PGC

Summary

PGC (progastricsin, HGNC:8890) is a protein-coding gene on chromosome 6p21.1, encoding Gastricsin (P20142). Hydrolyzes a variety of proteins.

This gene encodes an aspartic proteinase that belongs to the peptidase family A1. The encoded protein is a digestive enzyme that is produced in the stomach and constitutes a major component of the gastric mucosa. This protein is also secreted into the serum. This protein is synthesized as an inactive zymogen that includes a highly basic prosegment. This enzyme is converted into its active mature form at low pH by sequential cleavage of the prosegment that is carried out by the enzyme itself. Polymorphisms in this gene are associated with susceptibility to gastric cancers. Serum levels of this enzyme are used as a biomarker for certain gastric diseases including Helicobacter pylori related gastritis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 1.

Source: NCBI Gene 5225 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 72 total
• Druggable target: yes
• MANE Select transcript: NM_002630

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8890
Approved symbol	PGC
Name	progastricsin
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000096088
Ensembl biotype	protein_coding
OMIM	169740
Entrez	5225

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000356667, ENST00000373025, ENST00000415707, ENST00000425343, ENST00000950078, ENST00000950079, ENST00000950080

RefSeq mRNA: 2 — MANE Select: NM_002630 NM_001166424, NM_002630

CCDS: CCDS4859, CCDS55000

Canonical transcript exons

ENST00000373025 — 9 exons

Exon	Start	End
ENSE00000750752	41744658	41744808
ENSE00001814259	41736711	41737004
ENSE00001958407	41747276	41747397
ENSE00002162675	41744397	41744514
ENSE00002167075	41743271	41743389
ENSE00002434047	41740491	41740610
ENSE00002455652	41737730	41737828
ENSE00002472868	41739799	41739946
ENSE00002729699	41742290	41742489

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 99.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 20.2273 / max 16491.2838, expressed in 51 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73567	20.2273	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	99.99	gold quality
cardia of stomach	UBERON:0001162	99.96	gold quality
lower lobe of lung	UBERON:0008949	99.28	gold quality
seminal vesicle	UBERON:0000998	98.65	gold quality
right uterine tube	UBERON:0001302	96.08	gold quality
body of stomach	UBERON:0001161	95.46	gold quality
stomach	UBERON:0000945	94.76	gold quality
upper lobe of lung	UBERON:0008948	93.97	gold quality
upper lobe of left lung	UBERON:0008952	93.58	gold quality
fundus of stomach	UBERON:0001160	91.76	gold quality
lung	UBERON:0002048	91.50	gold quality
body of pancreas	UBERON:0001150	88.21	gold quality
ileal mucosa	UBERON:0000331	87.04	gold quality
duodenum	UBERON:0002114	86.31	gold quality
lower esophagus mucosa	UBERON:0035834	84.53	gold quality
right lung	UBERON:0002167	84.14	gold quality
right coronary artery	UBERON:0001625	82.90	gold quality
pancreatic ductal cell	CL:0002079	82.07	silver quality
prostate gland	UBERON:0002367	80.81	gold quality
mucosa of stomach	UBERON:0001199	80.47	gold quality
endocervix	UBERON:0000458	79.79	gold quality
pancreas	UBERON:0001264	78.81	gold quality
ectocervix	UBERON:0012249	78.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.06	gold quality
left uterine tube	UBERON:0001303	73.86	gold quality
visceral pleura	UBERON:0002401	73.67	gold quality
metanephros cortex	UBERON:0010533	73.17	gold quality
right ovary	UBERON:0002118	72.54	gold quality
descending thoracic aorta	UBERON:0002345	72.39	gold quality
adult organism	UBERON:0007023	71.63	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	6409.40
E-GEOD-86618	yes	1168.42
E-HCAD-1	yes	83.95
E-GEOD-130148	yes	12.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

13 targeting PGC, 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-4283	100.00	66.42	2097
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-188-5P	97.89	67.01	756
HSA-MIR-6866-3P	97.38	66.94	748
HSA-MIR-7106-3P	97.33	65.33	644
HSA-MIR-10398-5P	97.12	64.94	1051

Literature-anchored findings (GeneRIF, showing 40)

• Pepsinogen C is expressed in a quarter of ovarian carcinomas and might identify a subset of patients with different prognosis (PMID:12128264)
• These results suggest that there is some relation between pepsinogen C gene polymorphism and gastric cancer, and the person with homogenous allele 1 predisposes to gastric cancer more than those with other genotypes. (PMID:12508350)
• results suggested that only the PGA/PGC ratio can be considered as a biomarker for precancerous lesions of the stomach (PMID:12698190)
• human cathelicidin antimicrobial peptide-18 in seminal plasma is processed to generate a 38-amino acid antimicrobial peptide ALL-38 by the prostate-derived protease gastricsin when incubated at a pH corresponding to the vaginal pH (PMID:12759353)
• Pepsinogen C can be a good indicator in the screening and diagnosis of precursor of gastric cancer and gastric cancer. (PMID:15200883)
• pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors (PMID:15503827)
• Higher levels of Pepsinogen II is associated with early gastric cancer (PMID:15688378)
• pepsinogen C genetic variants have a role in gastric cancer (PMID:16937501)
• Helicobacter pylori eradication improves gastric histology and decreases serum gastrin, pepsinogen I and pepsinogen II levels in patients with duodenal ulcer. (PMID:17559360)
• pepsinogen C has a role in SP-B proteolytic processing in alveolar type 2 cells (PMID:18256027)
• role of an insertion/deletion polymorphism in the Pepsinogen C (PGC) gene in the clinical outcome of 172 breast cancer patients (PMID:18447628)
• pepsinogens may have a role in esophageal squamous dysplasia (PMID:18844222)
• The pepsinogen C gene polymorphism increases an individual’s susceptibility to gastric cancer and its precancerous conditions (PMID:19132389)
• Pepsinogen C insertion/deletion polymorphism and Helicobacter pylori infection seem to present a positive interaction in the development of gastric cancer. (PMID:19173902)
• PGC gene insertion/deletion polymorphism is negatively related to PGC protein expression in gastric mucosa, but is not related to the serum PGC level. (PMID:19624876)
• Decreased pepsinogen I/II ratio is a reliable marker for atrophy in the stomach corpus. (PMID:19731026)
• Chinese patients with sPGII greater than 10.25 microg/L are at greater risk of various H. pylori-related gastropathies. (PMID:21303408)
• Serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients, were measured. (PMID:22066020)
• Data suggest that serum pepsinogen I/II ratio (pepsinogen A/C ratio) is correlated with diabetic nephropathy and thus may be a biological marker for degree of urinary albumin excretion in patients with type 2 diabetes. (PMID:23047493)
• The serum levels of PG II and G-17 were significantly higher in Changle than those in Fuan. (PMID:23117263)
• Data suggest that subjects with higher PGI level, and PG I/II ratio are more likely to develop several dyspeptic symptoms. (PMID:23178618)
• Levels of pepsinogen/pepsin A and C are higher in the mouth swabs of infants with clinical gastroesophageal reflux. (PMID:23311720)
• plasma PG II level significantly correlated with H. pylori-infected gastric cancer (PMID:23326145)
• PGC rs6458238, PGC rs4711690 and PTPN11 rs12229892 were associated with susceptibilities to atrophic gastritis and/or gastric cancer. (PMID:23455381)
• High serum pepsinogen II is associated with gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis. (PMID:24009139)
• Pepsin and pepsinogen in middle ear effusion are probably caused by LPR and may be involved in the pathogenesis of OME. (PMID:24284944)
• An interaction effect of pri-let-7a-1 rs10739971 polymorphism with ERCC6 rs1917799 polymorphism was observed for the risk of gastric cancer. (PMID:24586594)
• High serum Pepsinogen II level is associ9ated with the progression of gastric precancerous lesions. (PMID:24895149)
• Pepsinogen II is a good marker of corpus morphological changes before and after H. pylori eradication. (PMID:25028655)
• The results highlight an important role of PGC rs3789210 and rs6939861 in altering susceptibility to atrophic gastritis and/or gastric cancer. (PMID:25551587)
• Results suggest that rs9471643 CG and rs6458238 AG/AA genotypes have important roles in up-regulating PGC expression, which may partially explain why individuals with these favorable genotypes have decreased risks of getting gastric cancer. (PMID:25857852)
• Data show that SNP interactions among H. pylori-related genes PGC, PTPN11, and IL1B, are associated with susceptibility to gastric carcinogenesis. (PMID:26158864)
• Pepsinogen-II 100 bp ins/del gene polymorphism and its elevated circulating levels are associated with gastric cancer, particularly with Helicobacter pylori infection and intestinal metaplasia. (PMID:26486507)
• serum levels correlated with age, sex and the level of Helicobacter pylori infection (PMID:27865295)
• Recombinant pepsin C and pepsinogen C were purified from transgenic rice culture medium, and the NH2-terminal 5-residue sequences were verified by amino acid sequencing. (PMID:29108629)
• Study found 15 pairwise PGC-lncRNAs SNPs had interactions: five pairs were associated with atrophic gastritis (AG) risk, and ten pairs were associated with gastric cancer (GC) risk. Several combinations showed obvious epistasis and cumulative effects on disease risk for AG and GC. (PMID:30155999)
• Clinical correlation between serum pepsinogen level and gastric atrophy in gastric neoplasm. (PMID:30400679)
• Diagnostic value of serum pepsinogen I, pepsinogen II, and gastrin-17 levels for population-based screening for early-stage gastric cancer. (PMID:32228342)
• the pepsinogen I/II ratio was the most reliable gastric mucosal-change biomarker. (PMID:32271765)
• Association between serum pepsinogen and atherosclerotic cardiovascular disease. (PMID:33127250)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pgc	ENSMUSG00000023987
rattus_norvegicus	Pgc	ENSRNOG00000014492
drosophila_melanogaster	Bace	FBGN0032049
drosophila_melanogaster	CG6508	FBGN0032303
drosophila_melanogaster	CG17134	FBGN0032304
drosophila_melanogaster	CG33128	FBGN0053128
caenorhabditis_elegans		WBGENE00000214
caenorhabditis_elegans		WBGENE00000218
caenorhabditis_elegans		WBGENE00012681
caenorhabditis_elegans		WBGENE00012682
caenorhabditis_elegans		WBGENE00012683
caenorhabditis_elegans		WBGENE00013973
caenorhabditis_elegans		WBGENE00017678
caenorhabditis_elegans		WBGENE00019104
caenorhabditis_elegans		WBGENE00019105
caenorhabditis_elegans		WBGENE00077655

Paralogs (9): CTSD (ENSG00000117984), NAPSA (ENSG00000131400), REN (ENSG00000143839), BACE2 (ENSG00000182240), BACE1 (ENSG00000186318), CTSE (ENSG00000196188), PGA4 (ENSG00000229183), PGA3 (ENSG00000229859), PGA5 (ENSG00000256713)

Protein

Protein identifiers

Gastricsin — P20142 (reviewed: P20142)

Alternative names: Pepsinogen C

All UniProt accessions (3): P20142, A2A3L9, Q4VXA6

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes a variety of proteins.

Subcellular location. Secreted.

Similarity. Belongs to the peptidase A1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P20142-1	1	yes
P20142-2	2

RefSeq proteins (2): NP_001159896, NP_002621* (*=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

Pfam: PF00026, PF07966

Enzyme classification (BRENDA):

• EC 3.4.23.3 — gastricsin (BRENDA: 10 organisms, 37 substrates, 18 inhibitors, 14 Km, 13 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-TYR-LEU-VAL-HIS METHYL ESTER	0.28–1.71	3
ACETYL-TYR-LEU-VAL-HIS-NH2	0.82–4.31	3
ACETYL-ALA-PHE-LEU-VAL-HIS-NH2	0.51–0.7	2
ACETYL-PHE-LEU-VAL-HIS-NH2	1.84–2.76	2
PRO-THR-GLU-PHE-(NO2)PHE-ARG-LEU	0.098–0.42	2
ACETYL-PHE-LEU-VAL-HIS METHYL ESTER	1.84	1
ACETYL-TYR-LEU-VAL-HIS-OH	0.82	1

UniProt features (55 total): strand 24, helix 16, turn 3, disulfide bond 3, sequence conflict 2, active site 2, signal peptide 1, propeptide 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1HTR	X-RAY DIFFRACTION	1.62
1AVF	X-RAY DIFFRACTION	2.36

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20142-F1	88.60	0.67

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): 91; 276

Disulfide bonds (3): 104–109, 267–271, 310–343

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 121 (showing top): MODULE_172, GOBP_DIGESTION, MODULE_92, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MODULE_379, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_HUMORAL_IMMUNE_RESPONSE, MODULE_88, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE

GO Biological Process (3): positive regulation of antibacterial peptide production (GO:0002803), proteolysis (GO:0006508), digestion (GO:0007586)

GO Molecular Function (3): aspartic-type endopeptidase activity (GO:0004190), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of antimicrobial peptide production	1
antibacterial peptide production	1
regulation of antibacterial peptide production	1
positive regulation of defense response to bacterium	1
protein metabolic process	1
multicellular organismal process	1
endopeptidase activity	1
aspartic-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGC	PGM1	P36871	830
PGC	PGD	P52209	796
PGC	CNDP2	Q96KP4	793
PGC	VPS18	Q9P253	784
PGC	F13B	P05160	690
PGC	NPR1	P16066	686
PGC	AK2	P54819	682
PGC	MPG	P29372	680
PGC	PEPD	P12955	654
PGC	PROC	P04070	649
PGC	FUCA1	P04066	594
PGC	PGM2	Q96G03	590
PGC	NPR3	P17342	588
PGC	GUCA2A	Q02747	575
PGC	CMPK1	P30085	547

IntAct

3 interactions, top by confidence:

A	B	Type	Score
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
TEX101	MAP4K4	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): PGC (Synthetic Lethality), PGC (Affinity Capture-MS), CCNT1 (Affinity Capture-Western), CDK9 (Affinity Capture-Western), PGC (Cross-Linking-MS (XL-MS)), ESR1 (Reconstituted Complex), PGC (Affinity Capture-MS)

ESM2 similar proteins: O93428, P00791, P00792, P00793, P00794, P00795, P03954, P03955, P04073, P0DJD7, P0DJD8, P0DJD9, P11489, P14091, P16228, P16476, P18276, P20142, P25796, P27677, P27678, P27821, P27822, P27823, P28712, P28713, P43159, P56272, P70269, P81497, P81498, Q03168, Q28389, Q64411, Q689Z7, Q800A0, Q805F2, Q805F3, Q8SQ41, Q9D7R7

Diamond homologs: A0A146F0J0, A1CBR4, A1DDK1, A2R3L3, B0Y1V8, B6HL60, B8MF81, B8NLY9, C5FBS2, C5FW52, C5FZ57, C5PEI9, D4AIC4, D4ANC3, D4AT39, D4D7C5, D4DE18, D4DGR1, E5A7T3, E5R1B9, O01530, O13340, O60020, O65390, O76856, O93885, P00791, P00792, P00798, P03954, P03955, P04073, P06026, P0CU33, P0DJD7, P0DJD8, P0DJD9, P10602, P11489, P11838

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1424 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41737723:GACTT:G	donor_loss	1.0000
6:41737724:ACTT:A	donor_loss	1.0000
6:41737725:CTTAC:C	donor_loss	1.0000
6:41737726:TTACA:T	donor_loss	1.0000
6:41737727:T:TG	donor_loss	1.0000
6:41737728:A:AC	donor_gain	1.0000
6:41737728:A:T	donor_loss	1.0000
6:41737729:C:CC	donor_gain	1.0000
6:41737729:CA:C	donor_gain	1.0000
6:41737729:CACT:C	donor_gain	1.0000
6:41737729:CACTG:C	donor_gain	1.0000
6:41737824:AGAAA:A	acceptor_gain	1.0000
6:41737825:GAAA:G	acceptor_gain	1.0000
6:41737826:AAA:A	acceptor_gain	1.0000
6:41737826:AAAC:A	acceptor_loss	1.0000
6:41737827:AA:A	acceptor_gain	1.0000
6:41737828:ACTG:A	acceptor_loss	1.0000
6:41737829:C:CC	acceptor_gain	1.0000
6:41737829:CTG:C	acceptor_loss	1.0000
6:41739807:A:AC	donor_gain	1.0000
6:41739808:C:CC	donor_gain	1.0000
6:41739811:AT:A	donor_gain	1.0000
6:41739811:ATCCT:A	donor_gain	1.0000
6:41740489:A:AC	donor_gain	1.0000
6:41740490:C:CC	donor_gain	1.0000
6:41740490:CT:C	donor_gain	1.0000
6:41741114:A:AC	donor_gain	1.0000
6:41741115:C:CC	donor_gain	1.0000
6:41742284:GCTCA:G	donor_loss	1.0000
6:41742285:CTCAC:C	donor_loss	1.0000

AlphaMissense

2556 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41736868:A:G	F384S	0.997
6:41736928:C:A	G364V	0.997
6:41736929:C:A	G364W	0.997
6:41742304:G:C	S211R	0.997
6:41742304:G:T	S211R	0.997
6:41742306:T:G	S211R	0.997
6:41736938:A:G	W361R	0.996
6:41736938:A:T	W361R	0.996
6:41742409:A:C	F176L	0.996
6:41742409:A:T	F176L	0.996
6:41742411:A:G	F176L	0.996
6:41744452:G:C	D91E	0.996
6:41744452:G:T	D91E	0.996
6:41744453:T:A	D91V	0.996
6:41744487:C:A	G80W	0.996
6:41739884:G:A	T277I	0.995
6:41739886:G:C	D276E	0.995
6:41739886:G:T	D276E	0.995
6:41743373:G:C	F115L	0.995
6:41743373:G:T	F115L	0.995
6:41743375:A:G	F115L	0.995
6:41744433:A:G	W98R	0.995
6:41744433:A:T	W98R	0.995
6:41744453:T:G	D91A	0.995
6:41736928:C:T	G364E	0.994
6:41739881:C:A	G278V	0.994
6:41739888:C:G	D276H	0.994
6:41740510:A:G	W250R	0.994
6:41740510:A:T	W250R	0.994
6:41742448:A:C	S163R	0.994

dbSNP variants (sampled 300 via entrez): RS1000033663 (6:41747796 T>A,G), RS1000188570 (6:41746252 G>A), RS1000408957 (6:41746533 G>A), RS1000831353 (6:41740290 A>C,G), RS1000985009 (6:41747612 G>A,C), RS1001478746 (6:41736415 G>A), RS1002131531 (6:41745116 T>G), RS1002311178 (6:41742184 C>T), RS1002474268 (6:41739244 G>A,C), RS1002646434 (6:41743446 C>A,T), RS1002864779 (6:41738145 C>A,T), RS1003040963 (6:41743718 A>G), RS1003082062 (6:41748288 G>C,T), RS1003376459 (6:41745018 C>A,T), RS1003480760 (6:41739141 G>A)

Disease associations

OMIM: gene MIM:169740 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010989_270	Body size at age 10	3.000000e-12
GCST90002398_367	Neutrophil count	8.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2136 (SINGLE PROTEIN)

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 3 [PMID: 8410973]	Inhibition	9.05	pKi

ChEMBL bioactivities

26 potent at pChembl≥5 of 27 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.05	Ki	0.9	nM	CHEMBL287423
8.14	Ki	7.2	nM	CHEMBL3142508
8.10	Ki	8	nM	CHEMBL62380
8.05	Ki	9	nM	CHEMBL88415
8.04	Ki	9.2	nM	CHEMBL3142505
7.89	Ki	13	nM	CHEMBL313773
7.85	Ki	14	nM	CHEMBL3142513
7.72	Ki	19	nM	CHEMBL84970
7.29	Ki	51	nM	CHEMBL3142507
7.11	Ki	78	nM	CHEMBL3142506
6.96	Ki	110	nM	CHEMBL418948
6.68	Ki	210	nM	CHEMBL3142509
6.00	IC50	1000	nM	CHEMBL173204
6.00	IC50	1000	nM	CHEMBL353944
6.00	IC50	1000	nM	CHEMBL169870
6.00	IC50	1000	nM	CHEMBL355128
6.00	IC50	1000	nM	CHEMBL1169538
6.00	IC50	1000	nM	CHEMBL170504
6.00	IC50	1000	nM	CHEMBL1169539
6.00	IC50	1000	nM	CHEMBL354505
6.00	IC50	1000	nM	CHEMBL171236
6.00	IC50	1000	nM	CHEMBL354360
6.00	IC50	1000	nM	CHEMBL170772
6.00	IC50	1000	nM	CHEMBL405692
6.00	IC50	1000	nM	CHEMBL94797

PubChem BioAssay actives

24 with measured affinity, of 49 total; 24 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
(4S)-5-cyclohexyl-2,2-difluoro-N-(2-morpholin-4-ylethyl)-4-[[(2S)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]pent-4-enoyl]amino]-3-oxopentanamide	74342: Binding affinity against human gastricsin	ki	0.0009	uM
methyl (2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]propanoyl]amino]pentanoyl]amino]heptanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.0072	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	74342: Binding affinity against human gastricsin	ki	0.0080	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	74342: Binding affinity against human gastricsin	ki	0.0090	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-2-[[(2S)-4-methyl-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]pentanoyl]amino]propanoyl]amino]heptanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.0092	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	74342: Binding affinity against human gastricsin	ki	0.0130	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]heptanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.0140	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	74342: Binding affinity against human gastricsin	ki	0.0190	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]propanoyl]amino]propanoyl]amino]heptanoyl]amino]-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.0510	uM
methyl (2S)-2-[[(2S)-2-[[(3S,4S)-3-hydroxy-6-methyl-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]propanoyl]amino]propanoyl]amino]heptanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.0780	uM
(2S)-N-[(2S,3S,5S)-1-cyclohexyl-3,5-dihydroxyheptan-2-yl]-6-(methylcarbamothioylamino)-2-[[(2S)-2-(morpholin-4-ylsulfonylamino)-3-phenylpropanoyl]amino]hexanamide	74342: Binding affinity against human gastricsin	ki	0.1100	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(3S,4S)-3-hydroxy-6-methyl-1-[[(2S)-1-(3-methylbutylamino)-1-oxopropan-2-yl]amino]-1-oxoheptan-4-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	156589: Compound was tested for inhibition of Rhizopus chinensis pepsin.	ki	0.2100	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3S)-1-methyl-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3R)-1-methyl-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1R,2S)-3-cyclohexyl-1-hydroxy-1-(1-methyl-2-oxopyrrolidin-3-yl)propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-[(3S,5S)-5-ethenyl-1-methyl-2-oxopyrrolidin-3-yl]-1-hydroxypropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-[(3S,5R)-5-ethenyl-1-methyl-2-oxopyrrolidin-3-yl]-1-hydroxypropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3S,5S)-1-methyl-2-oxo-5-(phenylmethoxymethyl)pyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3S,5S)-5-(methoxymethyl)-1-methyl-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3S)-1,5,5-trimethyl-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-1-[(3S)-1-butyl-5,5-dimethyl-2-oxopyrrolidin-3-yl]-3-cyclohexyl-1-hydroxypropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-[(3S)-1-cyclohexyl-2-oxopyrrolidin-3-yl]-1-hydroxypropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1S,2S)-3-cyclohexyl-1-hydroxy-1-[(3S,5S)-5-(hydroxymethyl)-1-methyl-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM
tert-butyl N-[(2S)-1-[[(2S)-1-[[(1R,2S)-3-cyclohexyl-1-hydroxy-1-(1-methyl-2-oxoazepan-3-yl)propan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	74338: Inhibitory concentration against Gastricsin	ic50	1.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Benzo(a)pyrene	affects methylation, affects expression	2
Cadmium	decreases expression, increases abundance	2
Cadmium Chloride	decreases expression, increases abundance	2
dicrotophos	decreases expression	1
bisphenol A	affects expression	1
formononetin	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Ampicillin	increases expression	1
Antimony	decreases expression	1
Antimony Potassium Tartrate	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Chromium	decreases expression	1
Dimethylnitrosamine	decreases expression	1
Mercury	decreases expression	1
Potassium Dichromate	decreases expression	1
Quercetin	increases expression	1
Dihydrotestosterone	increases expression	1
Tamoxifen	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Valproic Acid	increases methylation	1
Oxyquinoline	increases expression	1

ChEMBL screening assays

13 unique, capped per target: 12 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2329600	Binding	Inhibition of human recombinant pepsin C expressed in Escherichia coli using fluorescence-quenched Dabcyl-E-R-Nle-F-L-S-F-P-EDANS as substrate incubated for 1 hr prior to substrate addition measured after 1 hr by fluorescence polarization a	A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore. — J Med Chem
CHEMBL680906	Functional	Inhibitory concentration against Gastricsin	Renin inhibitors containing conformationally restricted P1-P1’ dipeptide mimetics. — J Med Chem

Clinical trials (associated diseases)

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