PREP

Summary

PREP (prolyl endopeptidase, HGNC:9358) is a protein-coding gene on chromosome 6q21, encoding Prolyl endopeptidase (P48147). Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.

The protein encoded by this gene is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides.

Source: NCBI Gene 5550 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 93 total — 2 pathogenic
• Regional missense constraint (gnomAD): 2 of 5 regions constrained (≈9% of expected missense variation)
• GTEx eGene: eQTL in 15 tissues, sQTL in 21 (q < 0.05)
• ChEMBL bioactivity: 4 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_002726
• Notable: 93 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9358
Approved symbol	PREP
Name	prolyl endopeptidase
Location	6q21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000085377
Ensembl biotype	protein_coding
OMIM	600400
Entrez	5550

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 5 nonsense_mediated_decay

MANE Select: ENST00000652536

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

ENST00000652536, ENST00000369110, ENST00000448705, ENST00000910821, ENST00000910822, ENST00000910823, ENST00000910824, ENST00000910825, ENST00000920421, ENST00000969640, ENST00000969641, ENST00001019715, ENST00001019716, ENST00001019717, ENST00001019718, ENST00001019719, ENST00001019720, ENST00001136172

RefSeq mRNA: 1 — MANE Select: NM_002726 NM_002726

CCDS: CCDS5053

Canonical transcript exons

ENST00000652536 — 15 exons

Exon	Start	End
ENSE00000421640	105377386	105377519
ENSE00000421642	105373369	105373578
ENSE00000761302	105281746	105281902
ENSE00000761324	105282451	105282582
ENSE00000761331	105285486	105285580
ENSE00000761338	105288758	105288894
ENSE00000761378	105376125	105376255
ENSE00000904122	105397853	105397927
ENSE00000974897	105368903	105369024
ENSE00000974898	105352972	105353077
ENSE00000974899	105333314	105333505
ENSE00000974900	105328829	105329026
ENSE00001448822	105402847	105403082
ENSE00002446678	105323665	105323768
ENSE00003842098	105273218	105278438

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.4639 / max 229.0095, expressed in 1825 samples.

Highest expression (Bgee): secondary oocyte, gastrocnemius, mucosa of transverse colon, rectum, muscle of leg.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PREP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 36 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	2.1e-23	+0.63	6:105322311:G:C
Skin Not Sun Exposed Suprapubic	sqtl	5.7e-21	+0.66	6:105328414:T:C
Muscle Skeletal	sqtl	9.7e-21	+0.53	6:105325234:A:C
Skin Sun Exposed Lower leg	eqtl	2.4e-16	-0.18	6:105401620:A:AC
Skin Not Sun Exposed Suprapubic	eqtl	1.0e-13	-0.20	6:105393660:T:C
Cells EBV-transformed lymphocytes	sqtl	6.5e-13	+0.76	6:105330192:C:T
Muscle Skeletal	eqtl	7.3e-13	-0.28	6:105364250:T:A
Skin Sun Exposed Lower leg	sqtl	5.2e-12	+0.48	6:105326186:T:C
Esophagus Mucosa	sqtl	5.4e-10	+0.50	6:105322311:G:C
Testis	sqtl	6.1e-10	+0.77	6:105325234:A:C
Esophagus Mucosa	eqtl	7.6e-10	-0.19	6:105335275:A:C
Breast Mammary Tissue	sqtl	9.8e-09	+0.52	6:105322311:G:C
Liver	eqtl	1.6e-08	-0.55	6:105401336:G:T
Thyroid	sqtl	1.7e-08	+0.55	6:105322311:G:C
Colon Transverse	sqtl	1.5e-07	+0.47	6:105328414:T:C
Nerve Tibial	sqtl	2.5e-07	+0.45	6:105351366:T:C
Stomach	sqtl	3.2e-07	+0.57	6:105341488:T:A
Adipose Subcutaneous	sqtl	5.8e-07	+0.45	6:105322311:G:C
Whole Blood	eqtl	4.9e-06	-0.11	6:105402837:A:G
Cells Cultured fibroblasts	eqtl	1.2e-05	-0.13	6:105363433:C:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
74876	35.4000	1823
74875	10.6812	1795
74877	0.3826	171

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.65	gold quality
gastrocnemius	UBERON:0001388	93.87	gold quality
mucosa of transverse colon	UBERON:0004991	93.43	gold quality
rectum	UBERON:0001052	93.34	gold quality
muscle of leg	UBERON:0001383	93.19	gold quality
triceps brachii	UBERON:0001509	92.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.46	gold quality
oocyte	CL:0000023	92.10	gold quality
muscle organ	UBERON:0001630	91.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.46	gold quality
gluteal muscle	UBERON:0002000	91.38	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.28	gold quality
cortical plate	UBERON:0005343	90.04	gold quality
biceps brachii	UBERON:0001507	90.03	gold quality
colonic mucosa	UBERON:0000317	90.00	gold quality
transverse colon	UBERON:0001157	89.74	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.29	gold quality
skeletal muscle tissue	UBERON:0001134	88.98	gold quality
skin of leg	UBERON:0001511	88.89	gold quality
stromal cell of endometrium	CL:0002255	88.87	gold quality
skin of abdomen	UBERON:0001416	88.78	gold quality
colonic epithelium	UBERON:0000397	88.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.91	gold quality
large intestine	UBERON:0000059	87.50	gold quality
colon	UBERON:0001155	87.49	gold quality
zone of skin	UBERON:0000014	87.33	gold quality
intestine	UBERON:0000160	87.24	gold quality
monocyte	CL:0000576	87.17	gold quality
diaphragm	UBERON:0001103	87.15	gold quality
duodenum	UBERON:0002114	87.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.05	gold quality
leukocyte	CL:0000738	86.94	gold quality
middle temporal gyrus	UBERON:0002771	86.84	gold quality
mononuclear cell	CL:0000842	86.79	gold quality
granulocyte	CL:0000094	86.60	gold quality
small intestine	UBERON:0002108	86.58	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.57	gold quality
vastus lateralis	UBERON:0001379	86.51	gold quality
quadriceps femoris	UBERON:0001377	86.44	gold quality
islet of Langerhans	UBERON:0000006	86.15	gold quality
muscle tissue	UBERON:0002385	85.86	gold quality
body of pancreas	UBERON:0001150	85.58	gold quality
gingival epithelium	UBERON:0001949	85.56	gold quality
heart left ventricle	UBERON:0002084	85.41	gold quality
right lung	UBERON:0002167	85.33	gold quality
jejunum	UBERON:0002115	85.28	gold quality
sigmoid colon	UBERON:0001159	85.24	gold quality
esophagus mucosa	UBERON:0002469	85.24	gold quality
prefrontal cortex	UBERON:0000451	85.14	gold quality
cardiac ventricle	UBERON:0002082	85.08	gold quality
right atrium auricular region	UBERON:0006631	85.03	gold quality
embryo	UBERON:0000922	84.79	gold quality
right adrenal gland	UBERON:0001233	84.79	gold quality
ganglionic eminence	UBERON:0004023	84.77	gold quality
right testis	UBERON:0004534	84.77	gold quality
apex of heart	UBERON:0002098	84.76	gold quality
esophagus	UBERON:0001043	84.69	gold quality
pancreas	UBERON:0001264	84.68	gold quality
gingiva	UBERON:0001828	84.55	gold quality
mucosa of urinary bladder	UBERON:0001259	84.54	silver quality
body of stomach	UBERON:0001161	84.51	gold quality
right adrenal gland cortex	UBERON:0035827	84.40	gold quality
left adrenal gland	UBERON:0001234	84.33	gold quality
minor salivary gland	UBERON:0001830	84.31	gold quality
right frontal lobe	UBERON:0002810	84.30	gold quality
lower esophagus mucosa	UBERON:0035834	84.18	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.17	gold quality
lower esophagus	UBERON:0013473	84.16	gold quality
vermiform appendix	UBERON:0001154	84.15	gold quality
upper lobe of left lung	UBERON:0008952	84.15	gold quality
epithelium of nasopharynx	UBERON:0001951	84.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.13	gold quality
heart	UBERON:0000948	84.06	gold quality
endometrium	UBERON:0001295	84.03	gold quality
left testis	UBERON:0004533	84.03	gold quality
caecum	UBERON:0001153	84.01	gold quality
deltoid	UBERON:0001476	83.95	gold quality
left adrenal gland cortex	UBERON:0035825	83.93	gold quality
mouth mucosa	UBERON:0003729	83.90	gold quality
jejunal mucosa	UBERON:0000399	83.79	gold quality
right ovary	UBERON:0002118	83.78	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.65	gold quality
popliteal artery	UBERON:0002250	83.64	gold quality
adrenal gland	UBERON:0002369	83.63	gold quality
tibial artery	UBERON:0007610	83.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.60	gold quality
ileal mucosa	UBERON:0000331	83.58	gold quality
frontal cortex	UBERON:0001870	83.57	gold quality
smooth muscle tissue	UBERON:0001135	83.55	gold quality
upper lobe of lung	UBERON:0008948	83.55	gold quality
testis	UBERON:0000473	83.50	gold quality
ectocervix	UBERON:0012249	83.48	gold quality
adrenal cortex	UBERON:0001235	83.33	gold quality
left coronary artery	UBERON:0001626	83.27	gold quality
cardiac atrium	UBERON:0002081	83.19	gold quality
omental fat pad	UBERON:0010414	83.17	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.17	gold quality
stomach	UBERON:0000945	83.15	gold quality
peritoneum	UBERON:0002358	83.15	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.15	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.42

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 160 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	56.7	medium
Tongue	tissue	55.7
Skeletal muscle	tissue	53.3	high
Postcentral gyrus	tissue	49.3
Retina	tissue	45.9
Tongue	tissue	43.8
Locus coeruleus	tissue	41.5
Thymus	tissue	39.5
Heart muscle	tissue	39.2	high
Rectum	tissue	35.3	high
Choroid plexus	tissue	34.1
Cerebral cortex	tissue	33.2	medium
Somatosensory cortex	tissue	33.2
Testis	tissue	32.3	medium
Hippocampus	tissue	32.1	high
Parathyroid gland	tissue	31.3	medium
Pons	tissue	30.9
Cerebral cortex	tissue	30.7	high
Somatosensory cortex	tissue	30.7
Nucleus accumbens	tissue	30.2
Colon	tissue	30.1	high
Motor cortex	tissue	30.0
Thalamus	tissue	29.9
Liver	tissue	29.6	medium
Adrenal gland	tissue	29.6	high
Superior colliculi	tissue	29.1
Kidney	tissue	29.1	high
Midbrain	tissue	28.9
Occipital cortex	tissue	28.3
Occipital cortex	tissue	28.0
Prefrontal cortex	tissue	27.6
Medulla oblongata	tissue	27.4
Substantia nigra	tissue	27.4
Adipose tissue	tissue	27.1	medium
Thalamus	tissue	26.7
Superior colliculi	tissue	26.5
Putamen	tissue	26.5
Hippocampal formation	tissue	26.4
Entorhinal cortex	tissue	26.4
Ovary	tissue	26.0	medium
Spinal cord	tissue	25.8
Temporal cortex	tissue	25.8
Motor cortex	tissue	25.7
Insular cortex	tissue	25.6
Retrosplenial cortex	tissue	25.3
Urinary bladder	tissue	25.2	high
Hypothalamus	tissue	25.2
Prefrontal cortex	tissue	24.9
Retrosplenial and cingulate cortex	tissue	24.8
Bone marrow	tissue	24.5	high
Smooth muscle	tissue	24.1	high
Ventral forebrain	tissue	24.1
Periaqueductal gray	tissue	24.1
Basal ganglia	tissue	24.0	medium
Retrosplenial and cingulate cortex	tissue	23.9
Pituitary gland	tissue	23.9
Basal ganglia	tissue	23.9	high
Hippocampal formation	tissue	23.6
Postcentral gyrus	tissue	23.6
Putamen	tissue	23.4

Brain sub-regions (HPA Brain Atlas): detected in 384; highest nTPM — Somatosensory cortex, postcentral gyrus, ventral (white matter) (44.4), Precentral gyrus (43.5), Somatomor cortex, precentral gyrus (white matter) (43.1), Postcentral gyrus, dorsal (41.6), Lateral geniculate body (40.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

showing 30 of 42 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-455-5P	98.74	67.31	795

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.395, missense Z 2.66 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000652536 splits into 5 regions with different missense tolerance; 2 are missense-constrained (≈9% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:105,278,147–105,281,797	121 / 154.8	0.78	no
6:105,281,798–105,282,489	20 / 58.9	0.34	yes (p 4.1e-07)
6:105,282,490–105,285,487	35 / 36.0	0.97	no
6:105,285,488–105,285,524	2 / 16.5	0.12	yes (p 3.6e-04)
6:105,285,525–105,402,891	517 / 620.3	0.83	no

Literature-anchored findings (GeneRIF, showing 37)

• The high activity of prolyl endopeptidase in the human cortex suggests that prolyl endopeptidase could play a role in cortical functions. Activity in humans is highest in the frontal lobe and cytosolic fractions. (PMID:11792464)
• The activities of pyroglutamyl peptidase I and prolyl endopeptidase in necrozoospermia were found to be higher in the corresponding soluble and particulate sperm fractions, respectively, with respect to those measured in normozoospermic semen (PMID:15380924)
• primary structure, recombinant expression and homology modelling of brain prolyl oligopeptidase (PMID:15838896)
• Mainly localized to perinuclear space and associated with microtubulin cytoskeleton in human neuroblastoma and glioma. Novel functions in axonal transport and/or protein secretion. PEP inhibitors may be useful in variety of related clinical conditions. (PMID:16092940)
• data demonstrate for the first time prolyl endopeptidase turnover of humanin by a limited post-cysteine as well as post-proline proteolysis resulting in the inactivation of this potentially apoptosis-related factor (PMID:16700513)
• Results describe the distribution of immunoreactive prolyl oligopeptidase in human and rat brain. (PMID:17401647)
• The results rule out a causative role of POP in the pathogenesis of CD and strongly suggest that other peptidases are needed to eliminate gliadin-derived, immunoactive and toxic peptides larger than 33-mer, which is a POP inhibitor. (PMID:17454876)
• Data reveal for the first time the presence of a new side opening in prolyl oligopeptidase that was not observed in any of the crystallographic structures described to date. (PMID:19782684)
• Cytosolic Prolyl endopeptidase activity significantly increased in clear cell renal cell carcinoma, urothelial carcinoma of the renal pelvis and head and neck squamous cell carcinoma. (PMID:20362629)
• Plasma levels of PREP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in multiple sclerosis (PMID:20370893)
• The constitutive expression of PREP mRNA in chronic lymphocytic leukemia was demonstrated. (PMID:20534982)
• Results indicate that there is no strong and direct interaction between POP and GAP43 at physiological conditions. (PMID:20869470)
• PREP is a regulatory target and a regulatory element in cell signalling. This is the first report of a direct influence of a cell signalling molecule, retinoic acid, on PREP expression. (PMID:21487212)
• These results indicate that POP is a part of the machinery that controls the cell cycle. (PMID:21620802)
• Molecular modeling and docking based approaches were used to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). (PMID:22132071)
• PREP may be associated with secretory processes as well as in reproduction. A more abundant expression of PREP in malignant than benign tumors suggests that PREP may be associated with expansion and metastasis of tumors. (PMID:22740343)
• analysis of the substrate preferences of two post-proline cleaving endopeptidases, prolyl oligopeptidase and fibroblast activation protein alpha (PMID:22750443)
• interaction between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase is required for cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death (PMID:23348613)
• first demonstration of colocalization of PREP and pathological proteins in the human brain, supporting the view that, at least in spatial terms, PREP could be associated with pathogenesis of neurodegenerative diseases (PMID:23562579)
• Oxidative stress and the levels of endogenous plasma prolyl oligopeptidase (PREP) inhibitor alpha-2-macroglobulin (alpha2M) decrease PREP activity in multiple sclerosis patients. (PMID:23643808)
• These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells. (PMID:24269815)
• The determination of PEP activity in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice. (PMID:24465166)
• Data indicate that SAXS analysis showed that presequence protease (hPreP) open states and substrate binding dynamics. (PMID:24931469)
• PREP redox inactivation is due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. (PMID:25236746)
• PEP was significantly and positively associated with delinquent, aggressive, externalizing and internalizing behavior subscales. (PMID:26165750)
• TLR4 activation releases prolyl endopeptidase containing exosomes from airway epithelial cells. (PMID:26222144)
• This study found that circulating PREP activity was substantially reduced in all cirrhotic patients but those changes did not have evident correlation to hepatic encephalopathy. (PMID:26420028)
• These findings provide evidence for newly-discovered roles for PREP in mechanisms regulating cellular plasticity through NCAM and PSA-NCAM. (PMID:27566163)
• Study shows that the expression of POP increases with hepatocyte steatosis suggesting an important role in hepatocytes steatosis and possibly NAFLD. (PMID:27760195)
• It was found that human PREP behaves identically to the porcine homolog, displaying a double bell-shaped pH profile and a pH-dependent solvent kinetic isotope effect of the kcat/Km, features that set it apart from the related exopeptidase dipeptidyl peptidase IV (DPP IV). (PMID:28062644)
• In mitotic phases, PREP shares its localization with tubulin in Sertoli cells, gonocytes, and spermatogonia. (PMID:30380361)
• Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington’s disease. (PMID:31565846)
• Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A. (PMID:31759088)
• DAAM1 and PREP are involved in human spermatogenesis. (PMID:31972124)
• Prolyl Oligopeptidase Regulates Dopamine Transporter Oligomerization and Phosphorylation in a PKC- and ERK-Independent Manner. (PMID:33579026)
• Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A. (PMID:33838285)
• Preliminary Investigation on the Involvement of Cytoskeleton-Related Proteins, DAAM1 and PREP, in Human Testicular Disorders. (PMID:34360857)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prep	ENSDARG00000057151
mus_musculus	Prep	ENSMUSG00000019849
rattus_norvegicus	Prep	ENSRNOG00000051061
drosophila_melanogaster	CG5355	FBGN0032242
drosophila_melanogaster	CG2528	FBGN0032969

Paralogs (1): PREPL (ENSG00000138078)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1270863) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 19 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased body weight	1
decreased body weight	1
increased startle reflex	1
decreased circulating free fatty acids level	1
increased liver weight	1
increased kidney weight	1
decreased kidney weight	1
increased spleen weight	1
increased percent body fat/body weight	1
increased circulating potassium level	1
increased circulating sodium level	1
increased circulating leptin level	1
decreased body mass index	1
increased body mass index	1
decreased prepulse inhibition	1
decreased total body fat amount	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to tooth bud stage	1
decreased thigmotaxis	1

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Sus scrofa	P23687	97.5%	Diamond
Bos taurus	Q9XTA2	97.5%	Diamond
Elizabethkingia meningoseptica	P27028	92.2%	Diamond
Elizabethkingia miricola	P27195	92.2%	Diamond
Lentinula edodes	A0A1Q3EPF5	76.7%	Diamond
Omphalotus olearius	P9WEN5	76.7%	Diamond
Amanita bisporigera	E2JFG2	76.4%	Diamond
Galerina marginata CBS 339.88	H2E7Q8	76.0%	Diamond
Dendrothele bispora CBS 962.96	A0A4S8L6U5	64.6%	Diamond
Aeromonas hydrophila	Q06903	56.8%	Diamond
Dictyostelium discoideum	Q86AS5	38.9%	Diamond
Rickettsia prowazekii str. Madrid E	P81171	38.2%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
PREP-AS1	ncRNA	139355238
POPDC1-AS1	ncRNA	154442
POPDC3	protein-coding	64208
LINC02836	ncRNA	105377922
LIN28B-AS1	ncRNA	100113403
LIN28B	protein-coding	389421
POPDC1	protein-coding	11149

Protein

Protein identifiers

Prolyl endopeptidase — P48147 (reviewed: P48147)

Alternative names: Post-proline cleaving enzyme

All UniProt accessions (3): A0A499FJL1, P48147, H0Y5Y0

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Post-translational modifications. The N-terminus is blocked.

Similarity. Belongs to the peptidase S9A family.

RefSeq proteins (1): NP_002717* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002470	Peptidase_S9A	Family
IPR002471	Pept_S9_AS	Active_site
IPR004106	Peptidase_S9_N_sf	Homologous_superfamily
IPR023302	Pept_S9A_N	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051167	Prolyl_oligopep/macrocyclase	Family

Pfam: PF00326, PF02897

Enzyme classification (BRENDA)

• EC 3.4.21.26 — prolyl oligopeptidase (BRENDA: 55 organisms, 511 substrates, 729 inhibitors, 161 Km, 156 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
L-LEU-4-NITROANILIDE	0.12–1.1	10
L-PHE-4-NITROANILIDE	0.063–6.2	10
BENZYLOXYCARBONYL-GLY-PRO-BETA-NAPHTHYLAMIDE	0.0054–0.14	5
CALCITONIN GENE-RELATED PEPTIDE	0.0012–0.0125	5
BENZYLOXYCARBONYL-GLY-PRO-P-NITROPHENOL	—	4
2-AMINOBENZOYL-GLY-PRO-GLN-N-(2,4-DINITROPHENYL)	0.0002–0.0022	3
BENZYLOXYCARBONYL-GLY-L-PRO-4-NITROANILIDE	0.0653–3.42	3
BENZYLOXYCARBONYL-GLY-PRO-SBZL	0.0015–0.016	3
Z-GLY-PRO-4-NITROANILIDE	0.0308–0.81	3
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0004–0.0008	2
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0009–0.0011	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0003–0.0005	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0008–0.0015	2
ABZ-GLY-L-PHE-L-ARG-L-PRO-L-PHE(NO2)-L-ARG-L-ALA	0.0008–0.0092	2
ARG-PRO-4-NITROANILIDE	0.0229–0.16	2

UniProt features (90 total): strand 44, helix 27, sequence conflict 7, turn 4, active site 3, modified residue 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

17 structures by resolution:

PDB	Title	Method	Resolution (Å)
9Q5X	Human prolyl endopeptidase (PREP) - complex with KT-2-74	X-RAY DIFFRACTION	1.41
9Q5Z	Human prolyl endopeptidase (PREP) - complex with KT-1-147	X-RAY DIFFRACTION	1.41
9Q5Y	Human prolyl endopeptidase (PREP) - complex with YX45	X-RAY DIFFRACTION	1.49
3DDU	Prolyl Oligopeptidase with GSK552	X-RAY DIFFRACTION	1.56
9XZZ	Human prolyl endopeptidase (PREP) - complex with KYP2047	X-RAY DIFFRACTION	1.58
9Q5G	Human prolyl endopeptidase (PREP) - apo form	X-RAY DIFFRACTION	1.63
9Q6L	Human prolyl endopeptidase (PREP) - complex with KT-2-197	X-RAY DIFFRACTION	1.66
9Q6X	Human prolyl endopeptidase (PREP) - complex with KT-2-186	X-RAY DIFFRACTION	1.66
9Q6I	Human prolyl endopeptidase (PREP) - complex with JP-6-1-7	X-RAY DIFFRACTION	1.73
9XYK	Human prolyl endopeptidase (PREP) - complex with JP-7-1-7	X-RAY DIFFRACTION	1.73
9Q6J	Human prolyl endopeptidase (PREP) - complex with KT-2-126	X-RAY DIFFRACTION	1.75
9XYL	Human prolyl endopeptidase (PREP) - complex with S17092	X-RAY DIFFRACTION	1.81
9Q62	Human prolyl endopeptidase (PREP) - complex with KT-2-108	X-RAY DIFFRACTION	1.83
9Q6K	Human prolyl endopeptidase (PREP) - complex with JP-2-1-7	X-RAY DIFFRACTION	1.85
9Q65	Human prolyl endopeptidase (PREP) - complex with KT-2-75	X-RAY DIFFRACTION	1.89
9Q64	Human prolyl endopeptidase (PREP) - complex with KT-2-59	X-RAY DIFFRACTION	1.94
9Q66	Human prolyl endopeptidase (PREP) - complex with JP-4-1-7	X-RAY DIFFRACTION	2.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48147-F1	98.13	0.99

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
554	charge relay system
641	charge relay system
680	charge relay system

Post-translational modifications (2)

Type	Positions
N-acetylmethionine	1
N6-acetyllysine	157

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 164 (showing top): GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GCM_GSPT1, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_REGULATION_OF_HORMONE_LEVELS, MORF_HDAC2, GOBP_PROTEIN_MATURATION, GOBP_AMIDE_METABOLIC_PROCESS, AACTTT_UNKNOWN, GFI1_01, GCM_NF2, JIANG_AGING_CEREBRAL_CORTEX_UP, MORF_AATF

GO Biological Process (2): angiotensin maturation (GO:0002003), proteolysis (GO:0006508)

GO Molecular Function (7): metallocarboxypeptidase activity (GO:0004181), serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), oligopeptidase activity (GO:0070012), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

GO top-level categories

17 GO namespaces:

Category	Terms
cellular anatomical structure	4
endopeptidase activity	2
regulation of angiotensin levels in blood	1
peptide hormone processing	1
protein metabolic process	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
membrane	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 974 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PREP	DPP8	Q6V1X1	938
PREP	DPP9	Q86TI2	937
PREP	PGPEP1	Q9NXJ5	936
PREP	DPP4	P27487	929
PREP	APEH	P13798	912
PREP	LAP3	P28838	909
PREP	PRCP	P42785	885
PREP	TRH	P20396	818
PREP	THOP1	P52888	794
PREP	PRSS16	Q9NQE7	759
PREP	NTS	P30990	667
PREP	MME	P08473	662
PREP	MMEL1	Q495T6	658
PREP	DPP7	Q9UHL4	655
PREP	NLN	Q9BYT8	631

IntAct

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

5 partners by confidence:

Partner	Interaction type	MIscore	Records
GAPDH	direct interaction	0.640	5
KRTAP19-6	association	0.350	1
HLA-B	physical association	0.000	1
PRKAB1	physical association	0.000	1
TRAF6	physical association	0.000	1

BioGRID (101 interactions; top human partners by supporting records): SGOL2 (Affinity Capture-MS; 3 records), KIF3A (Affinity Capture-MS; 2 records), MTG2 (Affinity Capture-MS; 2 records), NSMAF (Affinity Capture-MS; 2 records), PARK2 (Affinity Capture-MS; 2 records), RHPN1 (Affinity Capture-MS; 2 records), SNCA (PCA; 2 records), ADRM1 (Co-fractionation), AIP (Co-fractionation), ALDOA (Co-fractionation), ALDOC (Co-fractionation), AURKA (Affinity Capture-MS), BAP1 (Affinity Capture-MS), BRCA1 (Two-hybrid), CACYBP (Co-fractionation)

Disease & clinical

Genetic variants

Variant evidence for PREP: 93 ClinVar records (2 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	73
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4537358	NM_002726.5(PREP):c.1570_1573dup (p.Asn525fs)	Pathogenic	criteria provided, single submitter	1
4537359	NM_002726.5(PREP):c.1839-2A>G	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

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

AlphaMissense

2,258 missense substitutions predicted likely pathogenic (of 4,711 scored), across 533 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M583	9	0.862	0.990
D149	8	0.999	1.000
D641	8	0.999	1.000
H680	8	0.998	1.000
D642	8	0.996	0.999
D582	8	0.995	0.999
F476	8	0.993	1.000
D529	8	0.993	0.998
H648	8	0.993	0.998
D222	8	0.986	0.996
H213	8	0.981	0.998
H640	8	0.974	0.998
D639	8	0.964	0.992
N555	8	0.963	0.999
D598	8	0.962	0.996
F173	8	0.948	1.000
F699	8	0.933	0.996
H515	8	0.927	0.998
F530	8	0.924	0.989
N91	8	0.918	0.992

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	1.97e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.17e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000973

Disease associations

OMIM: gene MIM:600400 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3202 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 94,855 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

4 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL50	QUERCETIN	3	75,572
CHEMBL67279	TALABOSTAT	3	10,527
CHEMBL8260	BAICALEIN	2	8,718
CHEMBL267225	BOSWELLIC ACID	2	38

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S9: Prolyl oligopeptidase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
ARI-3531	Inhibition	8.89	pIC50
S 17092	Inhibition	8.8	pKi

Binding affinities (BindingDB)

789 measured of 1152 human assays (1231 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4-ethyl-4-methoxypiperidin-1-yl)quinoline-4-carboxamide	IC50	0.038 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.039 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4,5,6,7-tetrahydroindazol-2-yl)quinoline-4-carboxamide	IC50	0.04 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)quinoline-4-carboxamide	IC50	0.041 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
6-(5-azaspiro[2.4]heptan-5-yl)-N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]quinoline-4-carboxamide	IC50	0.041 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(1-methylpyrazol-4-yl)quinoline-4-carboxamide	IC50	0.041 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(6-methoxy-3-pyridinyl)quinoline-4-carboxamide	IC50	0.042 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinoline-4-carboxamide	IC50	0.043 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3R)-3-methyl-2-oxopyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.044 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4-propan-2-yloxypiperidin-1-yl)quinoline-4-carboxamide	IC50	0.045 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3R)-3-fluoropyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.045 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(5-fluoro-2-pyridinyl)quinoline-4-carboxamide	IC50	0.046 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(1S,5R)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl]quinoline-4-carboxamide	IC50	0.046 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3,3-dimethyl-1-oxa-6-azaspiro[3.3]heptan-6-yl)quinoline-4-carboxamide	IC50	0.047 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3-ethyl-3-fluoroazetidin-1-yl)quinoline-4-carboxamide	IC50	0.047 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
7-chloro-N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-morpholin-4-ylquinoline-4-carboxamide	IC50	0.048 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3-morpholin-4-ylazetidin-1-yl)quinoline-4-carboxamide	IC50	0.049 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]quinoline-4-carboxamide	IC50	0.05 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-4-carboxamide	IC50	0.05 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoline-4-carboxamide	IC50	0.051 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4-hydroxy-4-propan-2-ylpiperidin-1-yl)quinoline-4-carboxamide	IC50	0.051 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3R)-3-methoxypyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.052 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4-methoxy-4-methylpiperidin-1-yl)quinoline-4-carboxamide	IC50	0.053 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)quinoline-4-carboxamide	IC50	0.053 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-7-methyl-6-morpholin-4-ylquinoline-4-carboxamide	IC50	0.054 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[3-(methoxymethyl)-3-methylazetidin-1-yl]quinoline-4-carboxamide	IC50	0.055 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(2-fluoro-4-pyridinyl)quinoline-4-carboxamide	IC50	0.055 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(4-ethyl-4-hydroxypiperidin-1-yl)quinoline-4-carboxamide	IC50	0.056 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S)-3-fluoro-3-methylpyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.056 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(2-oxopyrrolidin-1-yl)quinoline-4-carboxamide	IC50	0.057 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[6-(difluoromethyl)-3-pyridinyl]quinoline-4-carboxamide	IC50	0.057 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(2,2-difluoromorpholin-4-yl)quinoline-4-carboxamide	IC50	0.058 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(7S)-7-methyl-1,4-oxazepan-4-yl]quinoline-4-carboxamide	IC50	0.058 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(5,5-difluoro-2-azaspiro[3.4]octan-2-yl)quinoline-4-carboxamide	IC50	0.059 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3-propan-2-ylazetidin-1-yl)quinoline-4-carboxamide	IC50	0.059 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(2,2,6,6-tetrafluoromorpholin-4-yl)quinoline-4-carboxamide	IC50	0.06 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(7R)-7-methyl-1,4-oxazepan-4-yl]quinoline-4-carboxamide	IC50	0.06 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3R)-3-fluoroazepan-1-yl]quinoline-4-carboxamide	IC50	0.061 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(6,6-dimethyl-4,5-dihydrocyclopenta[c]pyrazol-2-yl)quinoline-4-carboxamide	IC50	0.061 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[3-(difluoromethoxy)azetidin-1-yl]quinoline-4-carboxamide	IC50	0.061 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S)-3-methylpyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.062 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3-ethoxy-3-methylazetidin-1-yl)quinoline-4-carboxamide	IC50	0.062 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(1-cyclopropylpyrazol-4-yl)quinoline-4-carboxamide	IC50	0.063 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S)-3-fluoropyrrolidin-1-yl]quinoline-4-carboxamide	IC50	0.064 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(3,3-dimethyl-2-oxopyrrolidin-1-yl)quinoline-4-carboxamide	IC50	0.065 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S)-3-fluoropiperidin-1-yl]quinoline-4-carboxamide	IC50	0.065 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
6-(3-azabicyclo[3.1.0]hexan-3-yl)-N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]quinoline-4-carboxamide	IC50	0.065 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[(3S)-3-methylmorpholin-4-yl]quinoline-4-carboxamide	IC50	0.066 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-(1H-pyrazol-5-yl)quinoline-4-carboxamide	IC50	0.066 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES
N-[2-[(4R)-4-cyano-1,3-thiazolidin-3-yl]-2-oxoethyl]-6-[3-(1,1-difluoroethyl)azetidin-1-yl]quinoline-4-carboxamide	IC50	0.067 nM	US-20230312550: N-(2-(4-CYANOTHIAZOLIDIN-3-YL)-2-OXOETHYL)-QUINOLINE-4-CARBOXAMIDES

ChEMBL bioactivities

537 potent at pChembl≥5 of 675 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL189620
10.64	Ki	0.023	nM	CHEMBL189620
9.80	IC50	0.16	nM	CHEMBL6058811
9.77	IC50	0.17	nM	CHEMBL5813416
9.70	IC50	0.2	nM	CHEMBL5874048
9.68	Ki	0.21	nM	CHEMBL97152
9.66	IC50	0.22	nM	CHEMBL6052358
9.59	Ki	0.26	nM	CHEMBL95698
9.55	Ki	0.28	nM	CHEMBL318284
9.49	IC50	0.325	nM	CHEMBL5941199
9.47	Ki	0.34	nM	CHEMBL318630
9.46	IC50	0.35	nM	CHEMBL5941199
9.43	IC50	0.37	nM	CHEMBL6052358
9.40	Ki	0.4	nM	Z-PRO-PROLINAL
9.38	IC50	0.42	nM	CHEMBL302654
9.35	Ki	0.45	nM	CHEMBL99305
9.35	IC50	0.45	nM	CHEMBL65284
9.34	IC50	0.46	nM	CHEMBL291393
9.30	IC50	0.5	nM	CHEMBL22766
9.29	IC50	0.51	nM	CHEMBL5949449
9.28	IC50	0.52	nM	CHEMBL63745
9.26	IC50	0.55	nM	CHEMBL294367
9.18	IC50	0.66	nM	CHEMBL5768806
9.17	IC50	0.67	nM	CHEMBL5964348
9.14	Ki	0.73	nM	CHEMBL2333024
9.14	IC50	0.73	nM	CHEMBL5820353
9.12	Ki	0.75	nM	CHEMBL3817958
9.07	IC50	0.85	nM	CHEMBL65512
9.06	IC50	0.87	nM	CHEMBL5813416
9.06	IC50	0.87	nM	CHEMBL6040206
9.04	Ki	0.92	nM	CHEMBL189620
9.03	IC50	0.935	nM	CHEMBL5914777
9.02	Ki	0.95	nM	CHEMBL189620
9.01	Ki	0.97	nM	CHEMBL289651
9.01	IC50	0.97	nM	CHEMBL5916929
9.00	Ki	1	nM	CHEMBL3817958
9.00	Ki	1	nM	Z-PRO-PROLINAL
9.00	IC50	1	nM	CHEMBL4758377
9.00	IC50	1	nM	CHEMBL4762591
9.00	IC50	1	nM	CHEMBL4746891
9.00	IC50	1	nM	CHEMBL65338
8.96	IC50	1.1	nM	CHEMBL66088
8.96	IC50	1.1	nM	Z-PRO-PROLINAL
8.92	IC50	1.2	nM	CHEMBL5874048
8.92	IC50	1.2	nM	CHEMBL62580
8.90	Ki	1.25	nM	CHEMBL318284
8.90	IC50	1.27	nM	CHEMBL6027846
8.89	IC50	1.3	nM	CHEMBL2333024
8.89	IC50	1.3	nM	CHEMBL4464623
8.85	IC50	1.4	nM	CHEMBL5914777

PubChem BioAssay actives

459 with measured affinity, of 1174 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-1-[(2S)-1-(4-phenylbutanoyl)pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	1127417: Inhibition of prolyl oligopeptidase (unknown origin)	ki	<0.0001	uM
benzyl (2S)-2-[(2S)-2-(5-phenyl-1,2-oxazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0002	uM
benzyl 2-[2-(1,2-thiazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0003	uM
benzyl (2S)-2-[(2S)-2-[5-(phenylmethoxymethyl)-1,2-oxazole-3-carbonyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0003	uM
4-phenyl-1-[(2S)-2-[(2S)-2-[5-(phenylmethoxymethyl)-1,2-oxazole-3-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]butan-1-one	160234: In vitro inhibitory activity determined against prolyl oligopeptidase (PO) in human	ki	0.0003	uM
(2S)-1-[(2S)-1-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0004	uM
(2S)-1-[(2S)-1-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0004	uM
benzyl (2S)-2-[(2S)-2-formylpyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	1539752: Inhibition of recombinant human POP assessed as affinity constant of second step of inhibition pre-incubated for 2 hrs before addition of ZGP-pNA substrate and measured every 30 secs for first 60 mins followed by every 2 mins for next 5 hrs by dilution assay	ki	0.0004	uM
benzyl (2S)-2-[(2S)-2-(5-trimethylsilyl-1,2-oxazole-3-carbonyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate	160231: In vitro inhibitory activity determined against prolyl oligopeptidase (Tc80) in Trypanosoma cruzi	ki	0.0004	uM
(2S)-1-[(2S)-1-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0005	uM
(2S)-1-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0005	uM
(2S)-1-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0006	uM
[(2R)-1-[(2S)-3-methyl-2-(pyridine-3-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid	736680: Competitive inhibition of human PREP using Suc-GP-AMC as substrate by Lineweaver-Burk plot analysis	ki	0.0007	uM
(4R)-3-[(4R)-3-[2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]acetyl]-1,3-thiazolidine-4-carbonyl]-1,3-thiazolidine-4-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0008	uM
(2S)-1-[(3aS,4R,7aR)-2-benzyl-3-oxo-3a,4,5,7a-tetrahydro-1H-isoindole-4-carbonyl]pyrrolidine-2-carbonitrile	1307737: Inhibition of human POP by tight binding based Morrison equation analysis	ki	0.0008	uM
(2S)-1-[(4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbaldehyde	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(3,4-dichlorophenyl)sulfanylmethyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2,4-dichlorophenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2-iodophenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
4-phenyl-1-[(2S)-2-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl]butan-1-one	1127417: Inhibition of prolyl oligopeptidase (unknown origin)	ki	0.0010	uM
(2S)-1-[(4R)-3-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]-1,3-thiazolidine-4-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0011	uM
(2S)-1-[(2S)-1-[2-(2,3-dihydro-1H-inden-2-yl)acetyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonitrile	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0012	uM
[(2R)-1-[(2S)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid	1539747: Inhibition of POP (unknown origin)	ic50	0.0013	uM
[(2S,3aS,7aS)-2-(1,3-thiazolidine-3-carbonyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-[(1R,2R)-2-phenylcyclopropyl]methanone	1307744: Inhibition of human POP using Z-Gly-Pro-7-AMC substrate	ki	0.0015	uM
[(2R)-1-(4-oxo-4-phenylbutanoyl)pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0017	uM
[(2R)-1-[2-(naphthalene-1-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0018	uM
[(2R)-1-[2-(pyridine-3-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0018	uM
(3S)-8-acetyl-6-(2-phenylethoxy)-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0020	uM
[(2R)-1-[2-[(2,5-dichlorobenzoyl)amino]acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0022	uM
[(2R)-1-[2-(cyclopentanecarbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0023	uM
2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]-1-[(4R)-4-(1,3-thiazolidine-3-carbonyl)-1,3-thiazolidin-3-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0023	uM
[(2R)-1-[2-(cyclohexanecarbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0027	uM
[(2R)-1-[2-(3-oxo-1H-isoindol-2-yl)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0028	uM
benzyl N-[(2S)-1-[(2S)-2-cyanopyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate	470837: Inhibition of prolyl oligopeptidase in human LN229 cell extracts assessed as blockade of Z-Gly-Pro-AMC substrate hydrolysis by fluorimetric assay	ic50	0.0030	uM
(3S)-8-acetyl-6-[2-(4-fluorophenyl)ethoxy]-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0030	uM
2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]-1-[(2R)-2-(1,3-thiazolidine-3-carbonyl)pyrrolidin-1-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0034	uM
(2S)-1-(2-benzyl-3-oxo-1H-isoindole-4-carbonyl)pyrrolidine-2-carbaldehyde	1539752: Inhibition of recombinant human POP assessed as affinity constant of second step of inhibition pre-incubated for 2 hrs before addition of ZGP-pNA substrate and measured every 30 secs for first 60 mins followed by every 2 mins for next 5 hrs by dilution assay	ki	0.0035	uM
1-[(4R)-4-(pyrrolidine-1-carbonyl)-1,3-thiazolidin-3-yl]-2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0040	uM
(3S)-8-(benzenesulfonyl)-6-[(3,5-difluorophenyl)methoxy]-3-(pyrrolidine-1-carbonyl)-2,3-dihydro-1H-indolizin-5-one	341663: Inhibition of human recombinant POP expressed in sEscherichia coli	ic50	0.0040	uM
1-[(2S)-2-(cyclopentanecarbonyl)pyrrolidin-1-yl]-5-[(2S)-2-[(2S)-2-(2-hydroxyacetyl)pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-3,3-dimethylpentane-1,5-dione	2082814: Inhibition of recombinant human PREP proteolytic activity transfected in PREP knockout HEK293 cells using Suc-Gly-Pro-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by fluorescence based microplate reader analysis	ic50	0.0040	uM
[(2R)-1-[2-[(2,6-dichlorobenzoyl)amino]acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0044	uM
[(2R)-1-[2-(2-methylpropanoylamino)acetyl]pyrrolidin-2-yl]boronic acid	274093: Inhibitory constant against POP	ki	0.0045	uM
[(3S)-3-(pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.2]octan-2-yl]-[(1R,2S)-2-thiophen-2-ylcyclopropyl]methanone	161115: Inhibitory activity was evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0048	uM
1-[(2S,3aS,7aS)-2-(pyrrolidine-1-carbonyl)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-6,6,6-trifluoro-5-phenylhexan-1-one	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0050	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(4-methoxyphenyl)methyl]-1,3-thiazole-4-carboxamide	1709024: Inhibition of PREP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0050	uM
[(2R)-1-[2-(pyridine-4-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736684: Inhibition of human PREP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0050	uM
1-[(2R)-2-(pyrrolidine-1-carbonyl)pyrrolidin-1-yl]-2-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]ethanone	160213: In vitro inhibitory activity against purified prolyl endopeptidase (PEP) from canine brain.	ic50	0.0054	uM
tert-butyl (3R)-3-(pyrrolidine-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0055	uM
(2S)-2-[[(2S)-1-[(3R)-2-[(2S)-2-[[2-[[2-[[(2S,4R)-1-[(2S)-1-[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3-dihydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid	161116: Inhibitory activity evaluated against Post-proline cleaving enzyme from Flavobacterium meningosepticum	ic50	0.0055	uM
N-[3-methoxy-4-[(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]pyrrolidine-1-carbonyl]phenyl]acetamide	1520002: Inhibition of recombinant human N-terminal His-tagged POP (2 to 710 residues) expressed in SF21 cells using Z-Gly-Pro-AMC as substrate incubated for 5 to 10 mins followed by substrate addition and measured for 30 mins by fluorescence based assay	ki	0.0060	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
sulindac sulfide	increases expression	1
N-benzyloxycarbonylprolylprolinal	decreases activity	1
di-n-butylphosphoric acid	affects expression	1
sciadopitysin	decreases activity	1
CGP 52608	affects binding, increases reaction	1
JTP 4819	decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acetaminophen	affects response to substance	1
Aspirin	decreases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

197 unique, capped per target: 195 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1010602	Binding	Inhibition of POP	(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor. — *Bioorg Med Chem Lett*
CHEMBL5723281	Functional	Affinity Biochemical interaction: (inhibition of bovine prolyl endopeptidase in cleaving chromogenic substrate) EUB0002698a PREP	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3EU	Abcam HEK293T PREP KO	Transformed cell line	Female
CVCL_TG56	HAP1 PREP (-) 1	Cancer cell line	Male
CVCL_XR83	HAP1 PREP (-) 2	Cancer cell line	Male
CVCL_XR84	HAP1 PREP (-) 3	Cancer cell line	Male
CVCL_XR85	HAP1 PREP (-) 4	Cancer cell line	Male
CVCL_XR86	HAP1 PREP (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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