBL bioactivity: 8 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_001909
• Interaction hub: 3,522 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2529
Approved symbol	CTSD
Name	cathepsin D
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Aliases	CLN10
Ensembl gene	ENSG00000117984
Ensembl biotype	protein_coding
OMIM	116840
Entrez	1509

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 21 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

MANE Select: ENST00000236671

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1, TSL 5: 10

ENST00000236671, ENST00000367196, ENST00000429746, ENST00000433655, ENST00000438213, ENST00000497544, ENST00000636571, ENST00000636843, ENST00000637158, ENST00000637381, ENST00000637387, ENST00000637815, ENST00000637915, ENST00000637937, ENST00000677300, ENST00000678991, ENST00000907823, ENST00000907824, ENST00000907825, ENST00000907826, ENST00000916370, ENST00000962444, ENST00000962445, ENST00000962446, ENST00000962447, ENST00000979185, ENST00001056768, ENST00001056769, ENST00001056771, ENST00001056774, ENST00001088266, ENST00001126645, ENST00001139475

RefSeq mRNA: 1 — MANE Select: NM_001909 NM_001909

CCDS: CCDS7725

Canonical transcript exons

ENST00000236671 — 9 exons

Exon	Start	End
ENSE00000690124	1759516	1759639
ENSE00000690128	1758969	1759087
ENSE00000794681	1752755	1753670
ENSE00003491659	1754906	1755028
ENSE00003511072	1761309	1761468
ENSE00003557008	1753994	1754138
ENSE00003565133	1753803	1753901
ENSE00003787746	1757324	1757556
ENSE00003800544	1763792	1763927

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 429.3637 / max 8573.3752, expressed in 1829 samples.

Highest expression (Bgee): adrenal gland cortex, adrenal gland, metanephros cortex, apex of heart, adrenal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTSD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 26 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	sqtl	1.7e-14	-0.79	11:1728734:A:G
Liver	eqtl	5.6e-11	-0.48	11:1772322:C:T
Skin Sun Exposed Lower leg	sqtl	2.4e-09	+0.39	11:1732115:A:G
Skin Sun Exposed Lower leg	eqtl	5.3e-09	+0.18	11:1762527:A:G
Brain Cerebellum	sqtl	6.7e-09	-0.65	11:1748994:C:G
Stomach	eqtl	3.8e-07	-0.25	11:1755807:T:C
Muscle Skeletal	eqtl	1.5e-06	-0.20	11:1755807:T:C
Adipose Subcutaneous	sqtl	6.5e-05	-0.24	11:1753436:T:C
Artery Aorta	sqtl	9.5e-05	+0.41	11:1755417:G:C
Testis	eqtl	2.8e-04	+0.16	11:1762527:A:G
Skin Not Sun Exposed Suprapubic	sqtl	5.6e-04	+0.29	11:1746408:CAT:C
Skin Not Sun Exposed Suprapubic	eqtl	1.4e-03	+0.16	11:1762527:A:G
Pancreas	eqtl	1.6e-03	-0.36	11:1762527:A:G
Brain Cerebellar Hemisphere	eqtl	2.0e-03	+0.85	11:2492025:A:G
Testis	sqtl	3.9e-03	-0.39	11:1753436:T:C
Esophagus Mucosa	eqtl	4.3e-03	-0.12	11:1813076:T:C
Brain Caudate basal ganglia	eqtl	5.3e-03	+1.26	11:1392347:T:C
Brain Hippocampus	eqtl	5.4e-03	-0.28	11:1755807:T:C
Brain Anterior cingulate cortex BA24	eqtl	1.3e-02	-0.55	11:1978475:G:A
Adrenal Gland	eqtl	1.7e-02	-0.17	11:1924862:C:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
118034	213.4697	1761
118035	205.8433	1829
118036	5.8115	1716
118021	3.0492	985
118022	0.8505	387
118033	0.1692	88
118032	0.1269	82
118023	0.0435	17

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.84	gold quality
right adrenal gland	UBERON:0001233	99.81	gold quality
left adrenal gland	UBERON:0001234	99.80	gold quality
metanephros cortex	UBERON:0010533	99.80	gold quality
left adrenal gland cortex	UBERON:0035825	99.79	gold quality
apex of heart	UBERON:0002098	99.58	gold quality
adrenal cortex	UBERON:0001235	99.56	gold quality
stromal cell of endometrium	CL:0002255	99.55	gold quality
right lung	UBERON:0002167	99.55	gold quality
granulocyte	CL:0000094	99.54	gold quality
upper lobe of left lung	UBERON:0008952	99.54	gold quality
gall bladder	UBERON:0002110	99.50	gold quality
mucosa of transverse colon	UBERON:0004991	99.49	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.49	gold quality
ascending aorta	UBERON:0001496	99.47	gold quality
thoracic aorta	UBERON:0001515	99.47	gold quality
descending thoracic aorta	UBERON:0002345	99.42	gold quality
skin of leg	UBERON:0001511	99.40	gold quality
right coronary artery	UBERON:0001625	99.40	gold quality
skin of abdomen	UBERON:0001416	99.39	gold quality
minor salivary gland	UBERON:0001830	99.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.37	gold quality
right atrium auricular region	UBERON:0006631	99.37	gold quality
right uterine tube	UBERON:0001302	99.36	gold quality
peripheral nervous system	UBERON:0000010	99.35	gold quality
nerve	UBERON:0001021	99.35	gold quality
right lobe of liver	UBERON:0001114	99.35	gold quality
tibial nerve	UBERON:0001323	99.35	gold quality
left coronary artery	UBERON:0001626	99.34	gold quality
upper lobe of lung	UBERON:0008948	99.34	gold quality
monocyte	CL:0000576	99.32	gold quality
body of stomach	UBERON:0001161	99.30	gold quality
transverse colon	UBERON:0001157	99.29	gold quality
adrenal gland	UBERON:0002369	99.20	gold quality
right lobe of thyroid gland	UBERON:0001119	99.19	gold quality
aorta	UBERON:0000947	99.18	gold quality
body of pancreas	UBERON:0001150	99.17	gold quality
endocervix	UBERON:0000458	99.16	gold quality
omental fat pad	UBERON:0010414	99.16	gold quality
peritoneum	UBERON:0002358	99.13	gold quality
ectocervix	UBERON:0012249	99.13	gold quality
left lobe of thyroid gland	UBERON:0001120	99.11	gold quality
coronary artery	UBERON:0001621	99.10	gold quality
adenohypophysis	UBERON:0002196	99.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.05	gold quality
lower esophagus mucosa	UBERON:0035834	99.04	gold quality
popliteal artery	UBERON:0002250	99.03	gold quality
tibial artery	UBERON:0007610	99.03	gold quality
mucosa of stomach	UBERON:0001199	98.97	gold quality
right frontal lobe	UBERON:0002810	98.96	gold quality
spleen	UBERON:0002106	98.95	gold quality
leukocyte	CL:0000738	98.89	gold quality
gastrocnemius	UBERON:0001388	98.85	gold quality
mononuclear cell	CL:0000842	98.84	gold quality
left uterine tube	UBERON:0001303	98.81	gold quality
cardiac atrium	UBERON:0002081	98.80	gold quality
heart left ventricle	UBERON:0002084	98.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.79	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.74	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.66	gold quality
body of uterus	UBERON:0009853	98.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.61	gold quality
cardiac ventricle	UBERON:0002082	98.58	gold quality
esophagus mucosa	UBERON:0002469	98.54	gold quality
right ovary	UBERON:0002118	98.48	gold quality
lower esophagus	UBERON:0013473	98.47	gold quality
esophagus	UBERON:0001043	98.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.46	gold quality
right testis	UBERON:0004534	98.37	gold quality
small intestine	UBERON:0002108	98.34	gold quality
left ovary	UBERON:0002119	98.31	gold quality
left testis	UBERON:0004533	98.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.24	gold quality
thyroid gland	UBERON:0002046	98.23	gold quality
spinal cord	UBERON:0002240	98.22	gold quality
pituitary gland	UBERON:0000007	98.18	gold quality
stomach	UBERON:0000945	98.18	gold quality
muscle of leg	UBERON:0001383	98.07	gold quality
lymph node	UBERON:0000029	98.05	gold quality
adult mammalian kidney	UBERON:0000082	98.05	gold quality
prefrontal cortex	UBERON:0000451	98.05	gold quality
nucleus accumbens	UBERON:0001882	97.98	gold quality
heart	UBERON:0000948	97.96	gold quality
rectum	UBERON:0001052	97.96	gold quality
amygdala	UBERON:0001876	97.96	gold quality
mouth mucosa	UBERON:0003729	97.88	gold quality
cerebellar hemisphere	UBERON:0002245	97.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.79	gold quality
cerebellar cortex	UBERON:0002129	97.74	gold quality
cingulate cortex	UBERON:0003027	97.61	gold quality
anterior cingulate cortex	UBERON:0009835	97.48	gold quality
colon	UBERON:0001155	97.43	gold quality
pancreas	UBERON:0001264	97.42	gold quality
nasal cavity epithelium	UBERON:0005384	97.42	gold quality
caudate nucleus	UBERON:0001873	97.39	gold quality
putamen	UBERON:0001874	97.38	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.35	gold quality
saliva-secreting gland	UBERON:0001044	97.25	gold quality
islet of Langerhans	UBERON:0000006	97.24	gold quality
vagina	UBERON:0000996	97.24	gold quality

Single-cell (SCXA)

Detected in 43 experiment(s), a significant marker in 37.

Experiment	Marker?	Max mean expression
E-MTAB-7381	yes	8833.99
E-MTAB-10885	yes	8423.21
E-MTAB-6678	yes	6942.21
E-HCAD-15	yes	6167.16
E-MTAB-9435	yes	6119.97
E-MTAB-5061	yes	6035.53
E-MTAB-9841	yes	5738.78
E-CURD-122	yes	4548.18
E-MTAB-6701	yes	4384.07
E-CURD-126	yes	4293.73
E-MTAB-6653	yes	3457.55
E-HCAD-1	yes	3034.73
E-MTAB-7407	yes	2242.40
E-GEOD-149689	yes	2118.19
E-MTAB-7606	yes	639.79

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	1410.0
Lung	tissue	509.0	high
Bone marrow	tissue	471.2	low
Caudate putamen	tissue	466.5
Frontal cortex	tissue	440.0
Gallbladder	tissue	411.7	high
Adrenal gland	tissue	411.3	low
Locus coeruleus	tissue	409.2
Salivary gland	tissue	397.8	low
Small intestine	tissue	375.2	high
Duodenum	tissue	364.9	high
Liver	tissue	349.2	high
Spleen	tissue	341.9	medium
Spinal cord	tissue	307.9
Vagina	tissue	299.2	not detected
Hippocampus	tissue	280.1	high
Pancreas	tissue	268.6	medium
Heart muscle	tissue	267.4	low
Stomach 1	tissue	266.9	medium
Colon	tissue	262.7	medium
Urinary bladder	tissue	260.1	medium
Cervix	tissue	254.4	low
Kidney	tissue	246.1	high
Nucleus accumbens	tissue	243.6
Substantia nigra	tissue	237.9
Adipose tissue	tissue	228.0	medium
Medulla oblongata	tissue	227.4
Lymph node	tissue	225.8	low
Seminal vesicle	tissue	218.9	medium
Corpus callosum	tissue	212.4
Thalamus	tissue	208.2
Skeletal muscle	tissue	207.1	not detected
Pons	tissue	205.5
Superior colliculi	tissue	200.2
Midbrain	tissue	199.1
Skin 1	tissue	194.9	low
Postcentral gyrus	tissue	193.5
Appendix	tissue	193.4	high
Esophagus	tissue	191.2	not detected
Hypothalamus	tissue	170.8
Placenta	tissue	169.9	medium
Tongue	tissue	166.3
Periaqueductal gray	tissue	154.6
Thyroid gland	tissue	151.9	medium
Fallopian tube	tissue	151.7	high
Putamen	tissue	148.9
Cerebral cortex	tissue	147.2	high
Somatosensory cortex	tissue	147.2
Hippocampal formation	tissue	146.8
Rectum	tissue	144.1	medium
Motor cortex	tissue	137.5
Septum	tissue	137.3
Ventral forebrain	tissue	135.1
Occipital cortex	tissue	130.0
Parathyroid gland	tissue	129.0	medium
Prefrontal cortex	tissue	128.0
Entorhinal cortex	tissue	121.2
Pituitary gland	tissue	121.0
Retrosplenial cortex	tissue	119.7
Retrosplenial and cingulate cortex	tissue	119.5

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Lateral funiculus (white matter) (762.1), Anterior thalamic nucleus, ventral (721.5), Blood vessel (577.4), Dorsal funiculus (white matter) (560.8), Anterior funiculus (white matter) (529.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, ARNT, BRCA1, ESR1, ESR2, F2RL1, FOS, HIF1A, KLF5, MYB, MYCN, NFATC3, NFATC4, SP1, TP53, USF1, USF2

miRNA regulators (miRDB)

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

29 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-5196-3P	97.57	65.98	979
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6724-5P	96.41	63.11	507
HSA-MIR-4632-3P	96.26	58.52	123
HSA-MIR-4767	86.06	61.02	43
HSA-MIR-1538	85.86	60.08	75
HSA-MIR-4745-3P	83.50	60.58	126

Functional genomics

gnomAD constraint: pLI 1.48e-06, LOEUF 0.886, missense Z 1.24 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000236671 — one region, missense o/e 0.87.

Literature-anchored findings (GeneRIF, showing 40)

• Evaluation of Cath-D can act as a predictor of distant metastasis of salivary adenoid cystic carcinoma (SACC) and direct the clinical treatment. (PMID:11780226)
• polymorphism unrelated to Alzheimer disease in a Spanish population. (PMID:11840502)
• Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions. (PMID:11906282)
• expression of cathepsin D in cholesteatoma (PMID:12011767)
• procathepsin D interacts with prosaposin in human breast and ovarian cancer cells. (procathepsin D) (PMID:12083803)
• Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells. (PMID:12140763)
• Cathepsin D polymorphism in Italian sporadic and familial Alzheimer’s disease. patients and controls. our data do not support a role for the catD gene as a genetic risk factor in the development of AD. (PMID:12147324)
• Cerebrospinal fluid levels of beta-amyloid(42) in patients with Alzheimer’s disease are related to the exon 2 polymorphism of the cathepsin D gene. (PMID:12151789)
• cathepsin-D stimulates tumor growth by acting as a mitogenic factor on cancer and endothelial cells independently of its catalytic activity. Our results give the first evidence on the role of cathepsin-D at tumor progression steps, affecting angiogenesis (PMID:12185597)
• QTL associated with general intelligence is located within exon 2 of the cathepsin D (CTSD) gene. (PMID:12556904)
• Expressed in breast cancer and specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC protein that are also expressed in breast cancer. (PMID:12651610)
• Cat D triggers Bax activation, Bax induces the selective release of mitochondrial AIF, and the latter is responsible for the early apoptotic phenotype in T-cells (PMID:12782632)
• COX-2 exerts a negative feedback on the expression of cathepsin D to reduce the generation of the antiangiogenic factor angiostatin, hence promoting a proangiogenic environment. (PMID:12970159)
• cathepsin D has a role in promoting cancer cell proliferation and invasion (PMID:14767531)
• intracellular accumulation of poorly degradable, oxidized lipid-protein cross-links, may alter the turnover of cathepsin D, causing its mistargeting into the extracellular space (PMID:15158911)
• Review. Cathepsin D seems to facilitate early phases of tumor progression such as cell proliferation and local dissemination. (PMID:15168727)
• Cleaves prolactin whose fragments are potentially physiological antiangiogenic inhibitors of tumor growth. (PMID:15192082)
• defective acidification results in the aberrant secretion of proCD in certain cancer cells and interferes mainly with the normal disassembly of the receptor-enzyme complexes and efficient receptor reutilization in the Golgi (PMID:15258139)
• The inhibition of cathepsin D activity by pepstatin A decreased the number of apoptotic cells in catL-deficient A549 cells after anti-Fas treatment. (PMID:15318816)
• cathepsin D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity. (PMID:15668295)
• Plasma cathepsin D isoforms and their active metabolites increase after myocardial infarction and contribute to plasma renin activity. (PMID:15739123)
• Our results showed that lowering cathepsin D activity in antisense cell conditioned media abolished their inhibitory effect on osteoblast cell calcification. (PMID:15896324)
• review of cath-D action in cancer progression and metastasis, as well as its dual function in apoptosis [review] (PMID:16046058)
• The minimal lysosomal enzyme recognition domain has been identified in CPSD. (PMID:16081416)
• CTSD*T allele frequency showed a statistically significant increasing trend from Northern to Southern regions of Europe in AD patients and controls (PMID:16127101)
• CatD induces apoptosis via degradation of Trx protein, which is an essential anti-apoptotic and reactive oxygen species scavenging protein in endothelial cells (PMID:16263712)
• results imply that cytosolic cath-D stimulates apoptotic pathways by interacting with a member of the apoptotic machinery rather than by cleaving specific substrate(s) (PMID:16331270)
• Functional analysis indicated that proteolytic processing of DCD-1L by Cathepsin D in human sweat modulates the innate immune defense of human skin. (PMID:16354654)
• Possession of the CTSD T allele has a modulating effect on the pathogenesis of Alzheimer disease by increasing the amount of Abeta deposited as senile plaques in the brain. (PMID:16543533)
• A model is proposed in which cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas. (PMID:16709808)
• Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk. (PMID:16784755)
• Glucosamine sulfate-induced K562 cell apoptosis involves the translocation of cathepsin D from the lysosome to the cytosol. (PMID:16850161)
• Cathepsin D regulates intracellular transport of phospholipid and cholesterol and ABCA1-mediated lipid efflux. (PMID:17032648)
• The influence of aluminum (Al) on the Abeta peptide degradation by cathepsin D, was demonstrated. (PMID:17112520)
• Functional mapping of the N-terminal sequence of procathepsin D is reported; peptides derived from this sequence were used to localize and characterize the structural determinants involved in activity regulation of the enzyme’s catalytic core. (PMID:17176069)
• mutagenized the region of aminoacids (comprising the beta-hairpin loop) involved in the latter proteolytic maturation step and generated a mutant CD that cannot be converted into the mature double-chain form (PMID:17188016)
• cathepsin D was a typical secretory protein that exhibited the increased abundance inM-BE, a SV40T-transformed human bronchial epithelial cell line with the phenotypic features of early tumorigenesis at high passage (PMID:17284061)
• Myocardial STAT3 protein levels are reduced and serum levels of activated cathepsin D and 16 kDa prolactin are elevated in postpartum cardiomyopathy patients. (PMID:17289576)
• Results confirm that the proapoptotic effect of cathepsin D in the cytosol is independent of its catalytic activity and suggest that the interaction of cathepsin D with the downstream effector does not involve the active site of the enzyme. (PMID:17340625)
• Lysosome is the primary target and the axis cathepsin D-Bax as the effective pathway of hydrogen peroxide lethal activity in neuroblastoma cells. (PMID:17395004)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsd	ENSDARG00000057698
mus_musculus	Ctsd	ENSMUSG00000007891
rattus_norvegicus	Ctsd	ENSRNOG00000020206
drosophila_melanogaster	cathD	FBGN0029093
caenorhabditis_elegans		WBGENE00000217

Paralogs (9): PGC (ENSG00000096088), NAPSA (ENSG00000131400), REN (ENSG00000143839), BACE2 (ENSG00000182240), BACE1 (ENSG00000186318), CTSE (ENSG00000196188), PGA4 (ENSG00000229183), PGA3 (ENSG00000229859), PGA5 (ENSG00000256713)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88562) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 47 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	4
abnormal intestinal mucosa morphology	3
premature death	3
seizures	2
neuron degeneration	2
thymus atrophy	2
decreased double-positive T cell number	2
preweaning lethality, incomplete penetrance	2
abnormal microglial cell morphology	1
decreased hematocrit	1
abnormal hair cycle	1
abnormal crypts of Lieberkuhn morphology	1
abnormal thymus morphology	1
weakness	1
hippocampal neuron degeneration	1
weight loss	1
cornea opacity	1
abnormal retina morphology	1
ataxia	1
thymus hypoplasia	1
abnormal antigen presentation	1
deafness	1
blindness	1
gliosis	1
abnormal spleen white pulp morphology	1

+22 more (showing top 25).

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
Plasmodium falciparum HB3	P39898	100.0%	Diamond
Pan troglodytes	P60016	100.0%	Diamond
Plasmodium falciparum 3D7	Q7KQM4	100.0%	Diamond
Macaca fascicularis	Q6DLS0	99.8%	Diamond
Macaca mulatta	Q6DLW5	99.8%	Diamond
Candida albicans	P0CS83	99.7%	Diamond
Candida albicans SC5314	P0DJ06	99.7%	Diamond
Oryctolagus cuniculus	P27821	99.5%	Diamond
Aspergillus phoenicis	Q12567	99.5%	Diamond
Macaca fuscata fuscata	P03954	99.0%	Diamond
Trichophyton benhamiae CBS 112371	D4B385	98.3%	Diamond
Trichophyton verrucosum HKI 0517	D4DEN7	98.3%	Diamond
Cynara cardunculus	P85138	97.0%	Diamond
Echis ocellatus	Q18DC8	95.2%	Diamond
Bos taurus	P00794	94.5%	Diamond
Ovis aries	P18276	94.5%	Diamond
Callithrix jacchus	Q9TSZ1	94.1%	Diamond
Xenopus laevis	Q805F2	94.0%	Diamond
Sus scrofa	P00795	89.8%	Diamond
Canis lupus familiaris	Q4LAL9	89.8%	Diamond
Rhinolophus ferrumequinum	Q9GMY3	89.7%	Diamond
Microsporum canis CBS 113480	C5FS55	89.5%	Diamond
Suncus murinus	P81498	89.5%	Diamond
Sorex unguiculatus	Q9GMY4	89.5%	Diamond
Rhizopus niveus	P43232	86.2%	Diamond
Hordeum vulgare	P42210	85.5%	Diamond
Oryza sativa Japonica Group	Q42456	85.5%	Diamond
Camelus dromedarius	Q9GK11	84.0%	Diamond
Cavia porcellus	P25796	83.8%	Diamond
Arabidopsis thaliana	O65390	80.5%	Diamond
Chionodraco hamatus	O93428	80.0%	Diamond
Clupea harengus	Q9DEX3	80.0%	Diamond
Penicillium rubens Wisconsin 54-1255	B6HL60	78.1%	Diamond
Penicillium roqueforti	Q01972	78.1%	Diamond
Thunnus orientalis	P20140	77.4%	Diamond
Monodelphis domestica	Q689Z7	76.2%	Diamond
Cucurbita pepo	O04057	75.5%	Diamond
Rhizopus microsporus var. chinensis	P06026	74.2%	Diamond
Aquarana catesbeiana	Q800A0	72.2%	Diamond
Aspergillus fumigatus Af293	O42630	71.8%	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
PRADX	ncRNA	126568849
SYT8	protein-coding	90019
IFITM10	protein-coding	402778
LINC02708	ncRNA	100505570
KRTAP5-6	protein-coding	440023
TNNI2	protein-coding	7136
FAM99B	ncRNA	100132464

Protein

Protein identifiers

Cathepsin D — P07339 (reviewed: P07339)

All UniProt accessions (11): A0A1B0GV23, A0A1B0GVD5, A0A1B0GVP3, A0A1B0GW44, A0A1B0GWE8, A0A7I2V2N3, C9JH19, F8W787, F8WD96, P07339, V9HWI3

UniProt curated annotations — full annotation on UniProt →

Function. Acid protease active in intracellular protein breakdown. Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.

Subunit / interactions. Consists of a light chain and a heavy chain. Interacts with ADAM30; this leads to activation of CTSD. Interacts with GRN; stabilizes CTSD; increases its proteolytic activity.

Subcellular location. Lysosome. Melanosome. Secreted. Extracellular space.

Tissue specificity. Expressed in the aorta extracellular space (at protein level). Expressed in liver (at protein level).

Post-translational modifications. N- and O-glycosylated. Undergoes proteolytic cleavage and activation by ADAM30. As well as the major heavy chain which starts at Leu-169, 2 minor forms starting at Gly-170 and Gly-171 have been identified. An additional form starting at Ala-168 has also been identified.

Disease relevance. Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127] A form of neuronal ceroid lipofuscinosis with onset at birth or early childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The Val-58 allele is significantly overrepresented in demented patients (11.8%) compared with non-demented controls (4.9%). Carriers of the Val-58 allele have a 3.1-fold increased risk for developing AD than non-carriers.

Similarity. Belongs to the peptidase A1 family.

RefSeq proteins (1): NP_001900* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001461	Aspartic_peptidase_A1	Family
IPR001969	Aspartic_peptidase_AS	Active_site
IPR012848	Aspartic_peptidase_N	Domain
IPR021109	Peptidase_aspartic_dom_sf	Homologous_superfamily
IPR033121	PEPTIDASE_A1	Domain
IPR033144	Cathepsin_D	Family

Pfam: PF00026, PF07966

Enzyme classification (BRENDA)

• EC 3.4.23.5 — cathepsin D (BRENDA: 48 organisms, 328 substrates, 462 inhibitors, 97 Km, 111 kcat entries)

Substrate kinetics (BRENDA)

80 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
LYS-PRO-ILE-GLU-PHE-(4-NITRO)PHE-ARG-LEU	0.036–0.07	6
HEMOGLOBIN	0.0064–1.5	5
PRO-PRO-THR-ILE-PHE-(4-NITRO)PHE-ARG-LEU	0.015–0.04	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-GLY-SER-PRO-ALA-P	0.0022–0.0027	2
2-AMINOBENZOYL-AIKFFSAQ-N-(2,4-DINITROPHENYL)ETH	0.0005	2
2-AMINOBENZOYL-KITLLSAQ-(N-(2,4-DINITROPHENYL)ET	0.0005–0.0009	2
EEISEVNLDAEFRG	0.62–1.1	2
SEVNLDAEFR	1.45–1.67	2
(7-METHOXYCOUMARIN-4-YL)ACETYL-GLY-LYS-PRO-ILE-I	0.0037	1
(7-METHOXYCOUMARIN-4-YL)ACETYL-GLY-SER-SER-ALA-P	0.0021	1
2-AMINOBENZOYL-AAKFFSRQ-N-(2,4-DINITROPHENYL)ETH	0.0004	1
2-AMINOBENZOYL-AEKFFSRQ-N-(2,4-DINITROPHENYL)ETH	0.0003	1
2-AMINOBENZOYL-AIAFFSRQ-N-(2,4-DINITROPHENYL)ETH	0.0003	1
2-AMINOBENZOYL-AIEFFSRQ-N-(2,4-DINITROPHENYL)ETH	0.0002	1
2-AMINOBENZOYL-AIFFFSRQ-N-(2,4-DINITROPHENYL)ETH	0.0001	1

UniProt features (66 total): strand 28, helix 13, turn 6, disulfide bond 4, sequence variant 4, glycosylation site 3, chain 3, active site 2, signal peptide 1, propeptide 1, domain 1

Structure

Experimental structures (PDB)

9 structures by resolution:

PDB	Title	Method	Resolution (Å)
6QCB	Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 9	X-RAY DIFFRACTION	1.55
6QBG	Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 14	X-RAY DIFFRACTION	1.8
6QBH	Crystal structure of human cathepsin D in complex with macrocyclic inhibitor 33	X-RAY DIFFRACTION	1.85
4OD9	Structure of Cathepsin D with inhibitor …	X-RAY DIFFRACTION	1.9
1LYA	CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR …	X-RAY DIFFRACTION	2.5
1LYB	CRYSTAL STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN D: IMPLICATIONS FOR …	X-RAY DIFFRACTION	2.5
1LYW	CATHEPSIN D AT PH 7.5	X-RAY DIFFRACTION	2.5
4OC6	Structure of Cathepsin D with inhibitor …	X-RAY DIFFRACTION	2.64
4OBZ	Structure of Cathepsin D with inhibitor …	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07339-F1	85.69	0.63

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Aspartic-type peptidases, Metabolic proteins, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of lipid/glycolipid metabolism

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH supported

Functional residue map

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

Catalytic / active sites (2)

Position	Role
97
295

Disulfide bonds (4)

Type	Positions
Disulfide bond	91–160, 110–117, 286–290, 329–366

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) asparagine	263, 134
O-linked (galnac…) threonine	63

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 19; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-1442490	Collagen degradation	curated
R-HSA-9018519	Estrogen-dependent gene expression	curated
R-HSA-77387	Insulin receptor recycling	curated
R-HSA-2132295	MHC class II antigen presentation	curated
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-9979719	Processing of antigen in germinal center B cells	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-1474228	Degradation of the extracellular matrix	—
R-HSA-8939211	ESR-mediated signaling	—
R-HSA-1474244	Extracellular matrix organization	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-2980736	Peptide hormone metabolism	—
R-HSA-162582	Signal Transduction	—
R-HSA-74752	Signaling by Insulin receptor	—
R-HSA-9006931	Signaling by Nuclear Receptors	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—

MSigDB gene sets: 447 (showing top): MODULE_172, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, REACTOME_INNATE_IMMUNE_SYSTEM, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, GOBP_VACUOLE_ORGANIZATION, LU_IL4_SIGNALING, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, ENK_UV_RESPONSE_KERATINOCYTE_UP, BECKER_TAMOXIFEN_RESISTANCE_UP, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN

GO Biological Process (8): proteolysis (GO:0006508), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), insulin receptor recycling (GO:0038020), lipoprotein catabolic process (GO:0042159), positive regulation of apoptotic process (GO:0043065), regulation of establishment of protein localization (GO:0070201), execution phase of apoptosis (GO:0097194), insulin catabolic process (GO:1901143)

GO Molecular Function (7): aspartic-type endopeptidase activity (GO:0004190), cysteine-type endopeptidase activity (GO:0004197), peptidase activity (GO:0008233), aspartic-type peptidase activity (GO:0070001), endopeptidase activity (GO:0004175), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (15): extracellular region (GO:0005576), lysosome (GO:0005764), lysosomal membrane (GO:0005765), cytosol (GO:0005829), endosome membrane (GO:0010008), extracellular matrix (GO:0031012), endosome lumen (GO:0031904), specific granule lumen (GO:0035580), melanosome (GO:0042470), lysosomal lumen (GO:0043202), membrane raft (GO:0045121), extracellular exosome (GO:0070062), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), cytoplasm (GO:0005737)

Reactome top-level categories

13 top-level categories:

Category	Pathways
Immune System	2
Signal Transduction	2
Degradation of the extracellular matrix	1
Peptide hormone metabolism	1
Adaptive Immune System	1
Innate Immune System	1
Signaling by Insulin receptor	1
ESR-mediated signaling	1
Affinity selection of immunoglobulins	1
Extracellular matrix organization	1
Metabolism of proteins	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by Nuclear Receptors	1

GO top-level categories

42 GO namespaces:

Category	Terms
cellular anatomical structure	3
intracellular organelle lumen	3
protein catabolic process	2
apoptotic process	2
endopeptidase activity	2
peptidase activity	2
lysosome	2
endosome	2
protein metabolic process	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
receptor recycling	1
positive regulation of insulin receptor signaling pathway	1
lipoprotein metabolic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of protein localization	1
establishment of protein localization	1
cellular process	1
bleb assembly	1
insulin metabolic process	1
aspartic-type peptidase activity	1
cysteine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
lytic vacuole	1
lytic vacuole membrane	1
cytoplasm	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
external encapsulating structure	1
secretory granule lumen	1
specific granule	1
pigment granule	1
vacuolar lumen	1
membrane microdomain	1
extracellular vesicle	1
tertiary granule	1
ficolin-1-rich granule	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
execution phase of apoptosis	BP	direct assay
lipoprotein catabolic process	BP	direct assay
positive regulation of apoptotic process	BP	direct assay
proteolysis	BP	direct assay
regulation of establishment of protein localization	BP	direct assay
cytosol	CC	direct assay
endosome membrane	CC	direct assay
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
extracellular region	CC	high-throughput assay
lysosomal membrane	CC	direct assay
lysosome	CC	direct assay
membrane raft	CC	direct assay
peptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,522 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSD	CTSB	P07858	919
CTSD	CTSS	P25774	869
CTSD	PPT1	P50897	816
CTSD	CLN3	Q13286	795
CTSD	LAMP1	P11279	790
CTSD	CTSL	P07711	789
CTSD	CLN5	O75503	779
CTSD	MFSD8	Q8NHS3	760
CTSD	CLN6	Q9NWW5	749
CTSD	CLN8	Q9UBY8	747
CTSD	LAMP2	P13473	729
CTSD	TFEB	P19484	712
CTSD	CTSH	P09668	695
CTSD	CTSF	Q9UBX1	692
CTSD	PAQR8	Q8TEZ7	691

IntAct

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

showing 30 of 31 partners by confidence:

Partner	Interaction type	MIscore	Records
ZNF497	physical association	0.610	4
DLGAP2	physical association	0.560	3
EPN3	physical association	0.560	3
EPS8L2	physical association	0.560	3
GPR141	physical association	0.560	3
H3C1	physical association	0.560	3
IRAG1	physical association	0.560	3
KIF1A	physical association	0.560	3
LCE2A	physical association	0.560	3
MOGAT3	physical association	0.560	3
NPFF	physical association	0.560	3
PGLYRP3	physical association	0.560	3
SPRY4	physical association	0.560	3
SUMF2	physical association	0.560	3
SYT3	physical association	0.560	3
TEAD1	physical association	0.560	3
VDAC2	physical association	0.560	3
WTAP	physical association	0.560	3
WWP2	physical association	0.560	3
ZDHHC20	physical association	0.560	3
NAPSA	association	0.530	3
ADAM30	proximity	0.510	2
APP	cleavage reaction	0.440	2
HBA1	cleavage reaction	0.440	1
GRN	physical association	0.400	18
E6	physical association	0.370	3
NLGN3	physical association	0.370	2
HSPB2	physical association	0.370	1
ATP6V0A1	colocalization	0.270	1
MARCHF9	colocalization	0.270	1

BioGRID (200 interactions; top human partners by supporting records): NAPSA (Affinity Capture-MS; 3 records), TMEM192 (Affinity Capture-Western; 3 records), FBXO6 (Affinity Capture-MS; 2 records), GRHPR (Co-fractionation; 2 records), HUWE1 (Affinity Capture-MS; 2 records), LDHB (Co-fractionation; 2 records), MYC (Affinity Capture-MS; 2 records), PCBP1 (Co-fractionation; 2 records), PPT1 (Affinity Capture-MS; 2 records), SUCLG2 (Co-fractionation; 2 records), TMPRSS2 (Affinity Capture-MS; 2 records), UCHL5 (Reconstituted Complex; 2 records), ACADM (Co-fractionation), ACTA2 (Affinity Capture-MS), AGR2 (Proximity Label-MS)

SIGNOR signaling

showing 12 of 31 signaling interactions:

A	Effect	B	Mechanism
BRCA1	“down-regulates quantity by repression”	CTSD	“transcriptional regulation”
MYCN	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
F2RL1	“down-regulates quantity by repression”	CTSD	“transcriptional regulation”
TP53	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
USF2	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
USF1	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
CTSD	“down-regulates quantity by destabilization”	BGLAP	cleavage
CTSD	“down-regulates quantity by destabilization”	APP	cleavage
CTSD	“up-regulates activity”	APP	cleavage
TFEB	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
TFE3	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for CTSD: 776 ClinVar records (52 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	19
Uncertain significance	263
Likely benign	369
Benign	24

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 52 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
430138	NM_001909.5(CTSD):c.268dup (p.Gln90fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
1322174	NM_001909.5(CTSD):c.17_30dup (p.Leu11fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1489005	NM_001909.5(CTSD):c.228+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1441635	NM_001909.5(CTSD):c.908del (p.Gly303fs)	Pathogenic	criteria provided, single submitter	1
1452955	NM_001909.5(CTSD):c.949del (p.Ala317fs)	Pathogenic	criteria provided, single submitter	1
1987149	NM_001909.5(CTSD):c.1052dup (p.Glu352fs)	Pathogenic	criteria provided, single submitter	1
1999365	NM_001909.5(CTSD):c.914_947del (p.Val305fs)	Pathogenic	criteria provided, single submitter	1
2000275	NM_001909.5(CTSD):c.169C>T (p.Gln57Ter)	Pathogenic	criteria provided, single submitter	1
2010906	NM_001909.5(CTSD):c.658C>T (p.Gln220Ter)	Pathogenic	criteria provided, single submitter	1
2021035	NM_001909.5(CTSD):c.627_628del (p.Asn209fs)	Pathogenic	criteria provided, single submitter	1
2096023	NM_001909.5(CTSD):c.832G>T (p.Glu278Ter)	Pathogenic	criteria provided, single submitter	1
2103629	NM_001909.5(CTSD):c.550A>T (p.Lys184Ter)	Pathogenic	criteria provided, single submitter	1
2117602	NM_001909.5(CTSD):c.756dup (p.Lys253fs)	Pathogenic	criteria provided, single submitter	1
2135026	NM_001909.5(CTSD):c.984_985del (p.Pro328_Cys329insTer)	Pathogenic	criteria provided, single submitter	1
2160697	NM_001909.5(CTSD):c.468_469del (p.Ser157fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CTSD’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; 28 predictions of 668):

Position(s)	Effect	Δscore	Sites
11:1753801–1753802	donor_loss	1.0000	5
11:1753899	acceptor_gain	1.0000
11:1753903	acceptor_loss	1.0000	3
11:1753993	donor_loss	1.0000
11:1754905	donor_loss	1.0000	3
11:1755029	acceptor_gain	1.0000
11:1755029–1755030	acceptor_loss	1.0000	4
11:1757322–1757323	donor_loss	1.0000	5
11:1758967–1758968	donor_loss	1.0000	4
11:1759094	acceptor_gain	1.0000

AlphaMissense

1,210 missense substitutions predicted likely pathogenic (of 2,668 scored), across 270 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
D97	8	0.999	1.000
D295	8	0.999	1.000
D154	8	0.986	0.999
D387	8	0.986	0.996
F190	8	0.981	0.999
F195	8	0.981	1.000
D196	8	0.981	0.997
D76	8	0.976	0.996
H120	8	0.976	0.998
F179	8	0.975	0.997
F96	8	0.971	0.996
F92	8	0.970	0.997
F397	8	0.969	0.999
F389	8	0.967	0.995
F229	8	0.961	0.996
F138	8	0.956	0.994
F215	8	0.949	0.992
D216	8	0.940	0.978
D398	8	0.935	0.983
F370	8	0.930	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.15e-09
Rectum Adenocarcinoma (TCGA)	unfavorable	9.56e-05
Glioblastoma Multiforme (TCGA)	unfavorable	0.000503

Disease associations

OMIM: gene MIM:116840 | disease phenotypes: MIM:610127, MIM:256730, MIM:607131

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
neuronal ceroid lipofuscinosis	Definitive	Autosomal recessive
neuronal ceroid lipofuscinosis 10	Definitive	Autosomal recessive	3

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (14 panels, 13 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

14 panels:

Panel	Rating
DDG2P	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Lysosomal storage disorder	green
Neuronal ceroid lipofuscinosis	green
Paediatric disorders	green
Retinal disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Dystonia, chorea or related movement disorder, childhood onset	amber

Mondo (4): neuronal ceroid lipofuscinosis 10 (MONDO:0012414), neuronal ceroid lipofuscinosis (MONDO:0016295), multiple epiphyseal dysplasia, Al-Gazali type (MONDO:0011778), retinal disorder (MONDO:0005283)

Orphanet (4): CLN10 disease (Orphanet:228337), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome (Orphanet:166024)

HPO phenotypes

31 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000510	Rod-cone dystrophy
HP:0000572	Visual loss
HP:0001105	Retinal atrophy
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0002059	Cerebral atrophy
HP:0002063	Rigidity
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002093	Respiratory insufficiency
HP:0002104	Apnea
HP:0002133	Status epilepticus
HP:0002529	Neuronal loss in central nervous system
HP:0002878	Respiratory failure
HP:0003390	Sensory axonal neuropathy
HP:0003577	Congenital onset
HP:0003657	Vascular granular osmiophilic material deposition
HP:0003811	Neonatal death
HP:0005458	Premature closure of fontanelles
HP:0010864	Severe intellectual disability
HP:0011463	Childhood onset
HP:0032794	Myoclonic seizure

GWAS associations

4 associations:

Study	Trait	p-value
GCST009731_11	Blood protein levels in cardiovascular risk	1e-41
GCST006585_1743	Blood protein levels	8e-26
GCST90011899_35	Aspartate aminotransferase levels	9e-13
GCST007000_5	Logical memory (delayed recall) in mild cognitive impairment	2e-7

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0010611	cathepsin D measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D012164	Retinal Diseases	C11.768
C566438	Ceroid Lipofuscinosis, Neuronal, 10 *(supp.)*
C564621	Macrocephaly with Multiple Epiphyseal Dysplasia and Distinctive Facies *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2581 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 107,448 (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
CHEMBL116	AMPRENAVIR	4	29,469
CHEMBL222559	TIPRANAVIR	4	17,728
CHEMBL371064	BALICATIB	2	99
CHEMBL1232461	MOLIBRESIB	2	1,601
CHEMBL296588	PEPSTATIN	2	26,189
CHEMBL43185	PIPERINE	2	11,142
CHEMBL169	URSOLIC ACID	2	21,155
CHEMBL2333941	LY-2811376	1	65

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — A1: Pepsin

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
compound 1 [PMID: 10498202]	Inhibition	9.2	pIC50
compound 33 [PMID: 32003991]	Inhibition	8.6	pIC50
compound 3 [PMID: 8410973]	Inhibition	7.74	pKi
grassystatin A	Inhibition	7.58	pIC50
grassystatin G	Inhibition	7.18	pIC50
β-secretase inhibitor IV	Inhibition	6.35	pKi

Binding affinities (BindingDB)

4051 measured of 4321 human assays (4362 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide	IC50	0.0002 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide	IC50	0.0009 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.0009 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
(4aR,6R,8aS)-8a-[2,4-difluoro-5-[(2,2,2-trifluoroethylamino)methyl]phenyl]-6-(fluoromethyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine	IC50	0.006 nM	US-9045498: Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
N-[3-[(3R)-5-amino-3-methyl-1,1-dioxo-2,6-dihydro-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.0061 nM	US-9273042: 5-amino[1,4]thiazines as BACE 1 inhibitors
N-[2-[(4aR,6S,8aR)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-1,3-thiazol-4-yl]-5-methoxypyridine-2-carboxamide	IC50	0.014 nM	US-9315520: 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
CHEMBL4088234	IC50	0.024 nM
CHEMBL4212046	IC50	0.033 nM
CHEMBL4217023	IC50	0.034 nM
(1S,5S,6S)-3-amino-N-cyclopropyl-5-[2-fluoro-5-[[5-[(2S)-1-methoxypropan-2-yl]oxypyrazine-2-carbonyl]amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.059 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.07 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(2H-triazol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.09 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-(2,2-difluoroethyl)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.09 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
2-[2-(Morpholine-4-sulfonylamino)-3-phenyl-propionylamino]-pent-4-enoic acid (1-cyclohexylmethyl-2,4-dihydroxy-5-methyl-hexyl)-amide	KI	0.1 nM
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide	IC50	0.1 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
CHEMBL4203860	IC50	0.11 nM
(1S,5S,6S)-3-amino-5-[5-[[5-[(2S)-but-3-yn-2-yl]oxypyrazine-2-carbonyl]amino]-2,3-difluorophenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.11 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N2-[(2R,4S,5S)-5-{[N-{[(2,5-dimethyl-1,3-oxazol-4-yl)methoxy]carbonyl}-3-(methylsulfonyl)-L-alanyl]amino}-4-hydroxy-2,7-dimethyloctanoyl]-N-(2-methylpropyl)-L-valinamide	KI	0.12 nM
(1S,5S,6S)-3-amino-5-[2-fluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.14 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide	IC50	0.146 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(4aS,7aR)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine	IC50	0.149 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
(E)-3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylic acid	IC50	0.176 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-1-acetyl-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.178 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(4aR,7aS)-7a-[2-fluoro-5-[(Z)-2-fluoro-2-(5-prop-2-ynoxypyrazin-2-yl)ethenyl]phenyl]-6-pyrimidin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine	IC50	0.186 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
(1S,5S,6S)-3-amino-5-[2,3-difluoro-5-[[5-(2,2,3,3-tetrafluoropropoxy)pyrazine-2-carbonyl]amino]phenyl]-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.194 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-methyl-1-(trideuteriomethoxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.197 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-[2,3-difluoro-5-[(5-prop-2-ynoxypyrazine-2-carbonyl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.199 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1R,5S,6S)-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.2 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.2 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-[5-[(2-but-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]-2,3-difluorophenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.201 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-(1,1-dideuterioprop-2-ynoxy)pyrazine-2-carboxamide	IC50	0.209 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.22 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-1-(difluoromethyl)-5-[2,3-difluoro-5-[(2-prop-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.222 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-5-[5-[(2-but-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]-2-fluorophenyl]-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.236 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
6-[(Z)-2-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-1-fluoroethenyl]pyridine-3-carbonitrile	IC50	0.241 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
(1S,5S,6S)-1-(difluoromethyl)-5-[2-fluoro-5-[(2-prop-2-ynoxypyrido[3,4-b]pyrazin-5-yl)amino]phenyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.244 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.249 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
CHEMBL3352906	KI	0.25 nM
N-[3-[(1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluoro-5-methylphenyl]-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide	IC50	0.256 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.264 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.266 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.266 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide	IC50	0.268 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
[(1S,5S,6R)-3-amino-7,7-difluoro-5-[2-fluoro-5-[[7-(1,3-oxazol-2-ylmethoxy)pyrido[3,2-d]pyrimidin-4-yl]amino]-3-pyridinyl]-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]methanol	IC50	0.274 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1R,5S,6S)-3-amino-5-(fluoromethyl)-1-[(Z)-2-methyl-3-morpholin-4-yl-3-oxoprop-1-enyl]-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.274 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.276 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(2,2,2-trifluoroethoxymethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.28 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[(4aR,7aS)-7a-[5-[(Z)-2-(5-but-2-ynoxypyrazin-2-yl)-2-fluoroethenyl]-2-fluorophenyl]-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide	IC50	0.287 nM	US-11548903: Bicyclic thiazine and oxazine derivatives as beta-secretase inhibitors and methods of use
N-[3-[(1R,5S,6S)-3-amino-5-methyl-1-methylsulfonyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4,5-difluorophenyl]-5-prop-2-ynoxypyrazine-2-carboxamide	IC50	0.29 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use
N-[3-[(1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,2-oxazol-3-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-prop-2-ynoxypyridine-2-carboxamide	IC50	0.293 nM	US-20160046618: Cyclopropyl Fused Thiazin-2-Amine Compounds as Beta-Secretase Inhibitors and Methods of Use

ChEMBL bioactivities

1717 potent at pChembl≥5 of 2369 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	PEPSTATIN
10.96	Ki	0.011	nM	CHEMBL3342183
10.30	IC50	0.05	nM	PEPSTATIN
10.15	Ki	0.07	nM	CHEMBL81927
10.11	IC50	0.0783	nM	CHEMBL2181022
10.00	IC50	0.1	nM	PEPSTATIN
10.00	Ki	0.1	nM	CHEMBL84970
9.90	IC50	0.126	nM	CHEMBL2181024
9.76	IC50	0.173	nM	PEPSTATIN
9.75	IC50	0.178	nM	CHEMBL5192597
9.46	IC50	0.35	nM	PEPSTATIN
9.40	IC50	0.4	nM	CHEMBL5569371
9.40	Ki	0.4	nM	CHEMBL88415
9.31	IC50	0.49	nM	PEPSTATIN
9.30	IC50	0.5	nM	CHEMBL257594
9.26	IC50	0.55	nM	PEPSTATIN
9.22	IC50	0.6	nM	CHEMBL4576166
9.22	Ki	0.6	nM	CHEMBL87025
9.20	IC50	0.63	nM	CHEMBL1076907
9.16	IC50	0.693	nM	PEPSTATIN
9.15	Ki	0.7	nM	CHEMBL191130
9.15	Ki	0.7	nM	CHEMBL81927
9.15	Ki	0.7	nM	CHEMBL323806
9.15	IC50	0.7	nM	CHEMBL81927
9.12	Ki	0.75	nM	CHEMBL1644463
9.10	Ki	0.8	nM	CHEMBL88340
9.08	IC50	0.84	nM	CHEMBL2407339
9.00	IC50	1	nM	CHEMBL2408751
9.00	IC50	1	nM	CHEMBL3939441
9.00	IC50	1	nM	CHEMBL558488
9.00	IC50	1	nM	CHEMBL595066
8.96	IC50	1.1	nM	CHEMBL4558691
8.90	Ki	1.25	nM	CHEMBL3352906
8.89	Ki	1.29	nM	BALICATIB
8.89	Ki	1.3	nM	CHEMBL34323
8.80	Ki	1.6	nM	CHEMBL371417
8.72	Ki	1.9	nM	CHEMBL290115
8.70	IC50	2	nM	CHEMBL2030998
8.70	IC50	2	nM	CHEMBL2407492
8.70	IC50	2	nM	CHEMBL2408752
8.70	IC50	2	nM	CHEMBL5571122
8.70	Ki	2	nM	CHEMBL231522
8.70	IC50	2	nM	PEPSTATIN
8.70	Ki	2	nM	CHEMBL167514
8.64	IC50	2.3	nM	PEPSTATIN
8.60	Ki	2.5	nM	CHEMBL264770
8.60	IC50	2.5	nM	CHEMBL4514021
8.60	Ki	2.5	nM	CHEMBL62380
8.52	IC50	3	nM	CHEMBL2030997
8.52	Ki	3	nM	CHEMBL284440

PubChem BioAssay actives

1487 with measured affinity, of 2694 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
tert-butyl N-[cyano-(2-morpholin-4-yl-2-oxoethyl)amino]carbamate	1168917: Inhibition of human cathepsin K using Z-Leu-Arg-AMC fluorogenic substrate incubated for 60 mins	ki	<0.0001	uM
tert-butyl N-[[2-[benzyl(methyl)amino]-2-oxoethyl]-cyanoamino]carbamate	1168917: Inhibition of human cathepsin K using Z-Leu-Arg-AMC fluorogenic substrate incubated for 60 mins	ki	<0.0001	uM
tert-butyl N-[cyano-[2-(dibenzylamino)-2-oxoethyl]amino]carbamate	1168917: Inhibition of human cathepsin K using Z-Leu-Arg-AMC fluorogenic substrate incubated for 60 mins	ki	<0.0001	uM
(3S,4S)-3-hydroxy-4-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(3-methylbutanoylamino)butanoyl]amino]butanoyl]amino]heptanoyl]amino]propanoyl]amino]-6-methylheptanoic acid	48026: Binding affinity against human cathepsin D	ki	<0.0001	uM
(2S)-N-[(2S,3S,5S)-1-cyclohexyl-3,5-dihydroxy-6-methylheptan-2-yl]-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enamide	48025: Binding affinity against human cathepsin D	ki	0.0001	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-4-[[(2S)-5-amino-2-[methyl-[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxy-5-phenylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	1901890: Inhibition of recombinant human liver Cathepsin D using Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys-(Dnp)-D-Arg-NH2 as substrate incubated for 120 mins by fluorescence assay	ic50	0.0001	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-4-[[(2S)-5-amino-2-[methyl-[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxy-5-phenylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	711207: Inhibition of cathepsin D by fluorescence assay	ic50	0.0001	uM
2-bromo-N-[(2S,3S)-4-[2-(2,4-dichlorophenyl)ethyl-[3-(1,3-dioxoisoindol-2-yl)propanoyl]amino]-3-hydroxy-1-(3-phenoxyphenyl)butan-2-yl]-4,5-dimethoxybenzamide	254279: Binding affinity af the compound towards cathepsin D	ki	0.0001	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-4-[[(2S)-5-amino-2-[methyl-[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxy-5-phenylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]-methylamino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carboxylate	1901890: Inhibition of recombinant human liver Cathepsin D using Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys-(Dnp)-D-Arg-NH2 as substrate incubated for 120 mins by fluorescence assay	ic50	0.0002	uM
(4S)-5-cyclohexyl-2,2-difluoro-N-[(2S)-2-methylbutyl]-4-[[(2S)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enoyl]amino]-3-oxopentanamide	48025: Binding affinity against human cathepsin D	ki	0.0004	uM
(3S,4S)-3-hydroxy-4-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-3-methyl-2-[[(2R)-2-(3-methylbutanoylamino)-4-(trifluoromethylsulfanyl)butanoyl]amino]butanoyl]amino]heptanoyl]amino]propanoyl]amino]-6-methylheptanoic acid	2101464: Inhibition of human Cathepsin D using MCA labeled GKPILFFRLK(DNP)-D-R-NH2 as substrate preincubated for 10 mins followed by substrate addition by FRET assay	ic50	0.0004	uM
N’-(3,4-dimethylacridin-9-yl)-2-hydroxybenzohydrazide	331709: Inhibition of human cathepsin D by FRET assay	ic50	0.0005	uM
(3S,7S,8S)-7-hydroxy-8-(naphthalen-2-ylmethyl)-3-propan-2-yl-1,4,9-triazacyclohenicosane-2,5,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0006	uM
(2S)-N-[(2S,3S,5S)-1-cyclohexyl-5-(1,3-dithian-2-yl)-3,5-dihydroxypentan-2-yl]-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enamide	48025: Binding affinity against human cathepsin D	ki	0.0006	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(2S,3S,5R)-6-[[(2S)-1-(benzylamino)-3-methyl-1-oxobutan-2-yl]amino]-1-[(3,5-difluorophenyl)methoxy]-3-hydroxy-5-methyl-6-oxohexan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate	464228: Inhibition of human liver cathepsin D after 20 mins by homogeneous time resolved fluorescence assay	ic50	0.0006	uM
N-[(2S)-1-[[(2S,3S)-5-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-[[4-(1,3-benzodioxol-5-yl)phenyl]methoxy]-3-hydroxy-5-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyridine-2-carboxamide	238412: Inhibitory concentration against the human Cathepsin D	ki	0.0007	uM
N-[(2S)-3-[[2-(2-bromo-4,5-dimethoxyphenoxy)acetyl]amino]-2-hydroxy-4-(3-phenoxyphenyl)butyl]-N-[2-(2,4-dichlorophenyl)ethyl]-3-(1,3-dioxoisoindol-2-yl)propanamide	48046: Binding affinity against aspartic proteases	ki	0.0007	uM
(3R,4S)-5-cyclohexyl-2,2-difluoro-3-hydroxy-N-(2-morpholin-4-ylethyl)-4-[[(2S)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enoyl]amino]pentanamide	48025: Binding affinity against human cathepsin D	ki	0.0008	uM
(2S,4S)-N-[(1S)-2-(benzylamino)-2-oxo-1-propan-2-ylsulfanylethyl]-4-hydroxy-4-[(13S)-18-[methyl(methylsulfonyl)amino]-2,15-dioxo-4-phenyl-11-oxa-3,14-diazatricyclo[14.3.1.15,9]henicosa-1(19),5,7,9(21),16(20),17-hexaen-13-yl]-2-propan-2-ylbutanamide	551757: Inhibition of cathepsin D	ki	0.0008	uM
N-[(2S,3R)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1’-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]hex-5-enamide	761331: Inhibition of Cathepsin D (unknown origin) by FRET assay	ic50	0.0008	uM
(3S,14R,16S)-16-[(1R)-2-[[(4S)-2,2-dimethyl-6-propan-2-yl-3,4-dihydrochromen-4-yl]amino]-1-hydroxyethyl]-3,4,14-trimethyl-1,4-diazacyclohexadecane-2,5-dione	423180: Inhibition of human cathepsin D	ic50	0.0010	uM
(4S)-4-[(1R)-1-hydroxy-2-[[1-(3-propan-2-ylphenyl)cyclopropyl]amino]ethyl]-19-(methoxymethyl)-11-oxa-3,16-diazatricyclo[15.3.1.16,10]docosa-1(21),6(22),7,9,17,19-hexaen-2-one	453187: Inhibition of cathepsin D	ic50	0.0010	uM
N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(2S,4S)-6-(2,2-dimethylpropyl)-2-methyl-2-propyl-3,4-dihydrochromen-4-yl]amino]-3-hydroxybutan-2-yl]acetamide	762872: Inhibition of cathepsin-D (unknown origin) using C-terminal biotinylated peptide substrate treated 30 mins before addition of peptide substrate measured after 110 mins by fluorescence polarization assay	ic50	0.0010	uM
(3S,7S,8S)-8-benzyl-7-hydroxy-3-(pyridin-3-ylmethyl)-1,4,9-triazacyclohenicosane-2,5,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0011	uM
N-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(4-propylpiperazin-1-yl)benzamide	1168917: Inhibition of human cathepsin K using Z-Leu-Arg-AMC fluorogenic substrate incubated for 60 mins	ki	0.0013	uM
tert-butyl N-[(2S)-3-[[(4S,5S,7R)-5-hydroxy-2,7-dimethyl-8-[[(2S)-3-methyl-1-(2-methylpropylamino)-1-oxobutan-2-yl]amino]-8-oxooctan-4-yl]amino]-2-[[(2S)-2-methyl-3-(4-methyl-1,3-thiazol-2-yl)propanoyl]amino]-3-oxopropyl]carbamate	1176942: Inhibition of Cathepsin D (unknown origin)	ki	0.0013	uM
1-acetyl-N-[2-(1,3-benzodioxol-5-yl)ethyl]-N-[(2S,3S)-3-[[2-(3-chloroanilino)acetyl]amino]-2-hydroxy-4-phenylbutyl]piperidine-4-carboxamide	48032: Compound was tested for the inhibitory activity against human liver cathepsin D	ki	0.0013	uM
N-[(2S)-1-[[(2S,3S)-5-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-5-oxo-1-[(3-thiophen-3-ylphenyl)methoxy]pentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyridine-2-carboxamide	238412: Inhibitory concentration against the human Cathepsin D	ki	0.0016	uM
1-acetyl-N-[2-(1,3-benzodioxol-5-yl)ethyl]-N-[(2S,3S)-3-[[2-(3-chlorophenoxy)acetyl]amino]-2-hydroxy-4-phenylbutyl]piperidine-4-carboxamide	48032: Compound was tested for the inhibitory activity against human liver cathepsin D	ki	0.0019	uM
N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1’-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide	662321: Inhibition of cathepsin D	ic50	0.0020	uM
(11S)-11-[(1R)-2-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1’-cyclobutane]-4-yl]amino]-1-hydroxyethyl]-1,12-diazatricyclo[12.3.1.15,9]nonadeca-5(19),6,8,14(18),15-pentaene-13,17-dione	761331: Inhibition of Cathepsin D (unknown origin) by FRET assay	ic50	0.0020	uM
N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(2R,4S)-6-(2,2-dimethylpropyl)-2-methyl-2-propyl-3,4-dihydrochromen-4-yl]amino]-3-hydroxybutan-2-yl]acetamide	762872: Inhibition of cathepsin-D (unknown origin) using C-terminal biotinylated peptide substrate treated 30 mins before addition of peptide substrate measured after 110 mins by fluorescence polarization assay	ic50	0.0020	uM
5-bromo-N-[(2S,3R)-4-[[(4S)-6-ethylspiro[3,4-dihydrochromene-2,1’-cyclobutane]-4-yl]amino]-3-hydroxy-1-(3-prop-2-enylphenyl)butan-2-yl]-6-oxo-1-prop-2-enylpyridine-3-carboxamide	761331: Inhibition of Cathepsin D (unknown origin) by FRET assay	ic50	0.0020	uM
(12S)-12-[(1R)-2-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1’-cyclobutane]-4-yl]amino]-1-hydroxyethyl]-1,13-diazatricyclo[13.3.1.16,10]icosa-6(20),7,9,15(19),16-pentaene-14,18-dione	761331: Inhibition of Cathepsin D (unknown origin) by FRET assay	ic50	0.0020	uM
(3S,4S)-3-hydroxy-4-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-3-methyl-2-[[(2R)-3-methyl-2-(3-methylbutanoylamino)butanoyl]amino]butanoyl]amino]heptanoyl]amino]propanoyl]amino]-6-methylheptanoic acid	2101464: Inhibition of human Cathepsin D using MCA labeled GKPILFFRLK(DNP)-D-R-NH2 as substrate preincubated for 10 mins followed by substrate addition by FRET assay	ic50	0.0020	uM
(4R)-3-[(2S,3S)-3-[[2-(2,6-dimethylphenoxy)acetyl]amino]-2-hydroxy-4-phenylbutanoyl]-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide	437082: Inhibition of human liver cathepsin D	ki	0.0020	uM
(2S)-N-[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enamide	48025: Binding affinity against human cathepsin D	ki	0.0025	uM
N-[(2S)-1-[[(2S,3S)-5-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-5-oxo-1-[(4-phenylphenyl)methoxy]pentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyridine-2-carboxamide	238412: Inhibitory concentration against the human Cathepsin D	ki	0.0025	uM
(4S,5S,9S)-4-benzyl-5-hydroxy-9-propan-2-yl-1-oxa-3,8,11-triazacyclodocosane-2,7,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0025	uM
N-[2-(1,3-benzodioxol-5-yl)ethyl]-N-[(2S,3S)-3-[[2-(2,4-dichlorophenoxy)acetyl]amino]-2-hydroxy-4-phenylbutyl]-3-(1,3-dioxoisoindol-2-yl)propanamide	48033: Inhibitory activity of compound against human Cathepsin D	ki	0.0030	uM
(4S)-4-[(1R)-1-hydroxy-2-[[1-(3-propan-2-ylphenyl)cyclopropyl]amino]ethyl]-19-(methoxymethyl)-11,16-dioxa-3,18-diazatricyclo[15.3.1.16,10]docosa-1(20),6(22),7,9,17(21),18-hexaen-2-one	453187: Inhibition of cathepsin D	ic50	0.0030	uM
N-[(2S,3R)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1’-cyclobutane]-4-yl]amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]acetamide	662321: Inhibition of cathepsin D	ic50	0.0030	uM
(3S,7S,8S)-8-[(3,4-difluorophenyl)methyl]-7-hydroxy-3-propan-2-yl-1,4,9-triazacyclohenicosane-2,5,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0031	uM
N-[(2S)-1-[[(2S,3S)-5-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-5-oxo-1-[(4-thiophen-3-ylphenyl)methoxy]pentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyridine-2-carboxamide	238412: Inhibitory concentration against the human Cathepsin D	ki	0.0032	uM
(3R,4S)-5-cyclohexyl-2,2-difluoro-3-hydroxy-N-[(2S)-2-methylbutyl]-4-[[(2S)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enoyl]amino]pentanamide	48025: Binding affinity against human cathepsin D	ki	0.0032	uM
3-N-[(2S,3S,5S)-5-[[(2S)-1-(benzylamino)-3-methyl-1-oxobutan-2-yl]carbamoyl]-3-hydroxy-6-methyl-1-phenylmethoxyheptan-2-yl]-5-[methyl(methylsulfonyl)amino]-1-N-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide	551757: Inhibition of cathepsin D	ki	0.0033	uM
benzyl 3-[[(2R,3S)-3-acetamido-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino]-3-(3-tert-butylphenyl)piperidine-1-carboxylate	444269: Inhibition of cathepsin D assessed as reduction in polarization after 110 mins by oregon green based fluorescence polarization assay	ic50	0.0033	uM
(3S,7S,8S)-8-benzyl-7-hydroxy-3-propan-2-yl-1,4,9-triazacyclodocosane-2,5,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0035	uM
(3S,7S,8S)-8-benzyl-3-[(2R)-butan-2-yl]-7-hydroxy-1,4,9-triazacyclohenicosane-2,5,10-trione	1529188: Inhibition of human placenta CatD using Abz-Lys-Pro-Ala-Glu-Phe-Nph-Ala-Leu as substrate preincubated for 10 mins followed by substrate addition and measured by FRET assay	ic50	0.0038	uM
N-[(2S)-1-[[(2S,3S)-5-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-5-oxo-1-[(3-phenylphenyl)methoxy]pentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyridine-2-carboxamide	238412: Inhibitory concentration against the human Cathepsin D	ki	0.0039	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases activity, decreases reaction, affects reaction, affects binding, decreases expression (+5 more)	43
Fulvestrant	decreases expression, affects cotreatment, increases methylation, decreases reaction, increases expression (+2 more)	12
bisphenol A	decreases reaction, affects cotreatment, increases methylation, increases activity, increases expression (+5 more)	10
Tetrachlorodibenzodioxin	increases expression, increases reaction, affects cotreatment, decreases expression, affects binding (+3 more)	10
Resveratrol	affects localization, affects reaction, affects binding, affects response to substance, affects secretion (+7 more)	7
sodium arsenite	affects cotreatment, increases abundance, increases expression, increases activity, decreases expression	5
Tretinoin	increases expression, increases reaction	5
Benzo(a)pyrene	affects methylation, increases expression, decreases expression, decreases methylation, decreases reaction	4
Cadmium Chloride	increases abundance, increases expression, decreases reaction, decreases expression	4
nonylphenol	affects binding, increases reaction, decreases reaction, increases expression, increases activity	3
pepstatin	affects cotreatment, decreases expression, decreases reaction, decreases activity	3
Air Pollutants	decreases expression, increases expression, affects cotreatment, increases abundance, increases oxidation	3
Quercetin	decreases reaction, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Genistein	decreases reaction, increases expression	3
cobaltous chloride	increases expression	2
linalool	decreases reaction, increases expression	2
epigallocatechin gallate	increases expression	2
bisphenol AF	increases expression	2
Arsenic Trioxide	increases expression, increases reaction	2
Arsenic	increases abundance, increases expression, decreases expression, affects cotreatment	2
Cadmium	decreases expression, increases abundance, increases expression	2
Copper	increases expression, affects binding, decreases expression	2
Diethylhexyl Phthalate	decreases activity, increases expression, decreases reaction	2
Doxorubicin	decreases response to substance, increases expression	2
Glucosamine	affects localization, decreases expression, increases activity, decreases reaction	2
Smoke	decreases expression	2
Tamoxifen	decreases reaction, increases reaction, increases expression, affects binding	2
Valproic Acid	increases methylation, decreases expression, increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2

ChEMBL screening assays

352 unique, capped per target: 331 binding, 15 admet, 3 toxicity, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1021961	Binding	Inhibition of human liver cathepsin D after 30 mins by fluorometric end-point assay	Identification of 3-acetyl-2-aminoquinolin-4-one as a novel, nonpeptidic scaffold for specific calpain inhibitory activity. — *J Med Chem*
CHEMBL4042703	ADMET	Inhibition of Cathepsin D (unknown origin) by cell free assay	Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. — *J Med Chem*
CHEMBL5326793	Toxicity	Inhibition of human Cathepsin D	Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV). — *Eur J Med Chem*

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1BZ	Abcam A-431 CTSD KO	Cancer cell line	Female
CVCL_D1S2	Abcam U-87MG CTSD KO	Cancer cell line	Male
CVCL_D5EM	HeLa::TMEM192-3xHA CTSD KO	Cancer cell line	Female
CVCL_E1US	HAP1 CTSD (-)	Cancer cell line	Male
CVCL_F0PR	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) CTSD-/-	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

35 trials:

NCT	Phase	Status	Title
NCT01955135	Phase 4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT07685886	Phase 4	NOT_YET_RECRUITING	MIRACLE-T2D Montelukast Intervention for Renal, Cardiovascular and Eye Health in Type 2 Diabetes
NCT01373476	Phase 2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	Phase 2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00337636	Phase 1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	Phase 1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT07582484	Phase 1/2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies
NCT04311112	Phase 2/3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	Early Phase 1	RECRUITING	Feasibility and Safety of MB-102 in Ocular Angiography as Compared to Fluorescein Sodium
NCT00259701	Not specified	COMPLETED	Microvascular Reactivity.
NCT00331370	Not specified	UNKNOWN	Hypertension Related Damage to the Microcirculation in South Asian: Emergence, Predictive Power and Reversibility
NCT00618644	Not specified	WITHDRAWN	Ranibizumab for Neovascularization in Sickle Cell Retinopathy
NCT00735657	Not specified	COMPLETED	Anesthesia for Pars Plana Vitrectomy (PPV) With Insulin Needle
NCT00828425	Not specified	COMPLETED	Management of Diabetes Mellitus Patients With Retinopathy
NCT00969956	Not specified	TERMINATED	Time To Complications Occurs in Diabetes
NCT01412905	Not specified	COMPLETED	Telemedicine Retinal Screening Utilizing a Mobile Medical Unit
NCT01546766	Not specified	COMPLETED	Rapid, Non-invasive, Regional Functional Imaging of the Retina. (Diabetic Retinopathy Diagnosis Device)
NCT01552993	Not specified	TERMINATED	Registration and Treatment of Pain During Eye Examination of Prematurity
NCT01815567	Not specified	COMPLETED	DETECT and Retinal Outcomes in Hypertension
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NCT03901898	Not specified	COMPLETED	Feasibility of an Intervention to Increase Diabetic Retinopathy Screening Attendance
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Predicted chemistry — Sugi Predict

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