FAP

Summary

FAP (fibroblast activation protein alpha, HGNC:3590) is a protein-coding gene on chromosome 2q24.2, encoding Prolyl endopeptidase FAP (Q12884). Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth.

The protein encoded by this gene is a homodimeric integral membrane gelatinase belonging to the serine protease family. It is selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. This protein is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2191 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 126 total
• GTEx eGene: eQTL in 17 tissues, sQTL in 6 (q < 0.05)
• Drug target: yes — 3 curated mechanism-of-action drugs; 14 molecules with ChEMBL bioactivity (top 2% of genes corpus-wide)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_004460
• Notable: 126 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3590
Approved symbol	FAP
Name	fibroblast activation protein alpha
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	DPPIV
Ensembl gene	ENSG00000078098
Ensembl biotype	protein_coding
OMIM	600403
Entrez	2191

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 13 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000188790

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 3: 5, TSL 4: 1, TSL 5: 2

ENST00000188790, ENST00000422436, ENST00000443424, ENST00000447386, ENST00000450031, ENST00000461506, ENST00000462608, ENST00000465088, ENST00000465424, ENST00000480044, ENST00000480838, ENST00000493182, ENST00000497414, ENST00000856821, ENST00000856822, ENST00000856823, ENST00000963584, ENST00000963585, ENST00001001733, ENST00001010810, ENST00001107982, ENST00001107983, ENST00001111754, ENST00001111755, ENST00001144682

RefSeq mRNA: 2 — MANE Select: NM_004460 NM_001291807, NM_004460

CCDS: CCDS33311, CCDS77480

Canonical transcript exons

ENST00000188790 — 26 exons

Exon	Start	End
ENSE00000779544	162209952	162209996
ENSE00000779554	162226523	162226621
ENSE00001378583	162243322	162243445
ENSE00003299338	162198757	162198881
ENSE00003476170	162202872	162202942
ENSE00003476607	162173723	162173787
ENSE00003496869	162183414	162183468
ENSE00003508374	162200566	162200619
ENSE00003512558	162189656	162189754
ENSE00003519336	162173149	162173221
ENSE00003551517	162203041	162203145
ENSE00003552733	162188169	162188363
ENSE00003554519	162189103	162189172
ENSE00003564006	162174867	162174966
ENSE00003565447	162242908	162242992
ENSE00003570908	162219853	162219925
ENSE00003578117	162225483	162225577
ENSE00003595174	162213938	162214073
ENSE00003608429	162219063	162219183
ENSE00003646420	162172811	162172884
ENSE00003656394	162224466	162224540
ENSE00003666340	162194701	162194748
ENSE00003668648	162223608	162223660
ENSE00003687258	162217986	162218140
ENSE00003692825	162215898	162216001
ENSE00003843462	162170684	162171080

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 98.70.

FANTOM5 (CAGE): breadth broad, TPM avg 26.7184 / max 814.3201, expressed in 876 samples.

Highest expression (Bgee): stromal cell of endometrium, islet of Langerhans, body of uterus, smooth muscle tissue, cartilage tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FAP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 23 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	7.3e-65	+1.62	2:162198214:C:T
Cells Cultured fibroblasts	eqtl	6.5e-20	+0.38	2:162198214:C:T
Adipose Subcutaneous	eqtl	1.5e-09	+0.42	2:162224283:A:G
Adipose Subcutaneous	sqtl	8.8e-09	+1.26	2:162200393:C:T
Skin Sun Exposed Lower leg	eqtl	1.7e-08	+0.41	2:162282341:T:TA
Artery Tibial	eqtl	2.2e-08	+0.38	2:162224283:A:G
Artery Tibial	sqtl	4.0e-08	+0.85	2:162200414:T:TTATACTGATGTAG
Muscle Skeletal	eqtl	1.9e-07	+0.55	2:162171980:T:C
Nerve Tibial	eqtl	1.8e-06	+0.38	2:162290192:G:A
Skin Not Sun Exposed Suprapubic	eqtl	3.4e-06	+0.36	2:162328338:G:GC
Breast Mammary Tissue	sqtl	3.9e-06	+1.23	2:162229919:A:G
Thyroid	eqtl	3.9e-05	+0.48	2:162241090:G:C
Heart Atrial Appendage	eqtl	1.6e-03	+0.47	2:162247601:A:G
Artery Aorta	eqtl	2.0e-03	+0.37	2:162301649:C:T
Adipose Visceral Omentum	eqtl	4.5e-03	+0.55	2:162198558:T:G
Esophagus Mucosa	eqtl	8.3e-03	+0.28	2:162198214:C:T
Esophagus Muscularis	eqtl	1.2e-02	+0.48	2:163050775:A:G
Breast Mammary Tissue	eqtl	1.7e-02	+0.64	2:162212548:G:A
Brain Amygdala	eqtl	3.7e-02	+1.46	2:162300136:A:T
Colon Transverse	eqtl	3.8e-02	-0.45	2:161893728:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
31541	24.2599	812
31543	1.1392	371
31542	0.9483	399
31540	0.3587	165
31544	0.0122	3

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.70	gold quality
islet of Langerhans	UBERON:0000006	94.17	gold quality
body of uterus	UBERON:0009853	94.09	gold quality
smooth muscle tissue	UBERON:0001135	94.08	gold quality
cartilage tissue	UBERON:0002418	92.79	gold quality
gall bladder	UBERON:0002110	92.33	gold quality
decidua	UBERON:0002450	92.23	gold quality
descending thoracic aorta	UBERON:0002345	91.47	gold quality
myometrium	UBERON:0001296	90.55	gold quality
tendon of biceps brachii	UBERON:0008188	90.21	gold quality
right coronary artery	UBERON:0001625	89.48	gold quality
ascending aorta	UBERON:0001496	88.98	gold quality
thoracic aorta	UBERON:0001515	88.92	gold quality
endometrium	UBERON:0001295	87.74	gold quality
uterus	UBERON:0000995	87.62	gold quality
skin of hip	UBERON:0001554	87.05	gold quality
aorta	UBERON:0000947	86.24	gold quality
endocervix	UBERON:0000458	85.29	gold quality
left coronary artery	UBERON:0001626	85.04	gold quality
tibial artery	UBERON:0007610	84.52	gold quality
popliteal artery	UBERON:0002250	84.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.35	gold quality
visceral pleura	UBERON:0002401	83.91	gold quality
ectocervix	UBERON:0012249	83.73	gold quality
coronary artery	UBERON:0001621	82.98	gold quality
cauda epididymis	UBERON:0004360	82.49	gold quality
tendon	UBERON:0000043	81.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.28	gold quality
lower esophagus	UBERON:0013473	81.26	gold quality
pancreas	UBERON:0001264	80.60	gold quality
omental fat pad	UBERON:0010414	80.54	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.48	gold quality
peritoneum	UBERON:0002358	80.48	gold quality
pleura	UBERON:0000977	80.41	gold quality
calcaneal tendon	UBERON:0003701	80.35	gold quality
minor salivary gland	UBERON:0001830	80.16	gold quality
placenta	UBERON:0001987	79.43	gold quality
upper leg skin	UBERON:0004262	79.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	78.76	gold quality
parietal pleura	UBERON:0002400	78.67	gold quality
female reproductive system	UBERON:0000474	78.60	gold quality
layer of synovial tissue	UBERON:0007616	78.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	77.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.72	gold quality
colonic epithelium	UBERON:0000397	76.59	gold quality
apex of heart	UBERON:0002098	76.44	gold quality
skin of abdomen	UBERON:0001416	76.43	gold quality
synovial joint	UBERON:0002217	76.21	gold quality
upper lobe of left lung	UBERON:0008952	76.17	gold quality
left uterine tube	UBERON:0001303	75.72	gold quality
tibia	UBERON:0000979	75.60	gold quality
esophagus	UBERON:0001043	75.60	gold quality
skin of leg	UBERON:0001511	75.56	gold quality
mouth mucosa	UBERON:0003729	75.55	gold quality
body of pancreas	UBERON:0001150	75.38	gold quality
metanephros cortex	UBERON:0010533	75.38	gold quality
connective tissue	UBERON:0002384	75.17	gold quality
adipose tissue	UBERON:0001013	75.02	gold quality
zone of skin	UBERON:0000014	74.96	gold quality
upper lobe of lung	UBERON:0008948	74.89	gold quality
thoracic mammary gland	UBERON:0005200	74.36	gold quality
muscle of leg	UBERON:0001383	74.33	gold quality
saliva-secreting gland	UBERON:0001044	74.09	gold quality
vermiform appendix	UBERON:0001154	73.89	gold quality
mammary gland	UBERON:0001911	73.81	gold quality
uterine cervix	UBERON:0000002	73.78	gold quality
right lobe of thyroid gland	UBERON:0001119	73.75	gold quality
gastrocnemius	UBERON:0001388	73.48	gold quality
superficial temporal artery	UBERON:0001614	73.32	gold quality
vagina	UBERON:0000996	73.12	gold quality
mucosa of stomach	UBERON:0001199	73.05	gold quality
corpus epididymis	UBERON:0004359	72.86	gold quality
left lobe of thyroid gland	UBERON:0001120	72.78	gold quality
adrenal tissue	UBERON:0018303	72.69	gold quality
lower esophagus mucosa	UBERON:0035834	72.57	gold quality
thyroid gland	UBERON:0002046	72.11	gold quality
right lung	UBERON:0002167	72.07	gold quality
blood vessel layer	UBERON:0004797	71.61	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.46	gold quality
esophagus mucosa	UBERON:0002469	70.97	gold quality
sigmoid colon	UBERON:0001159	70.93	gold quality
muscle organ	UBERON:0001630	70.89	gold quality
skeletal muscle organ	UBERON:0014892	70.89	gold quality
rectum	UBERON:0001052	70.67	gold quality
prefrontal cortex	UBERON:0000451	70.34	gold quality
tibial nerve	UBERON:0001323	70.28	gold quality
heart left ventricle	UBERON:0002084	69.77	gold quality
right frontal lobe	UBERON:0002810	69.71	gold quality
seminal vesicle	UBERON:0000998	69.63	gold quality
right ovary	UBERON:0002118	69.37	gold quality
lung	UBERON:0002048	69.35	gold quality
right uterine tube	UBERON:0001302	69.21	gold quality
heart	UBERON:0000948	69.00	gold quality
cardiac ventricle	UBERON:0002082	68.85	gold quality
caecum	UBERON:0001153	68.32	gold quality
mammary duct	UBERON:0001765	68.26	silver quality
pigmented layer of retina	UBERON:0001782	67.95	gold quality
epithelium of mammary gland	UBERON:0003244	67.56	silver quality
left ovary	UBERON:0002119	67.36	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	939.53
E-MTAB-5061	yes	754.32
E-GEOD-81608	yes	650.02
E-GEOD-75688	yes	592.00
E-HCAD-31	yes	48.79
E-MTAB-8410	yes	37.21
E-GEOD-81547	yes	29.32
E-MTAB-10287	yes	18.79
E-GEOD-83139	yes	13.81
E-ANND-3	yes	11.83
E-CURD-112	yes	6.18

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Endometrium 1	tissue	29.4	high
Smooth muscle	tissue	24.7	high
Placenta	tissue	21.7	medium
Gallbladder	tissue	20.8	high
Urinary bladder	tissue	14.5	high
Cervix	tissue	14.3	low
Breast	tissue	9.4	medium
Epididymis	tissue	7.9	medium
Tongue	tissue	7.0
Retina	tissue	5.8
Seminal vesicle	tissue	5.5	low
Appendix	tissue	4.9	high
Heart muscle	tissue	4.5	medium
Skeletal muscle	tissue	4.1	medium
Cerebral cortex	tissue	4.0	low
Adipose tissue	tissue	4.0	not detected
Motor cortex	tissue	4.0
Retrosplenial cortex	tissue	4.0
Lung	tissue	3.8	medium
Occipital cortex	tissue	3.8
Vagina	tissue	3.4	low
Esophagus	tissue	3.4	medium
Fallopian tube	tissue	3.4	medium
Hippocampal formation	tissue	3.1
Entorhinal cortex	tissue	3.1
Retrosplenial and cingulate cortex	tissue	3.1
Somatosensory cortex	tissue	2.8
Skin 1	tissue	2.6	low
Prefrontal cortex	tissue	2.6
Ovary	tissue	2.4	not detected
Pancreas	tissue	2.4	not detected
Rectum	tissue	2.3	medium
Insular cortex	tissue	2.1
Prostate	tissue	1.8	medium
Temporal cortex	tissue	1.8
Salivary gland	tissue	1.5	low
Lymph node	tissue	1.4	low
Testis	tissue	1.4	medium
Locus coeruleus	tissue	1.3
Tonsil	tissue	1.3	not detected
Frontal cortex	tissue	1.2
Superior colliculi	tissue	1.2
Hippocampus	tissue	1.1	low
Colon	tissue	0.9	low
Thyroid gland	tissue	0.9	low
Postcentral gyrus	tissue	0.8
Caudate putamen	tissue	0.8
Parathyroid gland	tissue	0.7	not detected
Spinal cord	tissue	0.7
Corpus callosum	tissue	0.7
Olfactory bulb	tissue	0.7
Nucleus accumbens	tissue	0.6
Kidney	tissue	0.6	low
Stomach 1	tissue	0.5	not detected
Pituitary gland	tissue	0.4
Choroid plexus	tissue	0.4
Substantia nigra	tissue	0.4
Spleen	tissue	0.4	not detected
Small intestine	tissue	0.4	not detected
Duodenum	tissue	0.4	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Blood vessel (15.9), Supraoptic nucleus (3.3), Habenula (2.7), Nucleus rhomboideus (2.6), Corticomedial amygdala (2.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, ETV6, FOS, IRF8, TWIST1

miRNA regulators (miRDB)

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

29 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-1911-5P	98.92	67.53	325
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-125A-3P	97.04	66.92	902
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-345-5P	96.40	66.43	663
HSA-MIR-6738-5P	96.33	63.61	815
HSA-MIR-6891-3P	95.80	65.76	683
HSA-MIR-1914-3P	95.07	63.37	762

Functional genomics

gnomAD constraint: pLI 3.8e-08, LOEUF 0.892, missense Z 0.112 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000188790 — one region, missense o/e 1.01.

Literature-anchored findings (GeneRIF, showing 40)

• expression of the seprase-DPPIV complex is restricted to migratory cells involved in wound closure (PMID:12023964)
• seprase and the urokinase plasminogen activator receptor (uPAR), co-localize in the plasma membrane of LOX malignant melanoma cells (PMID:12376466)
• This protein and collagen are intrahepatically expressed in hepatitis C infection. (PMID:12675244)
• Seprase may be an early marker of tumor invasion in squamous lesions of the uterine cervix. (PMID:12926053)
• An abundant expression of seprase in colorectal cancer tissue is associated with lymph node metastasis. (PMID:12963128)
• Seprase may contribute to the pathogenesis of breast cancer by promoting growth of the primary tumor and by facilitating the growth of breast cancer cells in metastases at other sites of the body (PMID:14524536)
• These results suggested that there is a difference in seprase expression between intestinal- and diffuse-type gastric cancer; this difference may reflect distinct biological features of these types of cancer (PMID:14707457)
• the enzymatic activity of fibroblast activation protein plays an important role in the promotion of tumor growth (PMID:15767544)
• molecular determinants responsible for the substrate specificity and endopeptidase activity (PMID:15809306)
• analysis of response of CD4(+) and CD8(+) T-cells to the human stromal antigen, fibroblast activation protein (PMID:16061874)
• FAP has important nonenzymatic functions that in chronic liver injury may facilitate tissue remodeling through FAP-mediated enhancement of HSC cell adhesion, migration, and apoptosis (PMID:16175601)
• Increased expression of seprase is associated with lymph node metastasis in colorectal cancer (PMID:16196122)
• Circulating antiplasmin-cleaving enzyme (APCE) has a role in fibrinolysis and appears structurally similar to fibroblast activation protein (APCE). (PMID:16223769)
• Conversion of FAP to the more easily fibrin-incorporable form, Asn-alpha2AP, may increase plasmin inhibition within fibrin (PMID:16223769)
• fibroblast activation protein protease inhibition is based on dipeptide substrate specificity (PMID:16410248)
• FAP required substrates with Pro at P(1) and Gly or d-amino acids at P(2) and preferred small, uncharged amino acids at P(3), but tolerated most amino acids at P(4), P(1)(’) and P(2)(’). (PMID:16480718)
• Expression of active FAPalpha on chondrocyte membrane and elevated levels in cartilage from osteoarthritis patients. May have important pathological role in cartilage turnover prevalent in arthritic diseases. (PMID:16507127)
• overexpression in HEK293 cells reduced cell adhesion, migration and invasion on ECM components, increased proliferation and promoted apoptosis, independently of enzyme activity (PMID:16700525)
• The reported type 1 diabetes association is from a linkage disequilibrium region including three candidate genes, FAP, IFIH1 and GCA. (PMID:18071670)
• The substrate specificity of FAP was identified by mapping of cleavage sites within collagen I, and peptides synthesized based on these sites showed similar Km values for high and low ranked substrates, but the kcat values differed up to 100-fold. (PMID:18095711)
• FAP-alpha expression in metaplastic, dysplastic, and esophageal cancer tissue is associated with neoplastic progression of esophageal lesions. (PMID:18570153)
• Fibroblast activation protein is highly expressed in pancreatic adenocarcinoma, with greatest expression immediately adjacent to tumor. Higher FAP expression is associated with worse clinical outcome. (PMID:18665076)
• seprase may have a role in promotion of an invasive phenotype by collagenous matrices in ovarian tumor cells (PMID:18823010)
• This study examines FAP’s function in vitro by assaying the proliferation, migration and invasion of ovarian cancer cell line HO-8910PM.. (PMID:19747910)
• data suggest that FAP and DPP-IV are consistently expressed in bone and soft tissue tumour cells that are histogenetically related to activated fibroblasts and/or myofibroblasts, irrespective of their malignancy. (PMID:19817894)
• DPP8 and DPP9 prevail over canonical DPP-IV/CD26 and FAPalpha in all examined meningioma patients (PMID:20043068)
• central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in rheumatoid arthritis (PMID:20155839)
• Suggest fibroblast-activation protein as a histologic adjunct in confidently differentiating morpheaform/infiltrative basal cell carcinoma from desmoplastic trichoepithelioma. (PMID:20711172)
• FAP is overexpressed in Crohn disease strictures (PMID:20806341)
• role in the invasive behavior of keloids (PMID:20872224)
• Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. (PMID:21314817)
• These experiments suggest a functional association between UVR and FAP-alpha expression that UVR of malignant melanoma converts fibroblasts into FAP-alpha expressing and ECM degrading fibroblasts thus facilitating invasion and migration. (PMID:21491083)
• the associated dynamics of DPP-IV and FAP gene expression in glioblastoma cells further argues in favor of their putative joint involvement in biological processes (PMID:21526345)
• FAP remodels the ECM by modulating protein levels & increasing fibronectin levels & collagen fiber organization. FAP-dependent architectural/compositional ECM alterations promote tumor invasion along characteristic parallel fiber orientations. (PMID:21668992)
• immunostaining with FAP-alpha and Calponin can serve as a novel marker for pathologically diagnosing whether ductal carcinoma in situ has microinvasion. (PMID:22067528)
• Studies indicate that the identification of fibroblast activation protein alpha (FAP) as a target selectively expressed on carcinoma-associated fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit. (PMID:22323494)
• Data show that fibroblast activation protein is highly expressed in carcinoma cells and fibroblasts in PDAC tissues, and its expression is associated with desmoplasia and worse prognosis. (PMID:22371645)
• Strong FAPalpha and TGF-beta1 expressions were detected in myocardial cytoplasm in both acute and recurrent myocardial infarction groups. (PMID:22435331)
• REVIEW: key modulator of the microenvironment in multiple pathologies (PMID:22608558)
• FAP is an important regulator of the microenvironment in tumor formation (PMID:22614695)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fap	ENSMUSG00000000392
rattus_norvegicus	Fap	ENSRNOG00000005679
caenorhabditis_elegans		WBGENE00001055

Paralogs (6): DPP8 (ENSG00000074603), DPP6 (ENSG00000130226), DPP9 (ENSG00000142002), APEH (ENSG00000164062), DPP10 (ENSG00000175497), DPP4 (ENSG00000197635)

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
Microsporum canis	A0S5V9	100.0%	Diamond
Aspergillus flavus NRRL3357	B8N970	100.0%	Diamond
Microsporum canis CBS 113480	C5FJE3	100.0%	Diamond
Coccidioides posadasii C735 delta SOWgp	C5P334	100.0%	Diamond
Coccidioides posadasii str. Silveira	E9CUF4	100.0%	Diamond
Aspergillus oryzae RIB40	Q2UH35	100.0%	Diamond
Trichophyton equinum	A7UKV8	99.5%	Diamond
Trichophyton tonsurans	B6V868	99.5%	Diamond
Aspergillus niger	Q96VT7	99.3%	Diamond
Pan troglodytes	Q5IS50	99.0%	Diamond
Trichophyton benhamiae CBS 112371	D4APE2	98.6%	Diamond
Trichophyton verrucosum HKI 0517	D4DCG0	98.4%	Diamond
Trichophyton rubrum	Q5J6J3	97.9%	Diamond
Aspergillus fischeri NRRL 181	A1D7R6	95.8%	Diamond
Sordaria macrospora k-hell	D1Z9B4	94.5%	Diamond
Neurospora crassa OR74A	Q7SHU8	94.5%	Diamond
Bos taurus	A5D7B7	93.9%	Diamond
Metarhizium acridum CQMa 102	E9ED72	93.2%	Diamond
Metarhizium robertsii ARSEF 23	E9ETL5	93.2%	Diamond
Sus scrofa	P22411	91.0%	Diamond
Felis catus	Q9N2I7	88.0%	Diamond
Nannizzia gypsea CBS 118893	E4UYL6	87.5%	Diamond
Vespula vulgaris	B1A4F7	86.2%	Diamond
Vespa velutina	P0DRB8	86.2%	Diamond
Talaromyces marneffei ATCC 18224	B6QVW4	83.8%	Diamond
Talaromyces stipitatus ATCC 10500	B8MTH6	83.8%	Diamond
Aspergillus clavatus NRRL 1	A1CHP1	83.2%	Diamond
Podospora anserina S mat+	B2A951	72.1%	Diamond
Chaetomium globosum CBS 148.51	Q2HF90	72.1%	Diamond
Aspergillus nidulans FGSC A4	Q5AZ42	71.4%	Diamond
Fusarium vanettenii 77-13-4	C7YYG9	69.0%	Diamond
Pyricularia oryzae 70-15	A4QYQ5	64.3%	Diamond
Tuber melanosporum Mel28	D5GM60	62.8%	Diamond
Grosmannia clavigera kw1407	F0XS04	59.9%	Diamond
Apis mellifera	B2D0J4	54.8%	Diamond
Schizosaccharomyces pombe 972h-	O14073	42.6%	Diamond
Aeropyrum pernix K1	Q9YBQ2	32.8%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
DPP4-DT	ncRNA	100131604
DPP4	protein-coding	1803
GCG	protein-coding	2641
IFIH1	protein-coding	64135
GCA	protein-coding	25801
KCNH7	protein-coding	90134
KCNH7-AS1	ncRNA	101929570

Protein

Protein identifiers

Prolyl endopeptidase FAP — Q12884 (reviewed: Q12884)

Alternative names: 170 kDa melanoma membrane-bound gelatinase, Dipeptidyl peptidase FAP, Fibroblast activation protein alpha, Gelatine degradation protease FAP, Integral membrane serine protease, Post-proline cleaving enzyme, Serine integral membrane protease, Surface-expressed protease

All UniProt accessions (6): B4DLR2, C9J131, F8WF29, H0YG61, H7C4D9, Q12884

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface glycoprotein serine protease that participates in extracellular matrix degradation and involved in many cellular processes including tissue remodeling, fibrosis, wound healing, inflammation and tumor growth. Both plasma membrane and soluble forms exhibit post-proline cleaving endopeptidase activity, with a marked preference for Ala/Ser-Gly-Pro-Ser/Asn/Ala consensus sequences, on substrate such as alpha-2-antiplasmin SERPINF2 and SPRY2. Degrade also gelatin, heat-denatured type I collagen, but not native collagen type I and IV, vitronectin, tenascin, laminin, fibronectin, fibrin or casein. Also has dipeptidyl peptidase activity, exhibiting the ability to hydrolyze the prolyl bond two residues from the N-terminus of synthetic dipeptide substrates provided that the penultimate residue is proline, with a preference for Ala-Pro, Ile-Pro, Gly-Pro, Arg-Pro and Pro-Pro. Natural neuropeptide hormones for dipeptidyl peptidase are the neuropeptide Y (NPY), peptide YY (PYY), substance P (TAC1) and brain natriuretic peptide 32 (NPPB). The plasma membrane form, in association with either DPP4, PLAUR or integrins, is involved in the pericellular proteolysis of the extracellular matrix (ECM), and hence promotes cell adhesion, migration and invasion through the ECM. Plays a role in tissue remodeling during development and wound healing. Participates in the cell invasiveness towards the ECM in malignant melanoma cancers. Enhances tumor growth progression by increasing angiogenesis, collagen fiber degradation and apoptosis and by reducing antitumor response of the immune system. Promotes glioma cell invasion through the brain parenchyma by degrading the proteoglycan brevican. Acts as a tumor suppressor in melanocytic cells through regulation of cell proliferation and survival in a serine protease activity-independent manner.

Subunit / interactions. Homodimer; homodimerization is required for activity of both plasma membrane and soluble forms. The monomer is inactive. Heterodimer with DPP4. Interacts with PLAUR; the interaction occurs at the cell surface of invadopodia membranes. Interacts with ITGB1. Interacts with ITGA3. Associates with integrin alpha-3/beta-1; the association occurs in a collagen-dependent manner at the cell surface of invadopodia membranes.

Subcellular location. Cell surface. Cell membrane. Cell projection. Lamellipodium membrane. Invadopodium membrane. Ruffle membrane. Membrane Secreted Cytoplasm.

Tissue specificity. Expressed in adipose tissue. Expressed in the dermal fibroblasts in the fetal skin. Expressed in the granulation tissue of healing wounds and on reactive stromal fibroblast in epithelial cancers. Expressed in activated fibroblast-like synoviocytes from inflamed synovial tissues. Expressed in activated hepatic stellate cells (HSC) and myofibroblasts from cirrhotic liver, but not detected in normal liver. Expressed in glioma cells (at protein level). Expressed in glioblastomas and glioma cells. Isoform 1 and isoform 2 are expressed in melanoma, carcinoma and fibroblast cell lines.

Post-translational modifications. N-glycosylated. The N-terminus may be blocked.

Activity regulation. Gelatinase activity is inhibited by serine-protease inhibitors, such as phenylmethylsulfonyl fluoride (PMSF), 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride (AEBSF), 4-amidino phenylsulfonyl fluoride (APSF) and diisopropyl fluorophosphate (DFP), N-ethylmaleimide (NEM) and phenylmethylsulfonyl fluoride (PMSF). Dipeptidyl peptidase activity is inhibited by 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), diisopropylfluorophosphate (DFP). Prolyl endopeptidase activity is inhibited by the boronic acid peptide Ac-Gly-BoroPro, Ac-Gly-Pro-chloromethyl ketone and Thr-Ser-Gly-chloromethyl ketone.

Induction. In fibroblasts at times and sites of tissue remodeling during development, tissue repair and carcinogenesis. Up-regulated upon tumor stem cell differentiation. Up-regulated by transforming growth factor-beta, 12-O-tetradecanoyl phorbol-13-acetate and retinoids.

Miscellaneous. Major isoform. Upstream open reading frames ORF(s)-containing region inhibits the translation of its downstream ORF.

Similarity. Belongs to the peptidase S9B family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q12884-1	1, L, seprase-I	yes
Q12884-2	2, S, Truncated, seprase-s

RefSeq proteins (2): NP_001278736, NP_004451* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002469	Peptidase_S9B_N	Domain
IPR002471	Pept_S9_AS	Active_site
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR050278	Serine_Prot_S9B/DPPIV	Family

Pfam: PF00326, PF00930

Enzyme classification (BRENDA)

• EC 3.4.21.B28 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (125 total): strand 55, helix 25, mutagenesis site 10, turn 9, glycosylation site 6, disulfide bond 4, sequence conflict 3, active site 3, chain 2, topological domain 2, binding site 2, site 1, splice variant 1, sequence variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
1Z68	Crystal Structure Of Human Fibroblast Activation Protein alpha	X-RAY DIFFRACTION	2.6
9DVQ	Cryo-EM structure of Human Fibroblast Activation Protein alpha dimer with one SUMO-I3 …	ELECTRON MICROSCOPY	2.7
9DVR	Cryo-EM structure of Human Fibroblast Activation Protein alpha dimer with two SUMO-I3 …	ELECTRON MICROSCOPY	2.7
6Y0F	Structure of human FAPalpha in complex with linagliptin	X-RAY DIFFRACTION	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12884-F1	95.72	0.94

Antibody-complex structures (SAbDab)

2 antibodies co-crystallized with this protein: 9DVQ, 9DVR

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH uncertain

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 (4)

Position	Role
23–24	cleavage
624	charge relay system
702	charge relay system
734	charge relay system

Ligand- & substrate-binding residues (2)

Position	Role
203	substrate
204	substrate

Disulfide bonds (4)

Type	Positions
Disulfide bond	321–332, 438–441, 448–466, 643–755

Glycosylation sites (6)

Type	Positions
N-linked (glcnac…) asparagine	49, 92, 99, 227, 314, 679

Mutagenesis-validated functional residues (10)

Position	Phenotype
123	reduces dipeptidyl peptidase and endopeptidase activities.
203	reduces dipeptidyl peptidase and endopeptidase activities. does not inhibit cell adhesion, migration and invasion. inhibits dipeptidyl …
204	reduces dipeptidyl peptidase and endopeptidase activities. does not inhibit cell adhesion, migration and invasion. inhibits dipeptidyl …
624	reduces dipeptidyl peptidase and gelatinolytic activities. does not inhibit cell adhesion, migration and invasion.
656	reduces dipeptidyl peptidase and endopeptidase activities.
657	inhibits endopeptidase activity. increases dipeptidyl peptidase activity.
657	reduces dipeptidyl peptidase and endopeptidase activities.
657	inhibits endopeptidase activity. no change in dipeptidyl peptidase activity.
657	strongly reduces endopeptidase activity. no change in dipeptidyl peptidase activity.
704	reduces dipeptidyl peptidase and endopeptidase activities.

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: 287 (showing top): MODULE_172, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_REGULATION_OF_COAGULATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, MODULE_128, GNF2_PTX3, TAL1ALPHAE47_01, GOCC_RUFFLE, GOBP_REGULATION_OF_EXTRACELLULAR_MATRIX_ORGANIZATION, CEBPB_01, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_COAGULATION

GO Biological Process (15): angiogenesis (GO:0001525), proteolysis (GO:0006508), cell adhesion (GO:0007155), regulation of collagen catabolic process (GO:0010710), negative regulation of extracellular matrix disassembly (GO:0010716), endothelial cell migration (GO:0043542), regulation of cell cycle (GO:0051726), regulation of fibrinolysis (GO:0051917), negative regulation of cell proliferation involved in contact inhibition (GO:0060244), melanocyte proliferation (GO:0097325), positive regulation of execution phase of apoptosis (GO:1900119), melanocyte apoptotic process (GO:1902362), negative regulation of extracellular matrix organization (GO:1903054), apoptotic process (GO:0006915), protein catabolic process (GO:0030163)

GO Molecular Function (11): protease binding (GO:0002020), endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), integrin binding (GO:0005178), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), dipeptidyl-peptidase activity (GO:0008239), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (13): cytoplasm (GO:0005737), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell surface (GO:0009986), membrane (GO:0016020), lamellipodium (GO:0030027), lamellipodium membrane (GO:0031258), ruffle membrane (GO:0032587), apical part of cell (GO:0045177), basal part of cell (GO:0045178), peptidase complex (GO:1905368), extracellular region (GO:0005576), cell projection (GO:0042995)

GO top-level categories

56 GO namespaces:

Category	Terms
cellular anatomical structure	7
protein metabolic process	2
execution phase of apoptosis	2
peptidase activity	2
cell projection membrane	2
leading edge membrane	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cellular process	1
regulation of catabolic process	1
regulation of collagen metabolic process	1
collagen catabolic process	1
regulation of extracellular matrix disassembly	1
extracellular matrix disassembly	1
negative regulation of extracellular matrix organization	1
cell migration	1
cell cycle	1
regulation of cellular process	1
regulation of blood coagulation	1
fibrinolysis	1
negative regulation of cell population proliferation	1
contact inhibition	1
epithelial cell proliferation	1
positive regulation of apoptotic process	1
regulation of execution phase of apoptosis	1
apoptotic process	1
extracellular matrix organization	1
negative regulation of cellular component organization	1
regulation of extracellular matrix organization	1
programmed cell death	1
apoptotic signaling pathway	1
macromolecule catabolic process	1
enzyme binding	1
endopeptidase activity	1
serine-type peptidase activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
exopeptidase activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell-substrate junction	1
cell leading edge	1
plasma membrane bounded cell projection	1
lamellipodium	1
ruffle	1
catalytic complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 18 of 41 annotations. The rest are phylogenetic / computational / electronic (IEA).

18 experimentally-supported GO terms:

GO term	NS	Evidence
endothelial cell migration	BP	direct assay
negative regulation of extracellular matrix disassembly	BP	direct assay
negative regulation of extracellular matrix organization	BP	direct assay
proteolysis	BP	direct assay
regulation of collagen catabolic process	BP	direct assay
focal adhesion	CC	high-throughput assay
lamellipodium	CC	direct assay
peptidase complex	CC	mutant phenotype
plasma membrane	CC	direct assay
dipeptidyl-peptidase activity	MF	direct assay
endopeptidase activity	MF	direct assay
identical protein binding	MF	physical interaction
integrin binding	MF	physical interaction
peptidase activity	MF	direct assay
protease binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
serine-type endopeptidase activity	MF	direct assay
serine-type peptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,212 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAP	GCG	P01275	654
FAP	INS	P01308	642
FAP	DPP7	Q9UHL4	610
FAP	PREP	P48147	598
FAP	DPP4	P27487	597
FAP	GLP1R	P43220	570
FAP	GIP	P09681	515
FAP	MGAM	O43451	497
FAP	PYY	P10082	497
FAP	SI	P14410	497
FAP	CXCL12	P48061	485
FAP	S100A4	P26447	482
FAP	LOX	P28300	481
FAP	PDPN	Q86YL7	467
FAP	AMY2A	P04746	461

IntAct

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

10 partners by confidence:

Partner	Interaction type	MIscore	Records
GCG	cleavage reaction	0.440	4
VIP	cleavage reaction	0.440	2
ADCYAP1	cleavage reaction	0.440	1
GHRH	cleavage reaction	0.440	1
GIP	cleavage reaction	0.440	1
NPPB	cleavage reaction	0.440	1
NPY	cleavage reaction	0.440	1
PYY	cleavage reaction	0.440	1
TAC1	cleavage reaction	0.440	1
CABCOCO1	physical association	0.400	1

BioGRID (33 interactions; top human partners by supporting records): CAV1 (Affinity Capture-MS; 4 records), DPP4 (Affinity Capture-MS; 3 records), ERLIN2 (Affinity Capture-MS; 3 records), STOM (Affinity Capture-MS; 3 records), ADA (Affinity Capture-MS; 2 records), PHB2 (Affinity Capture-MS; 2 records), THY1 (Affinity Capture-MS; 2 records), CORO1C (Co-fractionation), CSK (Synthetic Lethality), ECT2 (Affinity Capture-MS), HUWE1 (Co-fractionation), MSRB1 (Affinity Capture-MS), MYC (Affinity Capture-MS), PHB (Affinity Capture-MS), PLAUR (FRET)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
EGR1	“up-regulates quantity by expression”	FAP	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	FAP	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ DPP4-FAP complex	2	DPP4, FAP

Disease & clinical

Genetic variants

Variant evidence for FAP: 126 ClinVar records (0 pathogenic / likely pathogenic); 9 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	92
Likely benign	6
Benign	9

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 2,630):

Position(s)	Effect	Δscore	Sites
2:162188296	acceptor_gain	1.0000
2:162195551	donor_gain	1.0000
2:162198882–162198883	acceptor_loss	1.0000	3
2:162200564–162200565	donor_loss	1.0000	4
2:162200620–162200621	acceptor_loss	1.0000	6
2:162226623	acceptor_gain	1.0000
2:162243320–162243321	donor_loss	1.0000	4
2:162171421	acceptor_gain	0.9900
2:162172815	donor_gain	0.9900
2:162173222–162173223	acceptor_loss	0.9900	6

AlphaMissense

1,699 missense substitutions predicted likely pathogenic (of 5,000 scored), across 462 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
D702	8	0.990	0.997
H734	8	0.980	0.992
D599	8	0.972	0.993
H698	8	0.971	0.992
D573	8	0.968	0.988
D198	8	0.945	0.981
D703	8	0.934	0.984
N491	8	0.931	0.985
D731	8	0.927	0.986
F357	8	0.904	0.986
H376	8	0.902	0.983
F455	8	0.900	0.984
H706	8	0.890	0.969
H743	8	0.888	0.957
C466	7	0.989	0.996
C438	7	0.985	0.993
W298	7	0.984	0.997
C448	7	0.978	0.992
W199	7	0.977	0.994
W346	7	0.975	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	3.63e-06
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	9.4e-05
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000277

Disease associations

OMIM: gene MIM:600403 | disease phenotypes:

GWAS associations

9 associations:

Study	Trait	p-value
GCST007932_19	Medication use (thyroid preparations)	2e-13
GCST005537_216	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	3e-13
GCST002740_41	Inflammatory skin disease	2e-12
GCST005752_118	Systemic lupus erythematosus	5e-12
GCST006921_3	Regular attendance at a pub or social club	2e-8
GCST007344_7	Estimated glomerular filtration rate	2e-8
GCST011956_103	Systemic lupus erythematosus	3e-8
GCST010866_161	Coronary artery disease	4e-8
GCST005984_6	Glomerular filtration rate	5e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0009933	Thyroid preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4683 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the FAP protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

3 curated-mechanism drugs:

Drug	Modality	Max phase
F19 131I	Unknown	3
SIBROTUZUMAB	Antibody	2
SIMLUKAFUSP ALFA	Protein	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 121,582 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

14 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL922	ADEFOVIR DIPIVOXIL	4	27,865
CHEMBL1929396	ANAGLIPTIN	4	1,153
CHEMBL454446	CEFDITOREN PIVOXIL	4	3,202
CHEMBL515387	GOSOGLIPTIN	4	823
CHEMBL237500	LINAGLIPTIN	4	5,545
CHEMBL1422	SITAGLIPTIN	4	26,952
CHEMBL1538	TENOFOVIR DISOPROXIL	4	8,005
CHEMBL1486	TENOFOVIR DISOPROXIL FUMARATE	4	13,310
CHEMBL142703	VILDAGLIPTIN	4	20,579
CHEMBL4296719	DUTOGLIPTIN	3	1,437
CHEMBL76688	SIVELESTAT	3	1,791
CHEMBL3182314	SIVELESTAT SODIUM	3	38
CHEMBL67279	TALABOSTAT	3	10,527
CHEMBL2107486	TEBIPENEM PIVOXIL	3	355

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 (3 total), top 3:

Ligand	Action	Affinity	Parameter
AZD2389	Inhibition	9.44	pIC50
compound 9 [PMID: 20718420]	Inhibition	7.72	pIC50
ARI-3099	Inhibition	7.44	pIC50

Binding affinities (BindingDB)

860 measured of 1177 human assays (1191 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US20250177582, Compound 28	IC50	0.03 nM	US-20250177582: HIGH-AFFINITY LIGANDS OF FIBROBLAST ACTIVATION PROTEIN FOR TARGETED DELIVERY APPLICATIONS
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
2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]-5-[4-[4-[[4-[[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]carbamoyl]quinolin-6-yl]amino]-4-oxobutanoyl]piperazin-1-yl]-5-oxopentanoic acid;copper	IC50	0.04 nM	US-20240173440: HIGH PURITY COPPER RADIOPHARMACEUTICAL COMPOSITIONS AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF
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

ChEMBL bioactivities

370 potent at pChembl≥5 of 461 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	IC50	0.089	nM	CHEMBL4877950
9.96	Ki	0.11	nM	CHEMBL6147832
9.89	IC50	0.13	nM	CHEMBL4878759
9.74	IC50	0.18	nM	CHEMBL4864809
9.72	IC50	0.19	nM	CHEMBL4853661
9.72	Ki	0.19	nM	CHEMBL4877950
9.68	IC50	0.21	nM	CHEMBL5569730
9.66	IC50	0.22	nM	CHEMBL4850601
9.64	IC50	0.23	nM	CHEMBL4877950
9.51	IC50	0.31	nM	CHEMBL4876026
9.49	IC50	0.32	nM	CHEMBL4868869
9.49	IC50	0.32	nM	CHEMBL5566777
9.48	IC50	0.33	nM	CHEMBL4850484
9.38	IC50	0.42	nM	CHEMBL4873985
9.38	IC50	0.42	nM	CHEMBL4867484
9.37	IC50	0.43	nM	CHEMBL3233842
9.36	IC50	0.44	nM	CHEMBL4864133
9.34	IC50	0.46	nM	CHEMBL5569691
9.33	IC50	0.47	nM	CHEMBL2333025
9.30	IC50	0.5	nM	CHEMBL4854865
9.28	IC50	0.53	nM	CHEMBL4871602
9.24	IC50	0.58	nM	CHEMBL4855449
9.20	IC50	0.63	nM	CHEMBL4859756
9.20	IC50	0.63	nM	CHEMBL4863249
9.20	IC50	0.63	nM	CHEMBL4868282
9.19	IC50	0.64	nM	CHEMBL4847764
9.17	IC50	0.67	nM	CHEMBL4851238
9.11	IC50	0.77	nM	CHEMBL4855309
9.10	IC50	0.8	nM	CHEMBL5572035
9.10	IC50	0.8	nM	CHEMBL6147832
9.00	IC50	1	nM	CHEMBL4762591
8.96	IC50	1.1	nM	CHEMBL2333023
8.96	IC50	1.1	nM	CHEMBL4846405
8.96	IC50	1.1	nM	CHEMBL4870279
8.96	IC50	1.1	nM	CHEMBL4870593
8.89	Ki	1.3	nM	CHEMBL1243153
8.85	IC50	1.4	nM	CHEMBL5562853
8.82	IC50	1.5	nM	CHEMBL4871573
8.77	IC50	1.7	nM	CHEMBL4861963
8.75	IC50	1.77	nM	CHEMBL5566659
8.74	IC50	1.8	nM	CHEMBL4869146
8.70	IC50	2	nM	CHEMBL4786982
8.68	IC50	2.1	nM	CHEMBL4864489
8.64	IC50	2.3	nM	CHEMBL1243373
8.64	IC50	2.3	nM	CHEMBL3233842
8.57	IC50	2.7	nM	CHEMBL4872140
8.48	IC50	3.3	nM	CHEMBL3233842
8.47	IC50	3.4	nM	CHEMBL2333030
8.47	IC50	3.4	nM	CHEMBL4850470
8.43	IC50	3.7	nM	CHEMBL4863606

PubChem BioAssay actives

329 with measured affinity, of 915 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
N-[2-[(2S)-2-[2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0001	uM
tert-butyl 2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0001	uM
6-[2-[3-[2-[2-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]ethoxy]-N-[2-[(2S)-2-[2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	2217813: Inhibition of recombinant human FAP extracted from S2 cells immobilized on plate surface using specific antibody assessed as inhibition constant measured after 2 hrs incubation by DNA-linked Inhibitor Antibody Assay (DIANA)	ki	0.0001	uM
2-[4,7-bis(carboxymethyl)-10-[2-[4-[3-[4-[[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]carbamoyl]quinolin-6-yl]oxypropyl]piperazin-1-yl]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid	2106067: Inhibition of FAP (unknown origin)	ic50	0.0002	uM
N-[2-[(2S)-2-[2-[2-(3,4-dimethoxyphenyl)ethylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0002	uM
N-[2-[(2S)-2-[2-[(3-methoxyphenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0002	uM
N-[2-[(2S)-2-[2-[(4-methoxyphenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0002	uM
methyl (2S)-5-(benzylamino)-5-oxo-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]pentanoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0003	uM
N-[2-[(2S)-2-[2-[(2-morpholin-4-yl-2-oxoethyl)amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0003	uM
methyl (2S)-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]-6-(phenylmethoxycarbonylamino)hexanoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0003	uM
benzenesulfonate;3-[4-[[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]carbamoyl]quinolin-6-yl]oxypropyl-(fluoromethyl)-dimethylazanium	2106032: Inhibition of FAP (unknown origin) using Z-Gly-Pro-7-amino-4-methylcoumarine as fluorogenic substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins	ic50	0.0003	uM
ethyl 2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0004	uM
N-[2-[(2S)-2-[2-[(4-fluorophenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0004	uM
methyl 4-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]benzoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0004	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	2106038: Inhibition of C-terminal His-tagged recombinant human FAP extracellular domain (27 to 760 residues) expressed in Sf9 cells	ic50	0.0004	uM
methyl (2S)-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]-3-phenylpropanoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0005	uM
N-[2-[(2S)-2-[2-[[2-(tert-butylamino)-2-oxoethyl]amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0005	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-6-[[(4S,5R)-5-(fluoromethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]quinoline-4-carboxamide	2106032: Inhibition of FAP (unknown origin) using Z-Gly-Pro-7-amino-4-methylcoumarine as fluorogenic substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins	ic50	0.0005	uM
[(2R)-1-[2-(pyridine-4-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736685: Inhibition of human FAP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0005	uM
N-[2-[(2S)-2-[2-(cyclopropylamino)-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0006	uM
N-[2-oxo-2-[(2S)-2-[2-oxo-2-(pentylamino)acetyl]pyrrolidin-1-yl]ethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0006	uM
N-[2-[(2S)-2-[2-[(2,4-dimethylphenyl)methylamino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0006	uM
5-O-benzyl 1-O-methyl (2S)-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]pentanedioate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0006	uM
N-[2-oxo-2-[(2S)-2-[2-oxo-2-(2-phenylethylamino)acetyl]pyrrolidin-1-yl]ethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0006	uM
N-[2-[(2S)-2-[2-[[2-(hexylamino)-2-oxoethyl]amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0007	uM
N-[2-[(2S)-2-[2-(benzylamino)-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0008	uM
2-[4-(carboxymethyl)-6-[carboxymethyl(methyl)amino]-6-[4-[2-[[2-[4-[4-[[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]carbamoyl]quinolin-6-yl]oxybutylamino]-3,4-dioxocyclobuten-1-yl]amino]ethylamino]butyl]-1,4-diazepan-1-yl]acetic acid	2106067: Inhibition of FAP (unknown origin)	ic50	0.0008	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2,4-dichlorophenyl)methyl]-1,3-thiazole-4-carboxamide	1709022: Inhibition of FAP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0010	uM
methyl 2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0011	uM
methyl 2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]propanoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0011	uM
N-[2-oxo-2-[(2S)-2-[2-oxo-2-[[2-oxo-2-(propan-2-ylamino)ethyl]amino]acetyl]pyrrolidin-1-yl]ethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0011	uM
[(2R)-1-[2-(pyridine-3-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736685: Inhibition of human FAP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0011	uM
(2S)-1-[(2S,4S)-4-[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]-5-oxopyrrolidine-2-carbonyl]-4,4-difluoropyrrolidine-2-carbonitrile	509577: Competitive inhibition of human recombinant FAP expressed in Hi5 insect cells by Lineweaver-Burke plot analysis	ki	0.0013	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-6-(3-fluoro-2-methoxypropoxy)quinoline-4-carboxamide	2106032: Inhibition of FAP (unknown origin) using Z-Gly-Pro-7-amino-4-methylcoumarine as fluorogenic substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins	ic50	0.0014	uM
N-[2-[(2S)-2-[2-(4-methoxyanilino)-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0015	uM
N-[2-[(2S)-2-[2-[[2-[(3,4-dimethoxyphenyl)methylamino]-2-oxoethyl]amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0017	uM
N-[2-oxo-2-[(2S)-2-[2-oxo-2-[(2-oxo-2-pyrrolidin-1-ylethyl)amino]acetyl]pyrrolidin-1-yl]ethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0018	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-6-[(2S,3R)-4-fluoro-2,3-dihydroxybutoxy]quinoline-4-carboxamide	2106032: Inhibition of FAP (unknown origin) using Z-Gly-Pro-7-amino-4-methylcoumarine as fluorogenic substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins	ic50	0.0018	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(3,4-dichlorophenyl)methyl]-1,3-thiazole-4-carboxamide	1709022: Inhibition of FAP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0020	uM
(4S)-5-methoxy-5-oxo-4-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]pentanoic acid	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0021	uM
[(2R)-1-[2-(naphthalene-1-carbonylamino)acetyl]pyrrolidin-2-yl]boronic acid	736685: Inhibition of human FAP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0023	uM
N-[2-[(2S)-2-[2-[[2-(cyclopropylamino)-2-oxoethyl]amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0027	uM
N-[2-[(2S)-2-[2-(benzhydrylamino)-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0034	uM
[(2R)-1-[(2R)-2-[(3-chloropyridine-4-carbonyl)amino]propanoyl]pyrrolidin-2-yl]boronic acid	736685: Inhibition of human FAP using Z-Gly-Pro-AMC as substrate preincubated for 10 mins prior to substrate addition by fluorescence assay	ic50	0.0034	uM
4-O-benzyl 1-O-methyl (2S)-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]butanedioate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0037	uM
N-[2-[(2S)-2-[2-[[2-(benzylamino)-2-oxoethyl]amino]-2-oxoacetyl]pyrrolidin-1-yl]-2-oxoethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0037	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-2-[(2-naphthalen-2-ylphenyl)methyl]-1,3-thiazole-4-carboxamide	1709022: Inhibition of FAP (unknown origin) using AMC substrate by fluorometric assay	ic50	0.0040	uM
N-[2-oxo-2-[(2S)-2-[2-oxo-2-(propan-2-ylamino)acetyl]pyrrolidin-1-yl]ethyl]quinoline-4-carboxamide	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0040	uM
methyl (2S)-5-amino-5-oxo-2-[[2-[[2-oxo-2-[(2S)-1-[2-(quinoline-4-carbonylamino)acetyl]pyrrolidin-2-yl]acetyl]amino]acetyl]amino]pentanoate	1783814: Inhibition of SF-tagged FAP (unknown origin) expressed in Drosophila S2 cells using fluorogenic substrate by spectrometric analysis	ic50	0.0043	uM
N-[2-[(2S)-2-cyano-4,4-difluoropyrrolidin-1-yl]-2-oxoethyl]-6-(3-fluoro-2-hydroxypropoxy)quinoline-4-carboxamide	2106032: Inhibition of FAP (unknown origin) using Z-Gly-Pro-7-amino-4-methylcoumarine as fluorogenic substrate preincubated for 15 mins followed by substrate addition and measured after 15 mins	ic50	0.0044	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, increases expression, decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases expression	2
bisphenol S	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
bisphenol F	increases expression	1
potassium chromate(VI)	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Roflumilast	decreases reaction, increases expression	1
bisphenol B	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Ursolic Acid	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Calcitriol	decreases expression	1
Cisplatin	increases expression, decreases response to substance	1
Dexamethasone	affects cotreatment, decreases expression, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, decreases expression, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Silicon Dioxide	increases expression	1
Tamoxifen	affects expression	1
Valproic Acid	decreases methylation	1
1-Methyl-3-isobutylxanthine	decreases expression, increases expression, affects cotreatment	1
Serine Proteinase Inhibitors	decreases reaction, increases cleavage, decreases activity	1

ChEMBL screening assays

130 unique, capped per target: 92 binding, 37 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003614	Binding	Binding affinity to human FAP assessed as enzyme mediated drug cleavage by measuring Pyro fluorescence	Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers. — *J Med Chem*
CHEMBL3091135	ADMET	Stability of the compound assessed as recombinant human FAPalpha-mediated compound degradation measuring intact level at 0.1 mM after 48 hrs by reverse-phase HPLC/MS analysis	A general method for making peptide therapeutics resistant to serine protease degradation: application to dipeptidyl peptidase IV substrates. — *J Med Chem*
CHEMBL5723527	Functional	Affinity On-target Cellular interaction: (Competitive radioligand binding assay with unlabelled inhibitor, HT-1080-FAP cells) EUB0002573a FAP	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

13 cell lines: 9 cancer cell line, 3 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8FS	Abcam HCT 116 FAP KO	Cancer cell line	Male
CVCL_B9HZ	Abcam A-549 FAP KO	Cancer cell line	Male
CVCL_D2F4	Abcam MCF-7 FAP KO	Cancer cell line	Female
CVCL_E1EF	Ubigene U-87 MG FAP KO	Cancer cell line	Male
CVCL_E6AD	HEK293-FAP	Transformed cell line	Female
CVCL_E6QC	Genomeditech CHO-K1 H_FAP	Spontaneously immortalized cell line	Female
CVCL_E8JG	HT1080 human FAP	Cancer cell line	Male
CVCL_F4N7	HyCyte NCI-H460 stable cell line for hFAP overexpression	Cancer cell line	Male
CVCL_F4NY	HyCyte A-549 stable cell line for hFAP overexpression	Cancer cell line	Male
CVCL_F4RH	HyCyte LL/2 (LLC1) stable cell line for hFAP overexpression	Cancer cell line

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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