HTRA1

Summary

HTRA1 (HtrA serine peptidase 1, HGNC:9476) is a protein-coding gene on chromosome 10q26.13, encoding Serine protease HTRA1 (Q92743). Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.

This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7.

Source: NCBI Gene 5654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CARASIL syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 41
• Clinical variants (ClinVar): 381 total — 15 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 71
• Druggable target: yes
• MANE Select transcript: NM_002775

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9476
Approved symbol	HTRA1
Name	HtrA serine peptidase 1
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	HtrA, IGFBP5-protease, ARMD7
Ensembl gene	ENSG00000166033
Ensembl biotype	protein_coding
OMIM	602194
Entrez	5654

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000368984, ENST00000420892, ENST00000648167, ENST00000869937, ENST00000869938, ENST00000962536, ENST00000962537

RefSeq mRNA: 1 — MANE Select: NM_002775 NM_002775

CCDS: CCDS7630

Canonical transcript exons

ENST00000368984 — 9 exons

Exon	Start	End
ENSE00001099153	122510096	122510153
ENSE00001099157	122511970	122512065
ENSE00001099158	122507370	122507402
ENSE00001099160	122508656	122508770
ENSE00001448520	122514191	122514907
ENSE00001448527	122461553	122462124
ENSE00001656483	122489422	122489626
ENSE00001691312	122506691	122506885
ENSE00001727698	122488902	122489001

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.4566 / max 1133.9481, expressed in 1450 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107451	46.3408	1409
107450	17.8092	1318
107452	5.4317	897
107449	3.5626	768
107456	0.3122	170

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.72	gold quality
renal glomerulus	UBERON:0000074	99.57	gold quality
metanephric glomerulus	UBERON:0004736	99.54	gold quality
descending thoracic aorta	UBERON:0002345	99.49	gold quality
stromal cell of endometrium	CL:0002255	99.48	gold quality
ascending aorta	UBERON:0001496	99.43	gold quality
thoracic aorta	UBERON:0001515	99.43	gold quality
middle frontal gyrus	UBERON:0002702	99.42	gold quality
layer of synovial tissue	UBERON:0007616	99.42	gold quality
synovial joint	UBERON:0002217	99.38	gold quality
putamen	UBERON:0001874	99.35	gold quality
calcaneal tendon	UBERON:0003701	99.34	gold quality
periodontal ligament	UBERON:0008266	99.32	gold quality
caudate nucleus	UBERON:0001873	99.31	gold quality
gall bladder	UBERON:0002110	99.31	gold quality
amygdala	UBERON:0001876	99.29	gold quality
right coronary artery	UBERON:0001625	99.26	gold quality
left ovary	UBERON:0002119	99.24	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.24	gold quality
nucleus accumbens	UBERON:0001882	99.18	gold quality
aorta	UBERON:0000947	99.12	gold quality
spinal cord	UBERON:0002240	99.12	gold quality
right ovary	UBERON:0002118	99.10	gold quality
corpus callosum	UBERON:0002336	98.99	gold quality
hypothalamus	UBERON:0001898	98.98	gold quality
inferior vagus X ganglion	UBERON:0005363	98.98	gold quality
endocervix	UBERON:0000458	98.96	gold quality
Ammon’s horn	UBERON:0001954	98.96	gold quality
substantia nigra	UBERON:0002038	98.96	gold quality
popliteal artery	UBERON:0002250	98.94	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	7740.61
E-GEOD-114530	yes	1012.11
E-MTAB-8530	yes	842.63
E-HCAD-13	yes	784.87
E-MTAB-8410	yes	33.57
E-GEOD-84465	yes	26.91
E-MTAB-10287	yes	26.80
E-CURD-114	yes	23.61
E-MTAB-6678	yes	16.69
E-GEOD-83139	yes	7.71
E-GEOD-137537	yes	6.11
E-MTAB-5061	yes	5.80
E-MTAB-10290	no	2216.10
E-MTAB-7037	no	812.79
E-MTAB-8381	no	460.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, IRF6, NFKB, PITX2, RELA, STAT1, TCF3

miRNA regulators (miRDB)

47 targeting HTRA1, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-181A-2-3P	98.91	67.60	1168

Literature-anchored findings (GeneRIF, showing 40)

• HTRA1 is a candidate tumor suppressor in ovarian cancer. (PMID:14716297)
• An HtrA1 inhibitor causes accumulation of Abeta in astrocyte cell culture supernatants and colocalizes with beta-amyloid deposits in human brain samples. (PMID:15855271)
• no association either with age-at-onset in AD cases or with disease risk in the case-control cohort but haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). (PMID:15917099)
• Contributes to the destruction of extracellular matrix through both direct and indirect mechanisms; its overexpression may contribute to arthritis. (PMID:16377621)
• RT-PCR analysis showed a significant reduction of HTRA1 and HTRA3 mRNA in endometrial cancer compared to normal endometrium. HTRA1 and HTRA3 protein showed a similar pattern of expression in EC tissue. (PMID:16650464)
• Data suggest that serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. (PMID:16767218)
• it is reported that a single-nucleotide polymorphism in the promoter region of HTRA1 is a major genetic risk factor for wet age-related macular degeneration (PMID:17053108)
• findings show a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for age-related macular degeneration at 10q26 (PMID:17053109)
• The distinct distribution of HtrA1 at the maternal-trophoblast interface suggests that HtrA1 may play a role in placental development. (PMID:17072861)
• Low expression of HtrA1 is associated with lymph node metastasis of lung cancer (PMID:17094466)
• highly upregulated during mucosal mast cell differentiation (PMID:17292962)
• the role of HTRA1 in Age-related macular degeneration (PMID:17426452)
• HTRA1 promoter polymorphism, rs11200638, is a strong candidate with a functional consequence that predisposes Japanese to develop neovascular age-related macular degeneration . (PMID:17438519)
• May increase susceptibility to age-related macular degeneration (AMD) development and can participate in a potential new molecular pathway for AMD pathogenesis. (PMID:17568988)
• Both the HTRA1 -625A allele and the complement factor H 402H allele are independently associated with exudative age-related macular degeneration in a Central European population. (PMID:17679948)
• The LOC387715/HTRA1 variants are associated with polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) in the Japanese population. (PMID:17692272)
• This article summarizes recent studies regarding the HtrA family of proteins, their structure, regulation and function. It also presents practical applications of this knowledge and perspective of its use in the future. (PMID:17718385)
• HTRA1 mRNA expression exhibits no significant change between control and age-related macular degeneration retinas. (PMID:17884985)
• the association of HTRA1 with wet age-related macular degeneration (choroidal neovascularization) (PMID:17904186)
• Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 (PMID:17962403)
• Although a role for PLEKHA1 could not be totally excluded, there was a four times higher age-related macular degeneration risk was associated with haplotype “A-T-A” involving “PLEKHA1-LOC387715-HTRA1” risk alleles. (PMID:18079691)
• HtrA1 may regulate matrix calcification via the inhibition of BMP-2 signaling, modulating osteoblast gene expression, and/or via the degradation of specific matrix proteins (PMID:18156628)
• Polymorphisms in the complement factor H gene, LOC387715, and the HTRA1 promoter are strongly associated with age-related macular degeneration. (PMID:18162041)
• Independent of CFH genotype or smoking history, an individual’s risk of AMD (age-related macular degeneration) could be increased or decreased, depending on their genotype or haplotype in the 10q26 region. (PMID:18164066)
• There is a significant decrease in HtrA1 mRNA in malignant ovarian tumors compared to benign; HtrA1 may function as a tumor suppressor. (PMID:18241672)
• The study demonstrated that both single-nucleotide polymorphisms were significantly associated with dry and wet (age-related macular degeneration) AMD. (PMID:18301036)
• A high impact of the additive effect of CFH and HTRA1 in the development of exudative AMD was shown. The HTRA1-smoking additive effect found in this study further suggests the importance of this environmental risk factor in AMD. (PMID:18316707)
• Possible association between occult or minimally classic choroidal neovascularization(CNV) and CFH polymorphism and between classic and predominantly classic CNV and HTRA1 polymorphism. (PMID:18362109)
• Up-regulation of HtrA1 is detected in the macular lesions of age-related macular degeneration suggest that rs11200638 in HtrA1 promoter is associated with disease development. (PMID:18427598)
• The present data provided an independent validation of the association of LOC387715 and HTRA1 SNPs, along with their risk estimates among Indian patients with AMD. (PMID:18436811)
• expression of HPV E6/E7 proteins is associated with a post-transcriptional up-regulation of HtrA1 (PMID:18452160)
• The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV (polypoidal choroidal vasculopathy) in Chinese patients. (PMID:18515590)
• A low HtrA1 score is strongly associated with a shorter overall survival in mesothelioma patients, independently from epidermal growth factor receptor expression levels. (PMID:18681782)
• Both the HTRA1 and LOC387715/ARMS2 single nucleotide polymorphysms appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH. (PMID:18682806)
• The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative age-related macular degeneration in a northern Chinese population. (PMID:18682812)
• Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking. (PMID:18718667)
• Patients with a homozygous HTRA1 rs11200638 risk allele had larger choroidal neovascular lesions. (PMID:18939352)
• The approximately 30 kDa HtrA1 form can be correlated to maternal preeclampsia while the significant down-regulation of total HtrA1 can be correlated to placental preeclampsia. (PMID:19056122)
• The rs10490924 Single nucleotide polymorphisms (SNP) in LOC387715/ARMS2 and the rs11200638 SNP in HTRA1 are strongly associated with neovascular age-related macular degeneration in this Israeli population. (PMID:19065273)
• In a Han Chinese population, HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative age-related macular degeneration. (PMID:19187590)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	htra1b	ENSDARG00000014907
danio_rerio	htra1a	ENSDARG00000032831
mus_musculus	Htra1	ENSMUSG00000006205
rattus_norvegicus	Htra1	ENSRNOG00000020533

Paralogs (3): HTRA2 (ENSG00000115317), HTRA4 (ENSG00000169495), HTRA3 (ENSG00000170801)

Protein

Protein identifiers

Serine protease HTRA1 — Q92743 (reviewed: Q92743)

Alternative names: High-temperature requirement A serine peptidase 1, L56, Serine protease 11

All UniProt accessions (3): A0A3B3IU24, Q92743, H0Y7G9

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.

Subunit / interactions. Forms homotrimers. In the presence of substrate, may form higher-order multimers in a PDZ-independent manner. Interacts with TGF-beta family members, including BMP4, TGFB1, TGFB2, activin A and GDF5.

Subcellular location. Cell membrane. Secreted. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level).

Disease relevance. A variant in the HTRA1 promoter may be associated with increased risk for developing age-related macular degeneration (ARMD), a multifactorial eye disease and common cause of vision loss. Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2 (CARASIL2) [MIM:600142] A cerebrovascular disease characterized by non-hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. The disease is caused by variants affecting the gene represented in this entry. Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2) [MIM:616779] A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The IGFBP N-terminal domain mediates interaction with TSC2 substrate.

Similarity. Belongs to the peptidase S1C family.

RefSeq proteins (1): NP_002766* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR001478	PDZ	Domain
IPR001940	Peptidase_S1C	Family
IPR002350	Kazal_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain

Pfam: PF00219, PF07648, PF13365, PF17820

Enzyme classification (BRENDA):

• EC 3.4.21.107 — peptidase Do (BRENDA: 41 organisms, 234 substrates, 57 inhibitors, 4 Km, 2 kcat entries)
• EC 3.4.21.108 — HtrA2 peptidase (BRENDA: 23 organisms, 127 substrates, 42 inhibitors, 35 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BETA-CASEIN	0.001–0.0093	24
ALA(7-METHOXYCOUMARIN-4-ACETIC ACID)-IRRVSYSF-(5	0.0007–0.001	3
BETA-CASEIN	0.0013	1
CSP-1 FRET PEPTIDE	—	1
L-ALA(MCA)IRRVSYSF-ANB-NH2	0.0002	1
SUCCINYL-LEU-LEU-VAL-TYR-4-METHYLCOUMARIN 7-AMID	0.0346	1
(7-METHOXYCOUMARIN-4-YL)AIRRVSYSF-(5-AMINO-2-NIT	0.0016	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-HIS-	0.0391	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-PHE-	0.0227	1
2-AMINOBENZOIC ACID-ILE-MET-THR-ABU-TYR-MET-TRP-	0.107	1
2-AMINOBENZOIC ACID-ILE-MET-THR-SER-TYR-MET-PHE-	0.354	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-ABU-TYR-MET-PHE-	0.0315	1
2-AMINOBENZOIC ACID-ILE-MET-VAL-SER-TYR-MET-PHE-	0.177	1
OLIGOMERIC ALPHA-SYNUCLEIN	0.0026	1
SPMFKGV-PARA-NITROANILINE	—	0

UniProt features (82 total): strand 30, sequence variant 14, helix 11, disulfide bond 8, turn 5, site 3, domain 3, active site 3, signal peptide 1, chain 1, mutagenesis site 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
3TJQ	X-RAY DIFFRACTION	2
7SJP	X-RAY DIFFRACTION	2.1
6Z0Y	X-RAY DIFFRACTION	2.2
3TJO	X-RAY DIFFRACTION	2.3
6Z0E	X-RAY DIFFRACTION	2.6
3NUM	X-RAY DIFFRACTION	2.75
3NZI	X-RAY DIFFRACTION	2.75
8SDP	X-RAY DIFFRACTION	2.87
8SE7	X-RAY DIFFRACTION	2.96
3TJN	X-RAY DIFFRACTION	3
8SDM	X-RAY DIFFRACTION	3.05
6Z0X	X-RAY DIFFRACTION	3.1
8SE8	X-RAY DIFFRACTION	3.18
3NWU	X-RAY DIFFRACTION	3.2
7SJO	ELECTRON MICROSCOPY	3.3
7SJN	ELECTRON MICROSCOPY	3.4
2JOA	SOLUTION NMR
2YTW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92743-F1	83.30	0.50

Antibody-complex structures (SAbDab): 3 — 7SJN, 7SJO, 7SJP

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 (6): 171 (involved in trimer stabilization); 278 (involved in trimer stabilization); 220 (charge relay system); 250 (charge relay system); 328 (charge relay system); 169 (involved in trimer stabilization)

Disulfide bonds (8): 37–62, 41–64, 46–65, 53–68, 76–89, 83–110, 112–130, 119–155

Mutagenesis-validated functional residues (1):

Position	Phenotype
328	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix

MSigDB gene sets: 394 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, LEE_NEURAL_CREST_STEM_CELL_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, HSIAO_HOUSEKEEPING_GENES, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, MODULE_66, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, ONKEN_UVEAL_MELANOMA_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, CASTELLANO_NRAS_TARGETS_DN, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (7): placenta development (GO:0001890), proteolysis (GO:0006508), programmed cell death (GO:0012501), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), positive regulation of apoptotic process (GO:0043065), chorionic trophoblast cell differentiation (GO:0060718)

GO Molecular Function (8): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), growth factor binding (GO:0019838), identical protein binding (GO:0042802), molecular function activator activity (GO:0140677), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
protein binding	2
animal organ development	1
protein metabolic process	1
signal transduction	1
cell death	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
cell differentiation	1
chorion development	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
molecular function regulator activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1
external encapsulating structure	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTRA1	ARMS2	P0C7Q2	781
HTRA1	CFH	P08603	768
HTRA1	PLEKHA1	Q9HB21	730
HTRA1	CLPP	Q16740	681
HTRA1	CSN2	P05814	662
HTRA1	CTRC	Q99895	649
HTRA1	PRSS2	P07478	639
HTRA1	PRSS3	P15951	638
HTRA1	HSPD1	P10809	615
HTRA1	CLPB	Q9H078	609
HTRA1	CLPX	O76031	609
HTRA1	CTRB2	Q6GPI1	603
HTRA1	GRPEL1	Q9HAV7	588
HTRA1	XIAP	P98170	588
HTRA1	HSPE1	P61604	583

IntAct

470 interactions, top by confidence:

A	B	Type	Score
HTRA1	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.800
HTRA1	HTRA1	psi-mi:“MI:0915”(physical association)	0.800
MAPT	HTRA1	psi-mi:“MI:0570”(protein cleavage)	0.750
MAPT	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.750
E	HTRA1	psi-mi:“MI:0915”(physical association)	0.710
HTRA1	E	psi-mi:“MI:0407”(direct interaction)	0.710
HTRA1	E	psi-mi:“MI:0915”(physical association)	0.710
E	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.710
E	HTRA1	psi-mi:“MI:0915”(physical association)	0.700
HTRA1	E	psi-mi:“MI:0407”(direct interaction)	0.700
HTRA1	E	psi-mi:“MI:0915”(physical association)	0.700
HTRA1	JAG1	psi-mi:“MI:0915”(physical association)	0.610
HTRA1	PTEN	psi-mi:“MI:0407”(direct interaction)	0.610
RPS6KA1	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.610
HTRA1	Tax	psi-mi:“MI:0407”(direct interaction)	0.610
HTRA1	Tax	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (57): HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Affinity Capture-MS), HTRA1 (Two-hybrid), HTRA1 (Protein-peptide), MAPT (Biochemical Activity)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D3ZA76, D3ZKF5, E1BJW1, F1N152, F4J3G5, O22609, O23614, O43464, P14543, P38935, P73940, P83105, P83110, Q14689, Q14703, Q297U2, Q3U213, Q5SNQ7, Q5XIL0, Q6GMI0, Q852K0, Q8BMS2, Q8IUL8, Q8IZJ1, Q91XF4

Diamond homologs: A0JNK3, A2RNT9, A2RT60, A4IHA1, A4XSC0, A5W8F5, A6VUA4, A6YFB5, A9JRB3, B0KV30, B1J4D7, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D0ZY51, D3ZA76, D3ZKF5, E1BJW1, E1V4H2, F1N152, F6AA62, O05942, O06291, O22609, O34358, O43464, O53896, O85291, P05676, P0A3Z5, P0AEE3, P0AEE4, P0C0V0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 165 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cell surface interactions at the vascular wall	9	7.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	16
Uncertain significance	185
Likely benign	86
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1459875	NC_000010.10:g.(?124221169)(124221660_?)del	Pathogenic
180747	NM_002775.5(HTRA1):c.126del (p.Glu42fs)	Pathogenic
1959435	NM_002775.5(HTRA1):c.184_185del (p.Cys62fs)	Pathogenic
221228	NM_002775.5(HTRA1):c.497G>T (p.Arg166Leu)	Pathogenic
221229	NM_002775.5(HTRA1):c.517G>C (p.Ala173Pro)	Pathogenic
221230	NM_002775.5(HTRA1):c.852C>A (p.Ser284Arg)	Pathogenic
221231	NM_002775.5(HTRA1):c.973-1G>A	Pathogenic
2424539	NC_000010.10:g.(?124248398)(124249162_?)del	Pathogenic
2570778	NM_002775.5(HTRA1):c.272dup (p.Pro92fs)	Pathogenic
4072349	NM_002775.5(HTRA1):c.89C>A (p.Ser30Ter)	Pathogenic
523574	NM_002775.5(HTRA1):c.543del (p.Ala182fs)	Pathogenic
523577	NM_002775.5(HTRA1):c.865C>T (p.Gln289Ter)	Pathogenic
560164	NM_002775.5(HTRA1):c.614C>G (p.Ser205Cys)	Pathogenic
7489	NM_002775.5(HTRA1):c.889G>A (p.Val297Met)	Pathogenic
7490	NM_002775.5(HTRA1):c.754G>A (p.Ala252Thr)	Pathogenic
1184139	NM_002775.5(HTRA1):c.820C>G (p.Arg274Gly)	Likely pathogenic
1341619	NM_002775.5(HTRA1):c.278_280delinsCC (p.Phe93fs)	Likely pathogenic
1387135	NM_002775.5(HTRA1):c.547G>A (p.Val183Met)	Likely pathogenic
1687432	NM_002775.5(HTRA1):c.972+1G>C	Likely pathogenic
1709968	NM_002775.5(HTRA1):c.671del (p.Asn224fs)	Likely pathogenic
1910224	NM_002775.5(HTRA1):c.497G>A (p.Arg166His)	Likely pathogenic
1973808	NM_002775.5(HTRA1):c.472+2T>C	Likely pathogenic
3619745	NM_002775.5(HTRA1):c.777+1G>A	Likely pathogenic
4081449	NM_002775.5(HTRA1):c.1120+1G>A	Likely pathogenic
424966	NM_002775.5(HTRA1):c.451C>T (p.Gln151Ter)	Likely pathogenic
4812856	NM_002775.5(HTRA1):c.1055C>A (p.Ser352Tyr)	Likely pathogenic
523572	NM_002775.5(HTRA1):c.359G>A (p.Gly120Asp)	Likely pathogenic
523573	NM_002775.5(HTRA1):c.536T>A (p.Ile179Asn)	Likely pathogenic
523576	NM_002775.5(HTRA1):c.827G>C (p.Gly276Ala)	Likely pathogenic
523578	NM_002775.5(HTRA1):c.971A>C (p.Asn324Thr)	Likely pathogenic

SpliceAI

2183 predictions. Top by Δscore:

Variant	Effect	Δscore
10:122489002:G:GG	donor_gain	1.0000
10:122489625:AG:A	donor_loss	1.0000
10:122489626:GGTAA:G	donor_loss	1.0000
10:122489628:T:TC	donor_loss	1.0000
10:122506881:TCAAC:T	donor_gain	1.0000
10:122506883:AAC:A	donor_gain	1.0000
10:122506883:AACGT:A	donor_loss	1.0000
10:122506884:AC:A	donor_gain	1.0000
10:122506884:ACG:A	donor_loss	1.0000
10:122506885:CGT:C	donor_loss	1.0000
10:122506886:G:GC	donor_loss	1.0000
10:122506886:G:GG	donor_gain	1.0000
10:122506887:T:G	donor_loss	1.0000
10:122507369:G:GA	acceptor_gain	1.0000
10:122507369:GT:G	acceptor_gain	1.0000
10:122508650:TTTCA:T	acceptor_loss	1.0000
10:122508651:TTCA:T	acceptor_loss	1.0000
10:122508654:A:AG	acceptor_gain	1.0000
10:122508654:AG:A	acceptor_gain	1.0000
10:122508654:AGG:A	acceptor_loss	1.0000
10:122508654:AGGAC:A	acceptor_gain	1.0000
10:122508655:G:A	acceptor_loss	1.0000
10:122508655:G:GA	acceptor_gain	1.0000
10:122508655:GG:G	acceptor_gain	1.0000
10:122508655:GGAC:G	acceptor_gain	1.0000
10:122508655:GGACG:G	acceptor_gain	1.0000
10:122508770:GGTA:G	donor_loss	1.0000
10:122508771:GTAG:G	donor_loss	1.0000
10:122510085:T:A	acceptor_gain	1.0000
10:122510094:A:AG	acceptor_gain	1.0000

AlphaMissense

3099 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:122488940:T:C	F171L	1.000
10:122488942:T:A	F171L	1.000
10:122488942:T:G	F171L	1.000
10:122488944:T:A	I172N	1.000
10:122488980:T:A	V184D	1.000
10:122489459:G:A	G204R	1.000
10:122489459:G:C	G204R	1.000
10:122489459:G:T	G204W	1.000
10:122489460:G:A	G204E	1.000
10:122489462:T:C	S205P	1.000
10:122489463:C:A	S205Y	1.000
10:122489463:C:T	S205F	1.000
10:122489465:G:A	G206R	1.000
10:122489465:G:C	G206R	1.000
10:122489465:G:T	G206W	1.000
10:122489466:G:A	G206E	1.000
10:122489468:T:C	F207L	1.000
10:122489470:T:A	F207L	1.000
10:122489470:T:G	F207L	1.000
10:122489493:T:A	I215N	1.000
10:122489496:T:A	V216E	1.000
10:122489499:C:A	T217K	1.000
10:122489499:C:G	T217R	1.000
10:122489499:C:T	T217I	1.000
10:122489503:T:A	N218K	1.000
10:122489503:T:G	N218K	1.000
10:122489504:G:C	A219P	1.000
10:122489507:C:A	H220N	1.000
10:122489507:C:G	H220D	1.000
10:122489507:C:T	H220Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000060543 (10:122480345 G>A), RS1000076729 (10:122494318 A>G), RS1000134846 (10:122480009 A>C,G,T), RS1000230151 (10:122497734 T>C), RS1000251744 (10:122493251 T>C), RS1000265329 (10:122475660 T>A,G), RS1000331956 (10:122485717 T>C), RS1000428422 (10:122474674 T>A), RS1000484104 (10:122464123 C>T), RS1000533614 (10:122507673 T>C), RS1000545736 (10:122513200 G>A,C,T), RS1000591282 (10:122497634 C>A,T), RS1000597967 (10:122513594 G>A), RS1000707781 (10:122470393 A>G), RS1000727654 (10:122464674 G>A)

Disease associations

OMIM: gene MIM:602194 | disease phenotypes: MIM:616779, MIM:600142, MIM:125310, MIM:610149

GenCC curated gene-disease

Disease	Classification	Inheritance
CARASIL syndrome	Definitive	Autosomal recessive
cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2	Strong	Autosomal dominant
genetic cerebral small vessel disease	Strong	Autosomal dominant
HTRA1-related autosomal dominant cerebral small vessel disease	Moderate	Autosomal dominant

Mondo (9): macular degeneration (MONDO:0003004), cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (MONDO:0014768), vascular dementia (MONDO:0004648), CARASIL syndrome (MONDO:0010829), cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (MONDO:0007432), age related macular degeneration 7 (MONDO:0012419), cerebral arterial disease (MONDO:0006693), HTRA1-related autosomal dominant cerebral small vessel disease (MONDO:0018832), (MONDO:0018787)

Orphanet (3): HTRA1-related cerebral small vessel disease (Orphanet:482072), Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy (Orphanet:199354), HTRA1-related autosomal dominant cerebral small vessel disease (Orphanet:482077)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000746	Delusion
HP:0000822	Hypertension
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001269	Hemiparesis
HP:0001288	Gait disturbance
HP:0001297	Stroke
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001596	Alopecia
HP:0002063	Rigidity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002200	Pseudobulbar signs
HP:0002293	Alopecia of scalp

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000006_1	Age-related macular degeneration (wet)	8.000000e-12
GCST000652_7	Age-related macular degeneration	4.000000e-60
GCST000653_9	Age-related macular degeneration	5.000000e-119
GCST000806_2	Age-related macular degeneration	1.000000e-60
GCST001100_7	Age-related macular degeneration	4.001932e-322
GCST001571_1	Age-related macular degeneration	3.000000e-72
GCST001577_1	Age-related macular degeneration (CNV vs. GA)	7.000000e-14
GCST001578_6	Age-related macular degeneration (geographic atrophy)	7.000000e-47
GCST001579_6	Age-related macular degeneration (choroidal neovascularisation)	2.000000e-138
GCST001814_1	Age-related macular degeneration	4.000000e-24
GCST001814_29	Age-related macular degeneration	1.000000e-25
GCST001884_11	Age-related macular degeneration	0.000000e+00
GCST001899_2	Age-related macular degeneration	1.000000e-16
GCST001986_3	Age-related macular degeneration	8.000000e-27
GCST001987_1	Age-related macular degeneration (extreme sampling)	3.000000e-29
GCST002766_5	Exudative age-related macular degeneration	1.000000e-103
GCST003219_4	Advanced age-related macular degeneration	0.000000e+00
GCST003720_10	Migraine	3.000000e-08
GCST004737_4	Neovascular age-related macular degeneration	5.000000e-17
GCST004813_2	Laterality in neovascular age-related macular degeneration	2.000000e-09
GCST005194_122	Coronary artery disease	5.000000e-10
GCST005195_104	Coronary artery disease	8.000000e-11
GCST005196_40	Coronary artery disease	4.000000e-07
GCST005358_4	Disease progression to choroidal neovascularization form in age-related macular degeneration	1.000000e-25
GCST005359_1	Disease progression in age-related macular degeneration	8.000000e-43
GCST005360_2	Disease progression to geographic atrophy form in age-related macular degeneration	1.000000e-25
GCST006479_55	Diverticular disease	2.000000e-07
GCST006482_16	Lung function (FEV1/FVC)	2.000000e-08
GCST006628_23	Systolic blood pressure	3.000000e-12
GCST007267_96	Systolic blood pressure	8.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0008372	laterality measurement
EFO:0008336	disease progression measurement
EFO:0009959	diverticular disease
EFO:0004713	FEV/FVC ratio
EFO:0006335	systolic blood pressure
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002539	Cerebral Arterial Diseases	C10.228.140.300.510.200; C14.907.253.560.200
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D008268	Macular Degeneration	C11.768.585.439
C563990	Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (supp.)
C565718	Macular Degeneration, Age-Related, 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523419 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11200638	Efficacy	4	bevacizumab;ranibizumab	Macular Degeneration

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11200638	HTRA1	4	-2.75	1	bevacizumab;ranibizumab

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
galegenimab	Inhibition	9.23	pKd

Binding affinities (BindingDB)

104 measured of 104 human assays (104 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2R)-2-(3,5-dichlorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-phenylpropanamide	IC50	0.976 nM	US-9980929: Trifluoromethylpropanamide derivatives
2-(3,4-dichlorophenoxy)-3-(3,4-dichlorophenyl)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	1.18 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-(3,5-dichlorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyrazin-2-ylpropanamide	IC50	2.88 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-[[(2R)-2-(3,5-dichlorophenoxy)-3-phenylpropanoyl]amino]-3-phenyl-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]propanamide	IC50	3.31 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoylthian-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-2H-benzotriazole-5-carboxamide	IC50	4 nM	US-11377439: Heterocyclic prolinamide derivatives
(2R)-2-(3,5-dichlorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-2-ylpropanamide	IC50	4.28 nM	US-9980929: Trifluoromethylpropanamide derivatives
3-cyclohexyl-2-(3,5-dichlorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	4.47 nM	US-9980929: Trifluoromethylpropanamide derivatives
2-(3,5-difluorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-phenylpropanamide	IC50	4.53 nM	US-9980929: Trifluoromethylpropanamide derivatives
3-(3,4-dichlorophenyl)-N-[(1S)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	6 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-(3,5-dichlorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-2-ylpropanamide	IC50	6.07 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoylthian-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1-oxo-8aH-isoquinoline-3-carboxamide	IC50	7 nM	US-11377439: Heterocyclic prolinamide derivatives
(E)-3-(3,4-dichlorophenyl)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]prop-2-enamide	IC50	9 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyl-1,1-dioxothian-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indazole-6-carboxamide	IC50	9 nM	US-11377439: Heterocyclic prolinamide derivatives
3-(3-chlorophenyl)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-phenylpropanamide	IC50	10 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-[[2-(3,5-dichlorophenoxy)-2-phenylacetyl]amino]-2-phenyl-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]acetamide	IC50	10 nM	US-9980929: Trifluoromethylpropanamide derivatives
3-(3,5-dichlorophenyl)-N-[(1S)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	10 nM	US-9980929: Trifluoromethylpropanamide derivatives
(E)-3-(3,4-dichlorophenyl)-N-[(1S)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]prop-2-enamide	IC50	10 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyloxan-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indole-6-carboxamide	IC50	10 nM	US-11377439: Heterocyclic prolinamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyl-1,1-dioxothian-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1-oxo-8aH-isoquinoline-3-carboxamide	IC50	10 nM	US-11377439: Heterocyclic prolinamide derivatives
(2S)-2-(3,5-dichlorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-3-ylpropanamide	IC50	10.1 nM	US-9980929: Trifluoromethylpropanamide derivatives
3-cyclohexyl-2-(3,5-dichlorophenoxy)-N-[(2S)-1-oxo-3-phenyl-1-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]propan-2-yl]propanamide	IC50	10.6 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyl-1,1-dioxothian-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indazole-7-carboxamide	IC50	12 nM	US-11377439: Heterocyclic prolinamide derivatives
benzyl N-[7-amino-5-[[(2S,4S)-1-[(2R)-3-cyclohexyl-2-(1H-indole-6-carbonylamino)propanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-6,7-dioxoheptyl]carbamate	IC50	14 nM	US-10730832: Aliphatic prolinamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyloxan-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indole-2-carboxamide	IC50	14 nM	US-11377439: Heterocyclic prolinamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyloxan-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indazole-6-carboxamide	IC50	14 nM	US-11377439: Heterocyclic prolinamide derivatives
(2S)-3-(3-chlorophenyl)-2-[[(E)-3-(3,4-dichlorophenyl)prop-2-enoyl]amino]-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]propanamide	IC50	15 nM	US-9980929: Trifluoromethylpropanamide derivatives
3-(3,4-dichlorophenyl)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	15 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2R)-3-(4-chlorophenyl)-2-(4-methoxyphenyl)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]propanamide	IC50	15.1 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-[[2-(3,5-dichlorophenoxy)acetyl]amino]-2-phenyl-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]acetamide	IC50	20 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(1S)-1-(4-chlorophenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-(3,4-dichlorophenyl)propanamide	IC50	20 nM	US-9980929: Trifluoromethylpropanamide derivatives
benzyl N-[7-amino-5-[[(2S,4S)-1-[(2R)-3-cyclohexyl-2-(1H-indole-2-carbonylamino)propanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-6,7-dioxoheptyl]carbamate	IC50	20 nM	US-10730832: Aliphatic prolinamide derivatives
3-(3-chlorophenyl)-N-[(1S)-1-(3-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-phenylpropanamide	IC50	23 nM	US-9980929: Trifluoromethylpropanamide derivatives
benzyl N-[7-amino-5-[[(2S,4S)-1-[(2R)-3-cyclohexyl-2-(1H-indole-5-carbonylamino)propanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-6,7-dioxoheptyl]carbamate	IC50	23 nM	US-10730832: Aliphatic prolinamide derivatives
benzyl N-[5-[[(2S,4S)-1-[(2R)-2-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazole-6-carbonylamino)-3-cyclohexylpropanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-7-amino-6,7-dioxoheptyl]carbamate	IC50	24 nM	US-10730832: Aliphatic prolinamide derivatives
(E)-N-[(1S)-1-(4-chlorophenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-(3,4-dichlorophenyl)prop-2-enamide	IC50	25 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyloxan-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-2H-benzotriazole-5-carboxamide	IC50	29 nM	US-11377439: Heterocyclic prolinamide derivatives
7-bromo-5-chloro-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-1-benzofuran-2-carboxamide	IC50	30 nM	US-9980929: Trifluoromethylpropanamide derivatives
benzyl N-[5-[[(2S,4S)-1-[(2R)-2-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazole-7-carbonylamino)-3-cyclohexylpropanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-7-amino-6,7-dioxoheptyl]carbamate	IC50	30 nM	US-10730832: Aliphatic prolinamide derivatives
benzyl N-[5-[[(2S,4S)-1-[(2R)-2-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazole-5-carbonylamino)-3-cyclohexylpropanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-7-amino-6,7-dioxoheptyl]carbamate	IC50	34 nM	US-10730832: Aliphatic prolinamide derivatives
(2S)-3-(4-chlorophenyl)-2-[[3-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)propanoyl]amino]-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]propanamide	IC50	35 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)acetyl]amino]-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]acetamide	IC50	35 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(1-oxamoylcyclohexyl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-1H-indazole-7-carboxamide	IC50	36.8 nM	US-11267803: Carbocyclic prolinamide derivatives
(2S)-2-[[3-(3-chlorophenyl)-3-phenylpropanoyl]amino]-3-phenyl-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]propanamide	IC50	37 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2S)-2-(3,5-dichlorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-2-ylpropanamide	IC50	37.3 nM	US-9980929: Trifluoromethylpropanamide derivatives
benzyl N-[7-amino-5-[[(2S,4S)-1-[(2R)-3-cyclohexyl-2-[(1-oxo-3,4,4a,5,6,7,8,8a-octahydro-2H-isoquinoline-3-carbonyl)amino]propanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-6,7-dioxoheptyl]carbamate	IC50	38 nM	US-10730832: Aliphatic prolinamide derivatives
benzyl N-[5-[[(2S,4S)-1-[(2R)-2-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazole-4-carbonylamino)-3-cyclohexylpropanoyl]-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]pyrrolidine-2-carbonyl]amino]-7-amino-6,7-dioxoheptyl]carbamate	IC50	43 nM	US-10730832: Aliphatic prolinamide derivatives
(2S)-3-(4-chlorophenyl)-2-[[2-(3,5-dichlorophenoxy)acetyl]amino]-N-[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]propanamide	IC50	45 nM	US-9980929: Trifluoromethylpropanamide derivatives
N-[(2R)-3-cyclohexyl-1-[(2S,4S)-4-[5-(2-hydroxypropan-2-yl)triazol-1-yl]-2-[(4-oxamoyloxan-4-yl)carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]-3H-benzimidazole-5-carboxamide	IC50	45 nM	US-11377439: Heterocyclic prolinamide derivatives
(2R)-2-(3,5-dichlorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)-2-oxo-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyrazin-2-ylpropanamide	IC50	48.3 nM	US-9980929: Trifluoromethylpropanamide derivatives
(2R)-2-(3,5-dichlorophenoxy)-N-[(1S)-2-oxo-1-phenyl-2-[[(3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl]amino]ethyl]-3-pyridin-2-ylpropanamide	IC50	48.6 nM	US-9980929: Trifluoromethylpropanamide derivatives

ChEMBL bioactivities

1268 potent at pChembl≥5 of 1271 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.58	IC50	0.262	nM	CHEMBL4589967
9.53	IC50	0.293	nM	CHEMBL4554156
9.52	IC50	0.3	nM	CHEMBL4542635
9.52	IC50	0.3	nM	CHEMBL4471645
9.52	IC50	0.3	nM	CHEMBL4533165
9.46	IC50	0.351	nM	CHEMBL4471714
9.40	IC50	0.4	nM	CHEMBL4540590
9.40	IC50	0.4	nM	CHEMBL4461666
9.40	IC50	0.4	nM	CHEMBL4585025
9.40	IC50	0.4	nM	CHEMBL4588306
9.40	IC50	0.4	nM	CHEMBL4551033
9.40	IC50	0.4	nM	CHEMBL5085441
9.34	IC50	0.461	nM	CHEMBL4472162
9.33	IC50	0.471	nM	CHEMBL4472070
9.31	IC50	0.49	nM	CHEMBL5074107
9.30	IC50	0.5	nM	CHEMBL4446982
9.30	IC50	0.5	nM	CHEMBL4453892
9.30	IC50	0.5	nM	CHEMBL4462378
9.30	IC50	0.5	nM	CHEMBL4557186
9.30	IC50	0.5	nM	CHEMBL4441695
9.30	IC50	0.5	nM	CHEMBL4542403
9.30	IC50	0.5	nM	CHEMBL4520550
9.30	IC50	0.5	nM	CHEMBL4576875
9.30	IC50	0.5	nM	CHEMBL4447637
9.30	IC50	0.5	nM	CHEMBL5085715
9.30	IC50	0.5	nM	CHEMBL6004725
9.27	IC50	0.538	nM	CHEMBL4517216
9.26	IC50	0.55	nM	CHEMBL4451038
9.24	IC50	0.574	nM	CHEMBL4462973
9.24	IC50	0.579	nM	CHEMBL4447513
9.22	IC50	0.6	nM	CHEMBL4530656
9.22	IC50	0.6	nM	CHEMBL4459683
9.22	IC50	0.6	nM	CHEMBL4468950
9.22	IC50	0.6	nM	CHEMBL4533961
9.22	IC50	0.6	nM	CHEMBL4524175
9.22	IC50	0.6	nM	CHEMBL4581447
9.22	IC50	0.602	nM	CHEMBL5083134
9.22	IC50	0.6	nM	CHEMBL5080837
9.21	IC50	0.62	nM	CHEMBL5075130
9.21	IC50	0.62	nM	CHEMBL5089492
9.18	IC50	0.667	nM	CHEMBL4587944
9.16	IC50	0.694	nM	CHEMBL4449164
9.16	IC50	0.686	nM	CHEMBL4450427
9.16	IC50	0.695	nM	CHEMBL5074725
9.15	IC50	0.7	nM	CHEMBL4444635
9.15	IC50	0.711	nM	CHEMBL4436099
9.15	IC50	0.71	nM	CHEMBL5076217
9.15	IC50	0.7	nM	CHEMBL5087160
9.12	IC50	0.76	nM	CHEMBL5075529
9.12	IC50	0.76	nM	CHEMBL5778730

PubChem BioAssay actives

23 with measured affinity, of 58 total; 23 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
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0100	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[(2,2-dimethyl-3-phenylpropanoyl)amino]propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0110	uM
[(R)-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[(2,2-dimethyl-3-phenylpropanoyl)amino]propanoyl]amino]-4-methylpentanoyl]amino]-cyclobutylmethyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0130	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-bromophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0170	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(3-methylphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0450	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(4-chlorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0730	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-fluorophenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.0880	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(3-phenylpropanoylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.1040	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4110	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-cyclohexyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4660	uM
[(1R)-1-[[(2S)-2-[[(2S)-2-(benzylcarbamoylamino)-3-(3-chlorophenyl)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.4950	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	0.5900	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(1-oxidopyridin-1-ium-3-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	0.6540	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-3-(1-oxidopyridin-1-ium-4-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	1.5400	uM
[(1R)-2-methyl-1-[[(2S)-4-methyl-2-[[(2S)-2-(phenylmethoxycarbonylamino)heptanoyl]amino]pentanoyl]amino]propyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	1.9200	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	2.0000	uM
(3S)-3-amino-4-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-borono-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-methylsulfanyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-oxobutanoic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	2.6000	uM
[(1R)-1-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-(3-phenylpropylamino)propanoyl]amino]-4-methylpentanoyl]amino]-2-methylpropyl]boronic acid	2112394: Inhibition of HTRA1 (unknown origin)	ic50	4.9000	uM
4-[[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4,4-dimethyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	6.0000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-3-cyclopropyl-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	6.3000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.3000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	7.7000	uM
4-[[6-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(1R)-1-diphenoxyphosphoryl-2-methylpropyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-6-oxohexyl]carbamoyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1954717: Inhibition of recombinant human HTRA1 using H2-OPT as substrate assessed as increase in fluorescence and measured for 2 hrs by fluorescent plate reader analysis	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	3
graphene oxide	increases expression	2
bisphenol A	increases expression, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
chloropicrin	affects expression, decreases expression	2
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
WT161	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, increases expression	1
tirbanibulin	decreases reaction, increases expression	1
terbufos	increases methylation	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
octa-2,4,6-trienoic acid	increases expression	1
chromium hexavalent ion	increases expression, increases abundance	1
seocalcitol	increases expression	1
corosolic acid	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1

ChEMBL screening assays

28 unique, capped per target: 28 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418419	Binding	Inhibition of N-terminal 6xHis-SUMO tagged human HTRA1 catalytic-PDZ domain (D161 to P480 residues) expressed in Escherichia coli BL21 (DE3) cells using Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys as substrate preincubated for 30 mins	New difluoroketamide derivatives as htra1 inhibitors

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1870	MEC-1	Cancer cell line	Male
CVCL_C0JG	KEIOi003-A	Induced pluripotent stem cell	Female
CVCL_C1LH	HAP1 HTRA1 (-) 1	Cancer cell line	Male
CVCL_C1LI	HAP1 HTRA1 (-) 2	Cancer cell line	Male
CVCL_C9ME	BJTTHi003-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00312351	PHASE4	TERMINATED	A Clinical Trial to Explore the Safety and Efficacy of Three Different Doses of Pegaptanib Sodium in Patients With Wet Age-Related Macular Degeneration (AMD)
NCT00324116	PHASE4	COMPLETED	Evaluation Of Safety And Efficacy Of 0.3 Mg/Eye Macugen In Patients With Small Age-Related Macular Degeneration Lesions
NCT00327470	PHASE4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00533520	PHASE4	COMPLETED	Evaluation of Dosing Interval of Higher Doses of Ranibizumab
NCT00813891	PHASE4	UNKNOWN	Efficacy of Ranibizumab in Combination With Photodynamic Therapy for Wet Age-Related Macular Degeneration
NCT01006538	PHASE4	COMPLETED	Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT)
NCT01213667	PHASE4	UNKNOWN	Genetics in Non-response to Anti-VEGF Treatment in Exudative AMD
NCT01831947	PHASE4	COMPLETED	Efficacy Study of Ranibizumab on Patients With Age-related Macular Degeneration.
NCT02581891	PHASE4	COMPLETED	Managing Neovascular (Known as Wet) Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye
NCT02689518	PHASE4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT03804099	PHASE4	COMPLETED	Effect Aflibercept on Ocular Perfusion
NCT07367282	PHASE4	NOT_YET_RECRUITING	Evaluate the Efficacy of Faricimab in Patients With Neovascular Age-related Macular Degeneration
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00000145	PHASE3	COMPLETED	Age-Related Eye Disease Study (AREDS)
NCT00000150	PHASE3	COMPLETED	Submacular Surgery Trials (SST)
NCT00000152	PHASE3	UNKNOWN	Randomized Trial of Beta-Carotene and Macular Degeneration
NCT00000158	PHASE3	UNKNOWN	Macular Photocoagulation Study (MPS)
NCT00000161	PHASE3	UNKNOWN	Randomized Trials of Vitamin Supplements and Eye Disease
NCT00000162	PHASE3	COMPLETED	Branch Vein Occlusion Study
NCT00000167	PHASE3	COMPLETED	Complications of Age-Related Macular Degeneration Prevention Trial
NCT00041483	PHASE3	COMPLETED	Phase 3 Study to Evaluate Anecortave Acetate vs. Visudyne for the Treatment of the Wet Form of AMD
NCT00042211	PHASE3	COMPLETED	Preventing Depression in Patients With Macular Degeneration
NCT00050479	PHASE3	COMPLETED	Laser and Medical Treatment of Diabetic Macular Edema
NCT00051129	PHASE3	COMPLETED	Anecortave Acetate in Subfoveal Choroidal Neovascularization (CNV) Due to Wet Age-Related Macular Degeneration (AMD)
NCT00056836	PHASE3	COMPLETED	A Study to Evaluate rhuFab V2 in Subjects With Minimally Classic or Occult Subfoveal Neovascular Macular Degeneration
NCT00058994	PHASE3	COMPLETED	An Evaluation of Safety and Efficacy of Anecortave Acetate Versus Placebo in Patients With Subfoveal CNV Due to Exudative AMD
NCT00061594	PHASE3	COMPLETED	A Study to Compare rhuFab V2 With Verteporfin Photodynamic in Treating Subfoveal Neovascular Macular Degeneration
NCT00065728	PHASE3	TERMINATED	Open-Label Posterior Juxtascleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients With AMD
NCT00078221	PHASE3	UNKNOWN	Rheopheresis Blood Filtration Study for the Treatment of Dry Age-Related Macular Degeneration (AMD)
NCT00090623	PHASE3	COMPLETED	A Study of rhuFab V2 (Ranibizumab) in Subjects With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD)
NCT00095433	PHASE3	COMPLETED	Extension Study of rhuFab V2 in Subjects With Neovascular Age-Related Macular Degeneration (AMD)
NCT00100009	PHASE3	COMPLETED	Triamcinolone Acetonide Plus Laser Therapy to Treat Age-Related Macular Degeneration
NCT00121407	PHASE3	COMPLETED	Visudyne® in Occult (VIO)
NCT00150202	PHASE3	COMPLETED	Clinical Study Of EYE001 For Wet-Type AMD (Age-Related Macular Degeneration)
NCT00157976	PHASE3	UNKNOWN	Double-Masked Study of Photrex (Rostaporfin) Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration
NCT00242580	PHASE3	COMPLETED	A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib
NCT00299507	PHASE3	COMPLETED	Anecortave Acetate in Patients With Exudative Age-related Macular Degeneration (AMD)