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): 760 total — 37 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001909

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: 25 — 18 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

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

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.

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

301 total, 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

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

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)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-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

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)

Protein

Protein identifiers

Cathepsin D — P07339 (reviewed: P07339)

All UniProt accessions (11): A0A1B0GV23, A0A1B0GVD5, A0A1B0GVP3, A0A1B0GW44, A0A1B0GWE8, A0A7I2V2N3, C9JH19, P07339, F8W787, F8WD96, 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 (63 total): strand 27, helix 11, 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.

PDB	Method	Resolution (Å)
6QCB	X-RAY DIFFRACTION	1.55
6QBG	X-RAY DIFFRACTION	1.8
6QBH	X-RAY DIFFRACTION	1.85
4OD9	X-RAY DIFFRACTION	1.9
1LYA	X-RAY DIFFRACTION	2.5
1LYB	X-RAY DIFFRACTION	2.5
1LYW	X-RAY DIFFRACTION	2.5
4OC6	X-RAY DIFFRACTION	2.64
4OBZ	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

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

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): 97; 295

Disulfide bonds (4): 91–160, 110–117, 286–290, 329–366

Glycosylation sites (3): 263, 63, 134

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-2132295	MHC class II antigen presentation
R-HSA-6798695	Neutrophil degranulation
R-HSA-77387	Insulin receptor recycling
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-1280218	Adaptive Immune System
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-74752	Signaling by Insulin receptor
R-HSA-8939211	ESR-mediated signaling
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 (9): autophagosome assembly (GO:0000045), 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 (16): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), 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

Rollup of top-12 pathways:

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
Extracellular matrix organization	1
Metabolism of proteins	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by Nuclear Receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

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
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
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

Protein interactions and networks

STRING

3914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSD	CTSB	P07858	923
CTSD	LAMP1	P11279	920
CTSD	CTSS	P25774	883
CTSD	IGF2R	P11717	850
CTSD	LAMP2	P13473	839
CTSD	PPT1	P50897	829
CTSD	CLN3	Q13286	818
CTSD	CTSH	P09668	817
CTSD	CTSL	P07711	806
CTSD	CLN5	O75503	804
CTSD	SORT1	Q99523	790
CTSD	MFSD8	Q8NHS3	787
CTSD	CLN6	Q9NWW5	766
CTSD	CLN8	Q9UBY8	765
CTSD	TFEB	P19484	726

IntAct

176 interactions, top by confidence:

A	B	Type	Score
LDHB	LDHA	psi-mi:“MI:0914”(association)	0.800
JADE1	KAT7	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ZNF497	CTSD	psi-mi:“MI:0915”(physical association)	0.610
CTSD	ZNF497	psi-mi:“MI:0915”(physical association)	0.610
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
KIF1A	CTSD	psi-mi:“MI:0915”(physical association)	0.560
	CTSD	psi-mi:“MI:0915”(physical association)	0.560
TEAD1	CTSD	psi-mi:“MI:0915”(physical association)	0.560
VDAC2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
H3C1	CTSD	psi-mi:“MI:0915”(physical association)	0.560
NPFF	CTSD	psi-mi:“MI:0915”(physical association)	0.560
DLGAP2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
WTAP	CTSD	psi-mi:“MI:0915”(physical association)	0.560
IRAG1	CTSD	psi-mi:“MI:0915”(physical association)	0.560
WWP2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
SUMF2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
EPN3	CTSD	psi-mi:“MI:0915”(physical association)	0.560
EPS8L2	CTSD	psi-mi:“MI:0915”(physical association)	0.560
SPRY4	CTSD	psi-mi:“MI:0915”(physical association)	0.560
SYT3	CTSD	psi-mi:“MI:0915”(physical association)	0.560
PGLYRP3	CTSD	psi-mi:“MI:0915”(physical association)	0.560
ZDHHC20	CTSD	psi-mi:“MI:0915”(physical association)	0.560
MOGAT3	CTSD	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (190): CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), CTSD (Affinity Capture-MS), ACADM (Co-fractionation), CTSD (Co-fractionation), CTSD (Co-fractionation), CTSD (Co-fractionation), CTSD (Co-fractionation), CTSD (Co-fractionation), CTSD (Co-fractionation)

ESM2 similar proteins: A8PZM4, C4YSF6, C5FEK4, C5FS55, C5FZ57, D4ANC3, D4AT39, D4B385, D4D7C5, D4DEN7, D4DGR1, O04057, O42630, O65390, O76856, P00799, P06026, P07267, P07339, P09177, P0CY26, P0CY27, P10602, P10977, P40782, P42210, P42211, P43093, P43094, P43095, P43231, P43232, P55956, P81214, Q00663, Q01294, Q03168, Q03699, Q18020, Q21966

Diamond homologs: A0A509AI82, A0A509AWX2, C5FS55, D4B385, D4DEN7, O09043, O42630, O76856, O93428, O96009, P00791, P00792, P00793, P00794, P00795, P00796, P00797, P03954, P03955, P04073, P06281, P07267, P07339, P08424, P0DJD7, P0DJD8, P0DJD9, P10977, P11489, P14091, P16228, P16476, P18242, P18276, P20142, P24268, P25796, P27677, P27678, P27821

SIGNOR signaling

31 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”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	16
Uncertain significance	259
Likely benign	363
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100733	NM_001909.4:c.486-12G>A	Pathogenic
1322174	NM_001909.5(CTSD):c.17_30dup (p.Leu11fs)	Pathogenic
1407027	NM_001909.5(CTSD):c.244G>T (p.Glu82Ter)	Pathogenic
1441635	NM_001909.5(CTSD):c.908del (p.Gly303fs)	Pathogenic
1452819	NM_001909.5(CTSD):c.268del (p.Gln90fs)	Pathogenic
1452955	NM_001909.5(CTSD):c.949del (p.Ala317fs)	Pathogenic
1703675	GRCh37/hg19 11p15.5(chr11:1621232-2228572)	Pathogenic
17573	NM_001909.5(CTSD):c.685T>A (p.Phe229Ile)	Pathogenic
17574	NM_001909.5(CTSD):c.1149G>C (p.Trp383Cys)	Pathogenic
17575	NM_001909.5(CTSD):c.764dup (p.Tyr255Ter)	Pathogenic
1987149	NM_001909.5(CTSD):c.1052dup (p.Glu352fs)	Pathogenic
1999365	NM_001909.5(CTSD):c.914_947del (p.Val305fs)	Pathogenic
2010906	NM_001909.5(CTSD):c.658C>T (p.Gln220Ter)	Pathogenic
2021035	NM_001909.5(CTSD):c.627_628del (p.Asn209fs)	Pathogenic
2096023	NM_001909.5(CTSD):c.832G>T (p.Glu278Ter)	Pathogenic
2103629	NM_001909.5(CTSD):c.550A>T (p.Lys184Ter)	Pathogenic
2117602	NM_001909.5(CTSD):c.756dup (p.Lys253fs)	Pathogenic
2135026	NM_001909.5(CTSD):c.984_985del (p.Pro328_Cys329insTer)	Pathogenic
2145840	NM_001909.5(CTSD):c.952del (p.Val318fs)	Pathogenic
2160697	NM_001909.5(CTSD):c.468_469del (p.Ser157fs)	Pathogenic
2419916	NM_001909.5(CTSD):c.153del (p.Val52fs)	Pathogenic
2424315	NC_000011.9:g.(?1774733)(1785089_?)del	Pathogenic
2424316	NC_000011.9:g.(?1785002)(1785089_?)del	Pathogenic
2701881	NM_001909.5(CTSD):c.190G>T (p.Glu64Ter)	Pathogenic
2757064	NM_001909.5(CTSD):c.465dup (p.Val156fs)	Pathogenic
2761352	NM_001909.5(CTSD):c.853del (p.Leu285fs)	Pathogenic
2770025	NM_001909.5(CTSD):c.728del (p.Gly243fs)	Pathogenic
2845392	NM_001909.5(CTSD):c.718C>T (p.Gln240Ter)	Pathogenic
2854203	NM_001909.5(CTSD):c.51del (p.Ala18fs)	Pathogenic
2985561	NM_001909.5(CTSD):c.457C>T (p.Gln153Ter)	Pathogenic

SpliceAI

1462 predictions. Top by Δscore:

Variant	Effect	Δscore
11:1753798:CTCA:C	donor_loss	1.0000
11:1753800:CACCT:C	donor_loss	1.0000
11:1753802:C:CA	donor_loss	1.0000
11:1753896:CATG:C	acceptor_gain	1.0000
11:1753897:ATGTA:A	acceptor_gain	1.0000
11:1753898:TGTA:T	acceptor_gain	1.0000
11:1753899:G:C	acceptor_gain	1.0000
11:1753899:GTA:G	acceptor_gain	1.0000
11:1753900:TA:T	acceptor_gain	1.0000
11:1753900:TACTA:T	acceptor_loss	1.0000
11:1753901:AC:A	acceptor_loss	1.0000
11:1753902:C:CA	acceptor_loss	1.0000
11:1753902:C:CC	acceptor_gain	1.0000
11:1753902:CTAAG:C	acceptor_loss	1.0000
11:1753989:CTCA:C	donor_loss	1.0000
11:1753990:TCAC:T	donor_loss	1.0000
11:1753991:CA:C	donor_loss	1.0000
11:1753991:CACCT:C	donor_loss	1.0000
11:1753992:A:AC	donor_gain	1.0000
11:1753992:A:T	donor_loss	1.0000
11:1753993:C:CC	donor_gain	1.0000
11:1753993:CCT:C	donor_gain	1.0000
11:1753993:CCTCG:C	donor_gain	1.0000
11:1754134:CCACC:C	acceptor_gain	1.0000
11:1754135:CACC:C	acceptor_gain	1.0000
11:1754135:CACCC:C	acceptor_gain	1.0000
11:1754137:CC:C	acceptor_gain	1.0000
11:1754138:CC:C	acceptor_gain	1.0000
11:1754139:C:CC	acceptor_gain	1.0000
11:1754901:CTCA:C	donor_gain	1.0000

AlphaMissense

2668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:1753585:C:A	G386V	1.000
11:1753595:A:G	W383R	1.000
11:1753595:A:T	W383R	1.000
11:1754081:G:C	D295E	1.000
11:1754081:G:T	D295E	1.000
11:1754082:T:A	D295V	1.000
11:1754082:T:G	D295A	1.000
11:1754083:C:G	D295H	1.000
11:1754925:A:G	W270R	1.000
11:1754925:A:T	W270R	1.000
11:1757443:G:C	F195L	1.000
11:1757443:G:T	F195L	1.000
11:1757445:A:G	F195L	1.000
11:1759558:A:G	W104R	1.000
11:1759558:A:T	W104R	1.000
11:1759578:T:A	D97V	1.000
11:1753551:A:C	F397L	0.999
11:1753551:A:T	F397L	0.999
11:1753553:A:G	F397L	0.999
11:1753585:C:T	G386D	0.999
11:1753586:C:G	G386R	0.999
11:1753593:C:A	W383C	0.999
11:1753593:C:G	W383C	0.999
11:1753638:G:C	S368R	0.999
11:1753638:G:T	S368R	0.999
11:1753640:T:G	S368R	0.999
11:1753645:C:G	C366S	0.999
11:1753646:A:G	C366R	0.999
11:1753646:A:T	C366S	0.999
11:1754067:A:G	L300P	0.999

dbSNP variants (sampled 300 via entrez): RS1000234974 (11:1763652 G>C), RS1000481866 (11:1754628 G>A,C,T), RS1000523826 (11:1765146 G>A), RS1000583892 (11:1764283 C>A,G), RS1000638456 (11:1759927 G>T), RS1000760645 (11:1755767 G>A), RS1000935319 (11:1758108 C>A,T), RS1001623943 (11:1763023 C>T), RS1001740072 (11:1763283 C>G), RS1001849614 (11:1763564 A>G), RS1001964174 (11:1763738 A>G), RS1001964613 (11:1764657 C>A,T), RS1002046976 (11:1754323 G>A), RS1002087215 (11:1759853 T>G), RS1002089381 (11:1759586 G>A,C)

Disease associations

OMIM: gene MIM:116840 | disease phenotypes: MIM:256730, MIM:610127, MIM:130650, MIM:607131

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Mondo (5): neuronal ceroid lipofuscinosis (MONDO:0016295), neuronal ceroid lipofuscinosis 10 (MONDO:0012414), Beckwith-Wiedemann syndrome (MONDO:0007534), multiple epiphyseal dysplasia, Al-Gazali type (MONDO:0011778), retinal disorder (MONDO:0005283)

Orphanet (5): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), CLN10 disease (Orphanet:228337), Beckwith-Wiedemann syndrome (Orphanet:116), Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome (Orphanet:166024)

HPO phenotypes

31 total (30 of 31 shown, 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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006585_950	Blood protein levels	8.000000e-26
GCST007000_5	Logical memory (delayed recall) in mild cognitive impairment	2.000000e-07
GCST009731_61	Blood protein levels in cardiovascular risk	1.000000e-41
GCST90011899_128	Aspartate aminotransferase levels	9.000000e-13

EFO canonical traits (3, from GWAS)

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

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
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

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 106,332 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL116	AMPRENAVIR	4	29,221
CHEMBL222559	TIPRANAVIR	4	17,513
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL169	URSOLIC ACID	2	20,825
CHEMBL296588	PEPSTATIN	2	26,094
CHEMBL371064	BALICATIB	2	97
CHEMBL43185	PIPERINE	2	10,980
CHEMBL2333941	LY-2811376	1	64

PharmGKB: 1 entry (VIP=true, CPIC=false)

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)

1747 measured of 1869 human assays (1895 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
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
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
(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
(3,5-dimethyl-1H-pyrazol-1-yl)methyl N-[(1R)-1-{[(1R,3S,4S)-3-hydroxy-1,6-dimethyl-1-{[(1S)-2-methyl-1-[(2-methylpropyl)carbamoyl]propyl]carbamoyl}heptan-4-yl]carbamoyl}-2-methanesulfonylethyl]carbamate	KI	0.3 nM
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide	IC50	0.3 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R,6R)-3-[5-[(3-chloro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-6-fluoro-3,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.33 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R,6R)-3-[5-[(3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-6-fluoro-3,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.38 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-(2-amino-3’-chloro-1’-fluorospiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl)-5-but-2-ynoxypyrazine-2-carboxamide	IC50	0.4 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[2-amino-1’-fluoro-3’-(2-fluoro-4-pyridinyl)spiro[5,6-dihydro-1,3-thiazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-methoxypyridine-2-carboxamide	IC50	0.4 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-but-2-ynoxypyridine-2-carboxamide	IC50	0.4 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
(1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-(but-2-yn-1-yloxy)pyrazin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbonitrile	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)((S)-3-fluoropyrrolidin-1-yl)methanone	IC50	0.4 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide	IC50	0.44 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-(difluoromethoxy)-3-methylpyridine-2-carboxamide	IC50	0.48 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-(cyclopropylmethoxy)pyrazine-2-carboxamide	IC50	0.5 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-fluoropyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.509 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((R)-3-fluoropyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.518 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((4aS,8aR)-decahydroisoquinoline-2-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.527 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
8-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluoroanilino]-1,7-naphthyridine-3-carbonitrile	IC50	0.54 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(6S)-8-amino-6-(fluoromethyl)-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-chloro-3-methylpyridine-2-carboxamide	IC50	0.54 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3S)-3-[2-fluoro-5-[(5-fluoro-3-methoxy-1,7-naphthyridin-8-yl)amino]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.55 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R)-3-[5-[(3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.56 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3S)-3-[2-fluoro-5-[(5-fluoro-3-isocyano-1,7-naphthyridin-8-yl)amino]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.56 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R)-3-[5-[(3-chloro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.59 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloro-3-ethenylpyridine-2-carboxamide	IC50	0.59 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-hydroxypyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.592 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
EVNXXAEF	IC50	0.6 nM
N-[2-amino-1’-fluoro-3’-(5-fluoro-3-pyridinyl)spiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-cyanopyridine-2-carboxamide	IC50	0.6 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[2-amino-1’-fluoro-3’-(5-fluoro-3-pyridinyl)spiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-chloropyrazine-2-carboxamide	IC50	0.6 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[2-amino-1’-fluoro-3’-(5-fluoro-3-pyridinyl)spiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-2-methyl-1,3-thiazole-4-carboxamide	IC50	0.6 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[2-amino-1’-fluoro-3’-(2-fluoro-4-pyridinyl)spiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-cyanopyridine-2-carboxamide	IC50	0.6 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloro-3-fluoropyridine-2-carboxamide	IC50	0.6 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-(difluoromethoxy)-3-methylpyridine-2-carboxamide	IC50	0.6 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(1R,5S,6S)-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine	IC50	0.6 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(prop-2-yn-1-yloxy)pyrazin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)((R)-3-methylmorpholino)methanone	IC50	0.6 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-1-((S)-3-hydroxy-3-methylpyrrolidine-1-carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.6 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxo-4lambda6-thia-7-azaspiro[2.5]oct-7-en-6-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.62 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(3R,6S)-5-amino-3-(5-((2-(but- 2-yn-1-yloxy)pyrido[3,4- b]pyrazin-5-yl)amino)-2- fluoropyridin-3-yl)-6- cyclopropyl-6-(fluoromethyl)- 3-methyl-3,6-dihydro-2H-1,4- thiazine 1,1-dioxide	KI	0.65 nM	US-9732088: C2-carbocyclic iminothiazine dioxides as BACE inhibitors, compositions, and their use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(pyrrolidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.673 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-1,3-oxazin-4-yl]-4-fluorophenyl]-5-but-2-ynoxypyrazine-2-carboxamide	IC50	0.7 nM	US-9296734: Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
(3R)-3-[5-[(3,5-dichloro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-amine	IC50	0.7 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[2-amino-3’-(3,6-dihydro-2H-pyran-4-yl)-1’-fluorospiro[5,6-dihydro-1,3-oxazine-4,5’-chromeno[2,3-c]pyridine]-7’-yl]-5-cyanopyridine-2-carboxamide	IC50	0.74 nM	US-9296759: Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use
6-((Z)-2-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-(trifluoromethyl)piperidine-1-carbonyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-1-fluorovinyl)nicotinonitrile	IC50	0.744 nM	US-10246429: Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
N-[3-[(7R)-9-amino-7-methyl-5,5-dioxo-5lambda6-thia-8-azaspiro[3.5]non-8-en-7-yl]-4-fluorophenyl]-5-cyano-3-methylpyridine-2-carboxamide	IC50	0.76 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
N-[3-[(3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	0.76 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists 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

1485 with measured affinity, of 2685 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

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases reaction, increases expression, affects reaction, decreases expression, increases secretion (+5 more)	43
Fulvestrant	affects binding, increases reaction, decreases expression, affects cotreatment, increases methylation (+2 more)	12
bisphenol A	decreases reaction, affects binding, increases reaction, decreases expression, increases activity (+5 more)	10
Tetrachlorodibenzodioxin	decreases expression, affects binding, decreases reaction, increases reaction, increases secretion (+3 more)	10
Resveratrol	affects localization, affects binding, increases activity, affects secretion, increases expression (+7 more)	7
sodium arsenite	increases expression, increases activity, decreases expression, affects cotreatment, increases abundance	5
Tretinoin	increases expression, increases reaction	5
Benzo(a)pyrene	decreases expression, decreases methylation, decreases reaction, affects methylation, increases expression	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	decreases reaction, decreases activity, affects cotreatment, decreases expression	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	increases expression, decreases reaction	2
epigallocatechin gallate	increases expression	2
bisphenol AF	increases expression	2
Arsenic Trioxide	increases expression, increases reaction	2
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Copper	affects binding, decreases expression, increases 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	affects binding, decreases reaction, increases reaction, increases expression	2
Valproic Acid	decreases expression, increases expression, increases methylation	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)

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

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT07582484	PHASE1/PHASE2	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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01916148	Not specified	AVAILABLE	18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT06346418	Not specified	RECRUITING	Maternal Genes and Epimutations: Beckwith-Wiedemann Syndrome & Reproductive Risks
NCT04311112	PHASE2/PHASE3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	EARLY_PHASE1	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
NCT02321904	Not specified	COMPLETED	Corneal Confocal Microscopy to Detect Diabetic Neuropathy in Children
NCT02466607	Not specified	COMPLETED	Study of Stimulus Parameters in Flicker Electroretinogram (ERG)
NCT02558478	Not specified	UNKNOWN	Identification of New Genes Implicated in Rare Neurosensory Diseases by Whole Exome Sequencing
NCT02702973	Not specified	UNKNOWN	Characteristic Analysis of Retinopathy Associated With High Doses of Interferon α-2b Therapy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT03542734	Not specified	RECRUITING	Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly
NCT03901898	Not specified	COMPLETED	Feasibility of an Intervention to Increase Diabetic Retinopathy Screening Attendance
NCT04819893	Not specified	RECRUITING	Study of the Involvement of Fatty Acids in Retinopathy of Prematurity: Relationship Between Retinopathy of Prematurity and the Rate of Expression of Transplacental Fatty Acid Receptors.
NCT05921981	Not specified	COMPLETED	Multisensory Stimulation Versus White Noise
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06355219	Not specified	COMPLETED	Macrovascular and Microvascular Morbidity and Mortality After Metabolic Surgery Versus Medicines
NCT06837181	Not specified	RECRUITING	Studying the Presence of CFRD Complications With Thoughtful Recruitment (SPeCTRuM)