DPP9

Summary

DPP9 (dipeptidyl peptidase 9, HGNC:18648) is a protein-coding gene on chromosome 19p13.3, encoding Dipeptidyl peptidase 9 (Q86TI2). Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.

This gene encodes a protein that is a member of the S9B family in clan SC of the serine proteases. The protein has been shown to have post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Although the activity of this protein is similar to that of dipeptidyl peptidase 4 (DPP4), it does not appear to be membrane bound. In general, dipeptidyl peptidases appear to be involved in the regulation of the activity of their substrates and have been linked to a variety of diseases including type 2 diabetes, obesity and cancer. Several transcript variants of this gene have been described but not fully characterized.

Source: NCBI Gene 91039 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hatipoglu immunodeficiency syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 203 total — 2 pathogenic, 2 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈1% of expected missense variation)
• GTEx eGene: eQTL in 27 tissues, sQTL in 21 (q < 0.05)
• Phenotypes (HPO): 57
• ChEMBL bioactivity: 8 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.65 (unconstrained)
• MANE Select transcript: NM_139159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18648
Approved symbol	DPP9
Name	dipeptidyl peptidase 9
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000142002
Ensembl biotype	protein_coding
OMIM	608258
Entrez	91039

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 21 protein_coding, 13 protein_coding_CDS_not_defined, 10 nonsense_mediated_decay, 6 retained_intron

MANE Select: ENST00000262960

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3, TSL 3: 6, TSL 4: 9, TSL 5: 5

ENST00000262960, ENST00000593973, ENST00000594671, ENST00000595327, ENST00000595940, ENST00000597024, ENST00000597145, ENST00000597253, ENST00000597726, ENST00000597849, ENST00000597900, ENST00000598041, ENST00000598360, ENST00000598800, ENST00000599163, ENST00000599248, ENST00000599998, ENST00000600556, ENST00000600621, ENST00000601130, ENST00000601173, ENST00000601720, ENST00000601764, ENST00000602161, ENST00000646573, ENST00000703253, ENST00000703254, ENST00000703255, ENST00000855532, ENST00000855533, ENST00000855534, ENST00000922035, ENST00000955625, ENST00000973073, ENST00000973074, ENST00000973075, ENST00000973076, ENST00001002739, ENST00001002740, ENST00001002741, ENST00001002742, ENST00001010195, ENST00001010197, ENST00001010198, ENST00001010202, ENST00001010204, ENST00001010205, ENST00001010206, ENST00001084785, ENST00001141417

RefSeq mRNA: 30 — MANE Select: NM_139159 NM_001365987, NM_001384611, NM_001384612, NM_001384613, NM_001384614, NM_001384615, NM_001384616, NM_001384617, NM_001384618, NM_001384619, NM_001384620, NM_001384621, NM_001384622, NM_001384623, NM_001384624, NM_001384625, NM_001384626, NM_001384627, NM_001384628, NM_001384629, NM_001384630, NM_001384631, NM_001384632, NM_001384633, NM_001384634, NM_001384635, NM_001384636, NM_001384637, NM_001384638, NM_139159

CCDS: CCDS45928, CCDS92491, CCDS92492

Canonical transcript exons

ENST00000262960 — 22 exons

Exon	Start	End
ENSE00001664703	4722499	4722551
ENSE00001720699	4684663	4684809
ENSE00003521481	4679835	4679946
ENSE00003545713	4719851	4719941
ENSE00003550866	4683477	4683629
ENSE00003567091	4682696	4682838
ENSE00003693297	4714081	4714337
ENSE00003827533	4685626	4685771
ENSE00003980737	4723674	4723842
ENSE00003988186	4700216	4700277
ENSE00003988187	4702027	4702155
ENSE00003988189	4697551	4697651
ENSE00003988190	4703886	4704054
ENSE00003988191	4689570	4689722
ENSE00003988192	4688757	4688892
ENSE00003988193	4690878	4690957
ENSE00003988194	4694661	4694823
ENSE00003988195	4704131	4704304
ENSE00003988196	4702603	4702716
ENSE00003988199	4695378	4695555
ENSE00003988200	4705858	4705970
ENSE00004475704	4675227	4676656

Expression profiles

Bgee: expression breadth ubiquitous, 236 present calls, max score 94.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.7327 / max 183.3407, expressed in 1820 samples.

Highest expression (Bgee): gastrocnemius, hindlimb stylopod muscle, lobe of liver, muscle of leg, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DPP9 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 27 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 48 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	sqtl	1.6e-39	+0.82	19:4717175:G:A
Skin Sun Exposed Lower leg	sqtl	1.1e-30	+0.62	19:4690247:T:C
Nerve Tibial	sqtl	3.4e-24	+0.71	19:4716386:T:C
Adipose Subcutaneous	sqtl	9.7e-23	+0.66	19:4716386:T:C
Whole Blood	eqtl	9.7e-23	-0.24	19:4717175:G:A
Nerve Tibial	eqtl	4.0e-19	-0.27	19:4716386:T:C
Lung	eqtl	8.9e-18	-0.29	19:4715116:A:T
Skin Not Sun Exposed Suprapubic	sqtl	1.6e-17	+0.59	19:4717175:G:A
Artery Aorta	sqtl	2.4e-16	+0.68	19:4716386:T:C
Breast Mammary Tissue	sqtl	1.9e-15	+0.70	19:4717175:G:A
Colon Sigmoid	eqtl	2.0e-15	-0.36	19:4717175:G:A
Artery Tibial	eqtl	2.3e-13	-0.23	19:4716386:T:C
Lung	sqtl	8.0e-13	+0.54	19:4717175:G:A
Esophagus Muscularis	sqtl	1.5e-11	+0.56	19:4716386:T:C
Brain Cerebellum	eqtl	2.8e-11	-0.41	19:4716386:T:C
Colon Sigmoid	sqtl	3.0e-11	+0.63	19:4717175:G:A
Colon Transverse	eqtl	7.4e-11	-0.20	19:4717175:G:A
Brain Cerebellar Hemisphere	eqtl	7.4e-11	-0.33	19:4716386:T:C
Artery Aorta	eqtl	8.8e-10	-0.24	19:4716386:T:C
Adipose Subcutaneous	eqtl	3.3e-09	-0.19	19:4717175:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
178491	27.9914	1818
178487	0.7404	172
178489	0.6961	284
178490	0.1043	54
178485	0.0689	7
178488	0.0559	18
208658	0.0462	18
178486	0.0295	10

Top tissues by expression

showing 100 of 252 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	94.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.00	gold quality
right lobe of liver	UBERON:0001114	93.93	gold quality
muscle of leg	UBERON:0001383	93.73	gold quality
granulocyte	CL:0000094	93.27	gold quality
pancreatic ductal cell	CL:0002079	92.51	silver quality
vermiform appendix	UBERON:0001154	91.81	gold quality
upper lobe of left lung	UBERON:0008952	91.72	gold quality
skeletal muscle organ	UBERON:0014892	91.43	gold quality
mucosa of transverse colon	UBERON:0004991	91.33	gold quality
colonic epithelium	UBERON:0000397	91.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.25	gold quality
apex of heart	UBERON:0002098	91.21	gold quality
skin of leg	UBERON:0001511	90.99	gold quality
stromal cell of endometrium	CL:0002255	90.96	gold quality
sural nerve	UBERON:0015488	90.93	gold quality
transverse colon	UBERON:0001157	90.92	gold quality
bone marrow cell	CL:0002092	90.73	gold quality
skin of abdomen	UBERON:0001416	90.60	gold quality
lower esophagus	UBERON:0013473	90.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.34	gold quality
spleen	UBERON:0002106	90.30	gold quality
upper lobe of lung	UBERON:0008948	90.21	gold quality
ectocervix	UBERON:0012249	90.20	gold quality
lower esophagus mucosa	UBERON:0035834	90.19	gold quality
heart left ventricle	UBERON:0002084	90.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.07	gold quality
small intestine	UBERON:0002108	89.95	gold quality
right lung	UBERON:0002167	89.93	gold quality
body of stomach	UBERON:0001161	89.91	gold quality
cardiac ventricle	UBERON:0002082	89.81	gold quality
ascending aorta	UBERON:0001496	89.77	gold quality
thoracic aorta	UBERON:0001515	89.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.75	gold quality
right coronary artery	UBERON:0001625	89.54	gold quality
esophagus	UBERON:0001043	89.42	gold quality
metanephros cortex	UBERON:0010533	89.38	gold quality
aorta	UBERON:0000947	89.37	gold quality
endocervix	UBERON:0000458	89.33	gold quality
popliteal artery	UBERON:0002250	89.25	gold quality
caecum	UBERON:0001153	89.24	gold quality
tibial artery	UBERON:0007610	89.23	gold quality
buccal mucosa cell	CL:0002336	89.20	silver quality
body of uterus	UBERON:0009853	89.19	gold quality
lymph node	UBERON:0000029	88.93	gold quality
esophagus mucosa	UBERON:0002469	88.88	gold quality
descending thoracic aorta	UBERON:0002345	88.82	gold quality
right lobe of thyroid gland	UBERON:0001119	88.67	gold quality
left coronary artery	UBERON:0001626	88.60	gold quality
tibial nerve	UBERON:0001323	88.59	gold quality
liver	UBERON:0002107	88.46	gold quality
right atrium auricular region	UBERON:0006631	88.42	gold quality
zone of skin	UBERON:0000014	88.41	gold quality
stomach	UBERON:0000945	88.33	gold quality
colon	UBERON:0001155	88.28	gold quality
minor salivary gland	UBERON:0001830	88.23	gold quality
left uterine tube	UBERON:0001303	88.19	gold quality
heart	UBERON:0000948	88.14	gold quality
coronary artery	UBERON:0001621	88.00	gold quality
right ovary	UBERON:0002118	87.98	gold quality
body of pancreas	UBERON:0001150	87.97	gold quality
intestine	UBERON:0000160	87.94	gold quality
leukocyte	CL:0000738	87.85	gold quality
left ovary	UBERON:0002119	87.77	gold quality
cardiac atrium	UBERON:0002081	87.73	gold quality
mucosa of stomach	UBERON:0001199	87.71	gold quality
monocyte	CL:0000576	87.67	gold quality
large intestine	UBERON:0000059	87.63	gold quality
left lobe of thyroid gland	UBERON:0001120	87.63	gold quality
omental fat pad	UBERON:0010414	87.58	gold quality
peritoneum	UBERON:0002358	87.55	gold quality
blood	UBERON:0000178	87.54	gold quality
saliva-secreting gland	UBERON:0001044	87.28	gold quality
uterine cervix	UBERON:0000002	87.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.98	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.88	gold quality
thyroid gland	UBERON:0002046	86.82	gold quality
vagina	UBERON:0000996	86.74	gold quality
pancreas	UBERON:0001264	86.74	gold quality
mouth mucosa	UBERON:0003729	86.59	gold quality
left adrenal gland cortex	UBERON:0035825	86.45	gold quality
fundus of stomach	UBERON:0001160	86.38	gold quality
left adrenal gland	UBERON:0001234	86.35	gold quality
gall bladder	UBERON:0002110	86.29	gold quality
right adrenal gland	UBERON:0001233	86.19	gold quality
smooth muscle tissue	UBERON:0001135	86.07	gold quality
right adrenal gland cortex	UBERON:0035827	85.99	gold quality
adrenal cortex	UBERON:0001235	85.83	gold quality
rectum	UBERON:0001052	85.82	gold quality
nasal cavity epithelium	UBERON:0005384	85.78	silver quality
ventricular zone	UBERON:0003053	85.73	gold quality
islet of Langerhans	UBERON:0000006	85.64	gold quality
parotid gland	UBERON:0001831	85.64	silver quality
right hemisphere of cerebellum	UBERON:0014890	85.56	gold quality
cortex of kidney	UBERON:0001225	85.48	gold quality
cerebellar hemisphere	UBERON:0002245	85.36	gold quality
adrenal gland	UBERON:0002369	85.35	gold quality
cerebellar cortex	UBERON:0002129	85.29	gold quality
prostate gland	UBERON:0002367	85.20	gold quality
skeletal muscle tissue	UBERON:0001134	84.96	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-112	no	3.69
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	33.2
Skeletal muscle	tissue	32.4	low
Frontal cortex	tissue	30.3
Caudate putamen	tissue	27.0
Bone marrow	tissue	22.2	medium
Tongue	tissue	20.0
Vagina	tissue	18.8	low
Appendix	tissue	18.1	medium
Lymph node	tissue	17.4	not detected
Hippocampus	tissue	16.5	medium
Heart muscle	tissue	16.2	medium
Small intestine	tissue	15.6	low
Locus coeruleus	tissue	15.6
Putamen	tissue	15.3
Liver	tissue	15.1	not detected
Spleen	tissue	14.6	medium
Thymus	tissue	14.6
Duodenum	tissue	14.5	low
Postcentral gyrus	tissue	14.5
Basal ganglia	tissue	14.0	medium
Cerebral cortex	tissue	13.8	medium
Somatosensory cortex	tissue	13.8
Urinary bladder	tissue	13.6	medium
Lung	tissue	13.6	high
Nucleus accumbens	tissue	13.4
Cerebellum	tissue	13.4	low
Skin 1	tissue	13.2	medium
Superior colliculi	tissue	13.2
Tonsil	tissue	13.0	medium
Occipital cortex	tissue	12.9
Thalamus	tissue	12.7
Spinal cord	tissue	12.7
Smooth muscle	tissue	12.5	not detected
Ventral forebrain	tissue	12.5
Midbrain	tissue	12.4
Corpus callosum	tissue	12.4
Colon	tissue	12.3	medium
Medulla oblongata	tissue	12.3
Substantia nigra	tissue	12.2
Pituitary gland	tissue	12.0
Adipose tissue	tissue	11.8	low
Esophagus	tissue	11.8	medium
Pons	tissue	11.7
Prefrontal cortex	tissue	11.6
Motor cortex	tissue	11.6
Hippocampal formation	tissue	11.6
Retrosplenial and cingulate cortex	tissue	11.4
Temporal cortex	tissue	11.4
Stomach 1	tissue	11.3	medium
Insular cortex	tissue	11.2
Entorhinal cortex	tissue	11.0
Rectum	tissue	10.9	medium
Septum	tissue	10.9
Hypothalamus	tissue	10.8
Olfactory bulb	tissue	10.7
Retrosplenial cortex	tissue	10.7
Periaqueductal gray	tissue	10.5
Salivary gland	tissue	10.4	medium
Seminal vesicle	tissue	10.3	not detected
Placenta	tissue	10.2	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Anterior thalamic nucleus, ventral (23.4), Centromedial thalamic nucleus (21.6), Blood vessel (20.9), Nucleus gracilis (20.4), Ventral posterolateral thalamic nucleus (20.2).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 8.93e-07, LOEUF 0.647, missense Z 1.44 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000262960 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈1% 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
19:4,676,567–4,684,790	209 / 280.4	0.75	no
19:4,684,791–4,685,651	3 / 16.9	0.18	yes (p 7.2e-04)
19:4,685,652–4,719,906	810 / 920.6	0.88	no

Literature-anchored findings (GeneRIF, showing 40)

• identification of two forms, their tissue distribution, cytoplasmic localization (PMID:15245913)
• cells overexpressing DP9 exhibit behavioral changesin the presence of ECM components; these effects were independent of enzyme activity (PMID:16700509)
• Dipeptidyl peptidase 8 and dipeptidyl peptidase 9 influence cell-extracellular matrix interactions, and thus may regulate tissue remodeling. (PMID:16704418)
• The DPP9 gene is not associated with the occurrence or curve severity of AIS. It is neither a disease-predisposition nor a disease-modifying gene of AIS. (PMID:18940951)
• results indicate that the biochemical property of DPP9 is very similar to that of DPP8, its homologous protease. DPP9 and DPP8 are likely redundant proteins carrying out overlapping functions in vivo (PMID:19268648)
• DP8 and DP9 tissue and cellular expression (PMID:19581630)
• DPP9, a poorly characterized cytoplasmic prolyl-peptidase, is rate-limiting for destruction of proline-containing substrates both in cell extracts and in intact cells (PMID:19667070)
• DPP8 and DPP9 prevail over canonical DPP-IV/CD26 and FAPalpha in all examined meningioma patients (PMID:20043068)
• This is the first study to demonstrate the presence of DP9 in chronic lymphocytic leukemia. (PMID:20534982)
• These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways. (PMID:21622624)
• Data identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. (PMID:21711053)
• residues important for dimer formation and enzymatic activity (PMID:22001206)
• this study demonstrates for the first time that DP8 and DP9 are expressed in breast and ovarian carcinoma cell lines (PMID:22736146)
• DPP9 binds to SUMO1 through a novel SUMO1 interacting motif. (PMID:23152501)
• analysis of dipeptidyl peptidases 8 and 9 reveals that they may have compensatory roles (PMID:23519473)
• DPP9 was found in macrophages of carotid atherosclerotic plaque and may play a role in disease progression. (PMID:23608773)
• Suggest roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis. (PMID:23704821)
• The SUMO1-E67 interacting loop peptide is an allosteric inhibitor of the dipeptidyl peptidases 8 and 9. (PMID:24072711)
• Whereas DPP9-short is present in the cytosol, DPP9-long localizes preferentially to the nucleus. (PMID:24562348)
• The DPP9 expressing cell model system is a very useful and promising system for investigating the selectivity and associated toxicity of DPP4 inhibitors on DPP9. (PMID:25464020)
• There was a concomitant decrease in the phosphorylation of focal adhesion kinase and paxillin, indicating that DPP9 knockdown or enzyme inhibition suppressed the associated adhesion signaling pathway, causing impaired cell movement. (PMID:25486458)
• The data of this study have shown that fibroblasts and keratinocytes of normal skin endogenously express DPP9 both at transcriptional and protein level. It is localized intracellularly, mostly in cytoplasm, whereby the sub-localization within Golgi is very scarce. (PMID:27682012)
• DPP9 has a role in promoting tumorgenicity, metastasis and the prediction of poor prognosis in non-small cell lung cancer (PMID:27943262)
• we found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19-translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3’ end of DPP9 corresponding to the breakpoints identified by RNA-seq. (PMID:28893231)
• DPP9 is an interacting partner of human NLRP1 and a related, human-specific inflammasome regulator, CARD8, and binds the autoproteolytic FIIND domain of both proteins. (PMID:30291141)
• Dipeptidyl Peptidase 9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer. (PMID:32734369)
• Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import. (PMID:32815200)
• Decrease of the pro-inflammatory M1-like response by inhibition of dipeptidyl peptidases 8/9 in THP-1 macrophages - quantitative proteomics of the proteome and secretome. (PMID:32998073)
• Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. (PMID:33731929)
• DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. (PMID:33731932)
• DPP9 restrains NLRP1 activation. (PMID:33785922)
• Profibrotic mechanisms of DPP8 and DPP9 highly expressed in the proximal renal tubule epithelial cells. (PMID:33932609)
• Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment. (PMID:34019797)
• CCR2 and DPP9 expression in the peripheral blood of COVID-19 patients: Influences of the disease severity and gender. (PMID:35131543)
• Inflammasome sensor NLRP1 disease variant M1184V promotes autoproteolysis and DPP9 complex formation by stabilizing the FIIND domain. (PMID:36309085)
• Hemophagocytic lymphohistiocytosis-like hyperinflammation due to a de novo mutation in DPP9. (PMID:37544411)
• DPP9 Stabilizes NRF2 to Suppress Ferroptosis and Induce Sorafenib Resistance in Clear Cell Renal Cell Carcinoma. (PMID:37713596)
• DPP8/9 inhibition attenuates the TGF-beta1-induced excessive deposition of extracellular matrix (ECM) in human mesangial cells via Smad and Akt signaling pathways. (PMID:38458339)
• Dipeptidyl-peptidase 9 regulates the dynamics of tumorigenesis and metastasis in breast cancer. (PMID:38531482)
• DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells. (PMID:39094401)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpp9	ENSDARG00000052606
mus_musculus	Dpp9	ENSMUSG00000001229
rattus_norvegicus	Dpp9	ENSRNOG00000050748
drosophila_melanogaster	CG3744	FBGN0039240
caenorhabditis_elegans	dpf-3	WBGENE00001056

Paralogs (6): DPP8 (ENSG00000074603), FAP (ENSG00000078098), DPP6 (ENSG00000130226), APEH (ENSG00000164062), DPP10 (ENSG00000175497), DPP4 (ENSG00000197635)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2443967) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 35 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating phosphate level	1
abnormal heart morphology	1
abnormal cranium morphology	1
abnormal maxilla morphology	1
abnormal mandible morphology	1
abnormal spleen morphology	1
tremors	1
decreased body weight	1
abnormal lens morphology	1
increased anxiety-related response	1
decreased locomotor activity	1
decreased exploration in new environment	1
abnormal suckling behavior	1
small heart	1
increased mean platelet volume	1
decreased circulating triglyceride level	1
short tibia	1
increased thigmotaxis	1
increased circulating alkaline phosphatase level	1
increased erythrocyte cell number	1
abnormal bone structure	1
decreased lean body mass	1
abnormal tongue muscle morphology	1
abnormal spine curvature	1
abnormal behavior	1

+10 more (showing top 25).

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
Aspergillus flavus NRRL3357	B8N076	100.0%	Diamond
Coccidioides posadasii C735 delta SOWgp	C5P334	100.0%	Diamond
Coccidioides posadasii str. Silveira	E9CUF4	100.0%	Diamond
Aspergillus oryzae RIB40	Q2UPW4	100.0%	Diamond
Aspergillus fumigatus A1163	B0XYK8	99.7%	Diamond
Aspergillus fumigatus Af293	Q4WX13	99.7%	Diamond
Aspergillus niger CBS 513.88	A2QEK7	99.3%	Diamond
Aspergillus niger	Q96VT7	99.3%	Diamond
Trichophyton benhamiae CBS 112371	D4APE2	98.6%	Diamond
Trichophyton verrucosum HKI 0517	D4DCG0	98.4%	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
Botrytis cinerea B05.10	A6SL49	93.5%	Diamond
Sclerotinia sclerotiorum 1980 UF-70	A7EQZ1	93.5%	Diamond
Nannizzia gypsea CBS 118893	E4UYL6	87.5%	Diamond
Vespula vulgaris	B1A4F7	86.2%	Diamond
Microsporum canis CBS 113480	C5FYZ3	84.1%	Diamond
Talaromyces stipitatus ATCC 10500	B8MTH6	83.8%	Diamond
Aspergillus clavatus NRRL 1	A1CHP1	83.2%	Diamond
Aspergillus terreus NIH2624	Q0CXB1	74.4%	Diamond
Podospora anserina S mat+	B2A951	72.1%	Diamond
Chaetomium globosum CBS 148.51	Q2HF90	72.1%	Diamond
Penicillium rubens Wisconsin 54-1255	B6HFS8	68.7%	Diamond
Colletotrichum graminicola M1.001	E3QKD2	66.1%	Diamond
Pyricularia oryzae 70-15	A4QYQ5	64.3%	Diamond
Oryza sativa Japonica Group	Q0IXP9	63.7%	Diamond
Grosmannia clavigera kw1407	F0XS04	59.9%	Diamond
Saccharomyces cerevisiae S288C	P33894	36.8%	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
TRV-CAC3-1	tRNA	100189416
TIPE1	protein-coding	126282
MYDGF	protein-coding	56005
TRG-TCC1-1	tRNA	7197
DPP9-AS1	ncRNA	100131094
MIR7-3HG	ncRNA	284424
MIR7-3	ncRNA	407045

Protein

Protein identifiers

Dipeptidyl peptidase 9 — Q86TI2 (reviewed: Q86TI2)

Alternative names: Dipeptidyl peptidase IV-related protein 2, Dipeptidyl peptidase IX, Dipeptidyl peptidase-like protein 9

All UniProt accessions (7): A0A2R8YF65, A0A8V8TR99, Q86TI2, M0QZ97, M0R145, M0R2A8, M0R2G6

UniProt curated annotations — full annotation on UniProt →

Function. Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8. Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation. The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition.

Subunit / interactions. Homodimer. Forms a ternary complex with NLRP1, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of NLRP1 (NACHT, LRR and PYD domains-containing protein 1, C-terminus). Forms a ternary complex with CARD8, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus). In the ternary complex, only one subunit of the DPP9 homodimer is bound to NLRP1 or CARD8.

Subcellular location. Cytoplasm. Cytosol Nucleus.

Tissue specificity. Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain.

Disease relevance. Hatipoglu immunodeficiency syndrome (HATIS) [MIM:620331] An autosomal recessive immunologic disorder manifesting in infancy or early childhood, and characterized by failure to thrive, short stature, skin pigmentation abnormalities, pancytopenia, and susceptibility to recurrent infections. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by the serine proteinase inhibitor 4-(2-aminoethyl)benzenesulphonyl fluoride (AEBSF), and by di-isopropylfluorophosphate. Inhibited by Val-boroPro (Talabostat, PT-100), a non-selective inhibitor, which triggers pyroptosis in monocytes and macrophages. Val-boroPro inhibits activity by binding to the active site, mimicking a substrate-bound state, thereby displacing the C-terminal fragment of NLRP1, leading to activation of the NLRP1 inflammasome. In contrast, Val-boroPro does not directly displaces CARD8: it acts by promoting degradation of the N-terminal part of CARD8, leading to indirect disruption of the ternary complex. Chemical inhibition of DPP9 by Val-boroPro in HIV-1-infected cells activates the CARD8 inflammasome, triggering cell death, offering a promising strategy for the elimination of HIV-1 reservoirs in people living with HIV-1.

Miscellaneous. Active peptidase. Contains a nuclear localization signal at positions 2-9.

Similarity. Belongs to the peptidase S9B family. DPPIV subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86TI2-1	1, DPP9-S, Short	yes
Q86TI2-2	2, DPP9-L, Long
Q86TI2-4	3

RefSeq proteins (30): NP_001352916, NP_001371540, NP_001371541, NP_001371542, NP_001371543, NP_001371544, NP_001371545, NP_001371546, NP_001371547, NP_001371548, NP_001371549, NP_001371550, NP_001371551, NP_001371552, NP_001371553, NP_001371554, NP_001371555, NP_001371556, NP_001371557, NP_001371558, NP_001371559, NP_001371560, NP_001371561, NP_001371562, NP_001371563, NP_001371564, NP_001371565, NP_001371566, NP_001371567, NP_631898* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002469	Peptidase_S9B_N	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR045785	Dpp_8/9_N	Domain
IPR050278	Serine_Prot_S9B/DPPIV	Family

Pfam: PF00326, PF00930, PF19520

Enzyme classification (BRENDA)

• EC 3.4.13.19 — membrane dipeptidase (BRENDA: 12 organisms, 121 substrates, 55 inhibitors, 49 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GLY-D-PHE	0.77–12.5	4
L-ARG-L-ASP	1.8–8.8	4
L-CYSTINYL-BIS-GLY	0.45–2.5	3
L-LEU-L-LEU	0.056–1.4	3
GLYCYLDEHYDROPHENYLALANINE	0.102–1	2
LEUKOTRIENE D4	0.005–0.01	2
BETA-LACTAM	0.111	1
GLY-L-LEU	1.22	1
GLY-L-PHE	0.99	1
GLY-L-TRP	2.03	1
GLY-L-VAL	11	1
GLY-LEU	0.79	1
L-ALA-D-ALA	4.4	1
L-ALA-GLY	0.8	1
L-ALA-L-ASP	13.8	1

UniProt features (124 total): strand 58, helix 31, turn 10, mutagenesis site 6, sequence conflict 5, sequence variant 4, active site 3, splice variant 2, initiator methionine 1, chain 1, region of interest 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDB	Title	Method	Resolution (Å)
7ZXS	Crystal structure of DPP9 in complex with a 4-oxo-b-lactam based inhibitor, A295	X-RAY DIFFRACTION	1.81
9GOC	Crystal structure of DPP9 Ser730Ala in complex with sulphostin.	X-RAY DIFFRACTION	1.89
9GON	Crystal structure of DPP9 in complex with sulphostin	X-RAY DIFFRACTION	1.89
7SVL	DPP9 IN COMPLEX WITH LIGAND ICeD-2	X-RAY DIFFRACTION	2.46
9GOD	Crystal structure of DPP9 in complex with N-phosphono-(S)-3-aminopiperidine-2-one-based …	X-RAY DIFFRACTION	2.49
7SVN	DPP9 IN COMPLEX WITH LIGAND ICeD-1	X-RAY DIFFRACTION	2.78
6EOR	DPP9 - 1G244	X-RAY DIFFRACTION	2.9
6X6C	Cryo-EM structure of NLRP1-DPP9-VbP complex	ELECTRON MICROSCOPY	2.9
7A3F	Crystal structure of apo DPP9	X-RAY DIFFRACTION	2.9
6EOQ	DPP9 - Apo	X-RAY DIFFRACTION	3
6QZV	DPP9 bound to a dipeptide (MP) from the N-terminus of BRCA2	X-RAY DIFFRACTION	3
7JKQ	Human DPP9-CARD8 complex	ELECTRON MICROSCOPY	3.3
7JN7	Human DPP9-CARD8 complex	ELECTRON MICROSCOPY	3.3
6X6A	Cryo-EM structure of NLRP1-DPP9 complex	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TI2-F1	92.96	0.83

Human Protein Atlas

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

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · 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
730	charge relay system
808	charge relay system
840	charge relay system

Ligand- & substrate-binding residues (1)

Position	Role
730	Val-boroPro

Post-translational modifications (1)

Type	Positions
N-acetylalanine	2

Mutagenesis-validated functional residues (6)

Position	Phenotype
96–97	reduced interaction with card8 without affecting the peptidase activity.
100–101	reduced interaction with nlrp1 and card8 without affecting the peptidase activity.
102–103	reduced interaction with card8 without affecting the peptidase activity.
102	reduced interaction with nlrp1 without affecting the peptidase activity.
597	reduced interaction with nlrp1 without affecting the peptidase activity.
730	abolished dipeptidyl peptidase activity and ability to sequester nlrp1 and inhibit pyroptosis.

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: 282 (showing top): GOBP_INFLAMMATORY_RESPONSE, CAGCTG_AP4_Q5, ATTCTTT_MIR186, GOBP_PROTEOLYSIS, chr19p13, GOCC_CELL_LEADING_EDGE, GOMF_PEPTIDASE_ACTIVITY, GOMF_AMINOPEPTIDASE_ACTIVITY, GOMF_DIPEPTIDYL_PEPTIDASE_ACTIVITY, GOMF_EXOPEPTIDASE_ACTIVITY, GOBP_PYROPTOTIC_INFLAMMATORY_RESPONSE, DELACROIX_RARG_BOUND_MEF, GOCC_SUPRAMOLECULAR_COMPLEX, GOCC_POLYMERIC_CYTOSKELETAL_FIBER, GOCC_SUPRAMOLECULAR_POLYMER

GO Biological Process (3): proteolysis (GO:0006508), negative regulation of programmed cell death (GO:0043069), pyroptotic inflammatory response (GO:0070269)

GO Molecular Function (7): aminopeptidase activity (GO:0004177), serine-type peptidase activity (GO:0008236), dipeptidyl-peptidase activity (GO:0008239), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), microtubule (GO:0005874), cell leading edge (GO:0031252)

GO top-level categories

18 GO namespaces:

Category	Terms
exopeptidase activity	2
cellular anatomical structure	2
protein metabolic process	1
programmed cell death	1
regulation of programmed cell death	1
negative regulation of cellular process	1
inflammatory response	1
peptidase activity	1
serine hydrolase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of programmed cell death	BP	direct assay
pyroptotic inflammatory response	BP	direct assay
cell leading edge	CC	direct assay
cytosol	CC	direct assay
microtubule	CC	direct assay
dipeptidyl-peptidase activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 874 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPP9	PREP	P48147	937
DPP9	DPP7	Q9UHL4	790
DPP9	LZTFL1	Q9NQ48	676
DPP9	TFDP3	Q5H9I0	653
DPP9	CARD8	Q9Y2G2	651
DPP9	ATP11A	P98196	610
DPP9	SLC6A20	Q9NP91	606
DPP9	IFNAR2	P48551	595
DPP9	TAC4	Q86UU9	573
DPP9	FAM13A	O94988	570
DPP9	NLRP1	Q9C000	570
DPP9	OAS1	P00973	569
DPP9	DPP3	Q9NY33	555
DPP9	TYK2	P29597	547
DPP9	MUC5B	Q9HC84	547

IntAct

Human interaction partners of DPP9 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
ANKRD10	physical association	0.500	1
ENSA	association	0.350	1
HSPA8	association	0.350	1
SHMT2	association	0.350	1

BioGRID (595 interactions; top human partners by supporting records): DPP8 (Affinity Capture-MS; 6 records), DMTN (Affinity Capture-MS; 4 records), FLNA (Reconstituted Complex; 4 records), ABHD12 (Affinity Capture-MS; 3 records), FAM175B (Affinity Capture-MS; 3 records), LPPR2 (Affinity Capture-MS; 3 records), SNAI1 (Affinity Capture-MS; 3 records), SYK (Co-localization; 3 records), TMCO6 (Affinity Capture-MS; 3 records), ANKRD10 (Affinity Capture-MS; 2 records), BRCC3 (Proximity Label-MS; 2 records), BRE (Affinity Capture-MS; 2 records), CARD8 (Affinity Capture-Western; 2 records), CBL (Co-localization; 2 records), CCDC102A (Affinity Capture-MS; 2 records)

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
DPP9-NLRP1 complex	2	DPP9, NLRP1

Disease & clinical

Genetic variants

Variant evidence for DPP9: 203 ClinVar records (4 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	141
Likely benign	21
Benign	4

Top pathogenic / likely-pathogenic (4)

Showing all 4 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
3256926	NM_139159.5(DPP9):c.2178G>A (p.Met726Ile)	Likely pathogenic	criteria provided, single submitter	1
4277662	NM_139159.5(DPP9):c.2482C>T (p.Arg828Cys)	Likely pathogenic	criteria provided, single submitter	1
2500000	NM_139159.5(DPP9):c.2551C>T (p.Gln851Ter)	Pathogenic	no assertion criteria provided	1
2500001	NM_139159.5(DPP9):c.331C>T (p.Arg111Ter)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore DPP9’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.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 2,623):

Position(s)	Effect	Δscore	Sites
19:4679947–4679948	acceptor_loss	1.0000	5
19:4682694–4682695	donor_loss	1.0000	4
19:4682699	donor_gain	1.0000
19:4682839	acceptor_gain	1.0000
19:4682839–4682840	acceptor_loss	1.0000	4
19:4682850	acceptor_gain	1.0000
19:4683475–4683476	donor_loss	1.0000	4
19:4683630–4683631	acceptor_loss	1.0000	6
19:4684661–4684662	donor_loss	1.0000	4
19:4685625	donor_loss	1.0000	2

AlphaMissense

2,508 missense substitutions predicted likely pathogenic (of 5,894 scored), across 596 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
D808	8	1.000	1.000
N810	8	1.000	1.000
H840	8	1.000	1.000
D678	8	0.996	0.999
H804	8	0.996	0.999
D763	8	0.994	0.999
D704	8	0.993	0.999
H815	8	0.990	0.999
H812	8	0.989	0.999
N312	8	0.985	0.998
H850	8	0.984	0.998
F747	8	0.975	0.999
F250	8	0.974	0.997
F813	8	0.956	0.997
F244	8	0.955	1.000
D164	8	0.954	0.982
F689	8	0.954	0.998
F153	8	0.952	0.995
F386	8	0.952	0.991
H453	8	0.950	0.988

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	1.56e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000837

Disease associations

OMIM: gene MIM:608258 | disease phenotypes: MIM:620331

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
hatipoglu immunodeficiency syndrome	Strong	Autosomal recessive	2
autoinflammatory syndrome	Strong	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): hatipoglu immunodeficiency syndrome (MONDO:0957229), autoinflammatory syndrome (MONDO:0019751)

HPO phenotypes

57 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000337	Broad forehead
HP:0000403	Recurrent otitis media
HP:0000494	Downslanted palpebral fissures
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000967	Petechiae
HP:0000970	Anhidrosis
HP:0001047	Atopic dermatitis
HP:0001058	Poor wound healing
HP:0001063	Acrocyanosis
HP:0001072	Thickened skin
HP:0001328	Specific learning disability
HP:0001350	Slurred speech
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0001954	Recurrent fever
HP:0002020	Gastroesophageal reflux
HP:0002099	Asthma
HP:0002110	Bronchiectasis
HP:0002206	Pulmonary fibrosis
HP:0002216	Premature graying of hair
HP:0002286	Fair hair
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002837	Recurrent bronchitis
HP:0002875	Exertional dyspnea
HP:0002937	Hemivertebrae
HP:0003508	Proportionate short stature
HP:0003546	Exercise intolerance
HP:0003593	Infantile onset
HP:0005353	Recurrent herpes
HP:0006530	Abnormal pulmonary interstitial morphology
HP:0007441	Hyperpigmented/hypopigmented macules
HP:0010444	Pulmonic regurgitation
HP:0011968	Feeding difficulties
HP:0012378	Fatigue
HP:0012393	Allergy
HP:0012735	Cough
HP:0025175	Honeycomb lung
HP:0025179	Ground-glass opacification
HP:0025390	Reticular pattern on pulmonary HRCT
HP:0030830	Crackles
HP:0031631	Subpleural honeycombing
HP:0031950	Usual interstitial pneumonia
HP:0032341	Reduced forced vital capacity
HP:0033367	Orthodeoxia
HP:0045051	Decreased DLCO
HP:0100759	Clubbing of fingers

GWAS associations

3 associations:

Study	Trait	p-value
GCST001968_9	Interstitial lung disease	2e-12
GCST009758_15	Idiopathic pulmonary fibrosis	3e-12
GCST90000255_18	Severe COVID-19 infection with respiratory failure (analysis I)	5e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0000768	idiopathic pulmonary fibrosis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885564 (PROTEIN FAMILY), CHEMBL4793 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 86,152 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

8 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL515387	GOSOGLIPTIN	4	823
CHEMBL237500	LINAGLIPTIN	4	5,545
CHEMBL385517	SAXAGLIPTIN ANHYDROUS	4	18,818
CHEMBL1422	SITAGLIPTIN	4	26,952
CHEMBL2147777	TENELIGLIPTIN	4	1,471
CHEMBL142703	VILDAGLIPTIN	4	20,579
CHEMBL4296719	DUTOGLIPTIN	3	1,437
CHEMBL67279	TALABOSTAT	3	10,527

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 (9 total), top 9:

Ligand	Action	Affinity	Parameter
talabostat	Inhibition	9.12	pKi
ICeD-2	Inhibition	9.05	pIC50
compound 42 [PMID: 37721854]	Inhibition	8.47	pIC50
1G244	Inhibition	7.28	pIC50
compound 24dd [PMID: 20684603]	Inhibition	6.72	pKi
vildagliptin	Inhibition	6.64	pIC50
tominostat	Inhibition	6.59	pIC50
teneligliptin	Inhibition	6.27	pIC50
compound 9 [PMID: 20718420]	Inhibition	5.57	pIC50

Binding affinities (BindingDB)

1174 measured of 1580 human assays (1608 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
UAMC-000-5364	IC50	0.001 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5377	IC50	0.005 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5376	IC50	0.005 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5366	IC50	0.006 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5380	IC50	0.008 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5379	IC50	0.009 nM	US-20250353833: DPP9 BINDING COMPOUNDS
CHEMBL5279548	IC50	0.027 nM
UAMC-000-5111	IC50	0.051 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5215	IC50	0.094 nM	US-20250353833: DPP9 BINDING COMPOUNDS
2-[[8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-2,6-dioxopurin-1-yl]methyl]-5-chlorobenzoic acid	IC50	0.1 nM	US-20240115577: SMALL MOLECULE REGULATORS OF ALVEOLAR TYPE 2 CELL PROLIFERATION FOR THE TREATMENT OF PULMONARY DISEASES
UAMC-000-5114	IC50	0.102 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5365	IC50	0.117 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5113	IC50	0.127 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5382	IC50	0.127 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5112	IC50	0.145 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5360	IC50	0.161 nM	US-20250353833: DPP9 BINDING COMPOUNDS
CHEMBL4465482	IC50	0.18 nM
[(2R)-1-[(2S)-2-aminopropanethioyl]pyrrolidin-2-yl]boronic acid	IC50	0.2 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
Boronic acid derivative	IC50	0.2 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
N-((3S)-1-(6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carbonyl)pyrrolidin-3-yl)methanesulfonamide	KI	0.2 nM
N4-(4-chlorobenzyl)-2,4-diaminobutanoylpiperidine	IC50	0.22 nM
CHEMBL4461587	IC50	0.22 nM
UAMC-000-5116	IC50	0.222 nM	US-20250353833: DPP9 BINDING COMPOUNDS
2-(S)-Amino-4-(2-chloro-benzylamino)-1-piperidin-1-yl-butan-1-one	IC50	0.23 nM
UAMC-000-5361	IC50	0.244 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5363	IC50	0.27 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5035	IC50	0.276 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5359	IC50	0.295 nM	US-20250353833: DPP9 BINDING COMPOUNDS
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	KI	0.3 nM
CHEMBL2063040	IC50	0.3 nM
(R)-2-((2-(3-Aminopiperidin-1-yl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)benzonitrile	IC50	0.33 nM
CHEMBL2058971	IC50	0.37 nM
UAMC-000-5357	IC50	0.403 nM	US-20250353833: DPP9 BINDING COMPOUNDS
CHEMBL4588692	IC50	0.44 nM
UAMC-000-5378	IC50	0.476 nM	US-20250353833: DPP9 BINDING COMPOUNDS
(S)-2,4-Diamino-N-((R)-1-boron-dihydroxide-pentyl)-butyramide	IC50	0.48 nM
(R)-1-((S)-2,4-diaminobutanamido)pentylboronic acid	IC50	0.48 nM
(6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone	KI	0.5 nM
(6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)(4,4-dimethyloxazolidin-3-yl)methanone	KI	0.6 nM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-(pyridin-2-yl)ethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	KI	0.7 nM
(+)-Ethyl 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate	IC50	0.7 nM
(S)-2,4-Diamino-1-(2-boron-dihydroxide-pyrrolidin-1-yl)-butan-1-one	IC50	0.72 nM
CHEMBL4536341	IC50	0.72 nM
UAMC-000-5356	IC50	0.757 nM	US-20250353833: DPP9 BINDING COMPOUNDS
UAMC-000-5381	IC50	0.793 nM	US-20250353833: DPP9 BINDING COMPOUNDS
[(2R)-1-[(2S)-2-amino-3-methylbutanethioyl]pyrrolidin-2-yl]boronic acid	IC50	0.8 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
Boronic acid derivative	IC50	0.8 nM	US-11559537: Combination therapies using caspase-1 dependent anticancer agents and PGE2 antagonists
CHEMBL2441846	KI	0.8 nM
CHEMBL4856337	IC50	0.8 nM
UAMC-000-5032	IC50	0.812 nM	US-20250353833: DPP9 BINDING COMPOUNDS

ChEMBL bioactivities

593 potent at pChembl≥5 of 894 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.92	IC50	0.12	nM	VILDAGLIPTIN
9.72	Ki	0.19	nM	CHEMBL1215376
9.55	Ki	0.28	nM	CHEMBL1215374
9.52	Ki	0.3	nM	CHEMBL2441845
9.52	Ki	0.3	nM	CHEMBL1215375
9.51	IC50	0.31	nM	CHEMBL2063040
9.39	Ki	0.41	nM	CHEMBL67089
9.30	Ki	0.5	nM	CHEMBL2441839
9.28	Ki	0.53	nM	CHEMBL63860
9.26	Ki	0.55	nM	CHEMBL1215236
9.22	Ki	0.6	nM	CHEMBL1215167
9.12	Ki	0.76	nM	TALABOSTAT
9.10	Ki	0.8	nM	CHEMBL2441955
9.08	Ki	0.83	nM	CHEMBL1215087
9.07	Ki	0.86	nM	CHEMBL1215299
9.05	Ki	0.9	nM	CHEMBL2441954
9.05	Ki	0.9	nM	CHEMBL2441844
9.05	Ki	0.9	nM	CHEMBL1215089
9.05	Ki	0.9	nM	CHEMBL1215233
9.03	Ki	0.94	nM	CHEMBL1215164
9.00	IC50	1	nM	CHEMBL5425473
9.00	Ki	1	nM	CHEMBL1214942
8.92	Ki	1.2	nM	CHEMBL2441831
8.89	Ki	1.3	nM	CHEMBL2441846
8.89	Ki	1.3	nM	CHEMBL2441829
8.89	Ki	1.3	nM	CHEMBL1215017
8.85	Ki	1.4	nM	CHEMBL1214877
8.82	Ki	1.5	nM	CHEMBL1214944
8.74	Ki	1.8	nM	CHEMBL2441953
8.72	Ki	1.9	nM	CHEMBL2441836
8.72	Ki	1.9	nM	CHEMBL1215016
8.72	Ki	1.9	nM	CHEMBL1215302
8.70	IC50	2	nM	CHEMBL195189
8.70	IC50	2	nM	TALABOSTAT
8.70	Ki	2	nM	CHEMBL1215088
8.68	IC50	2.1	nM	CHEMBL2063033
8.68	Ki	2.1	nM	CHEMBL1215448
8.66	IC50	2.2	nM	TALABOSTAT
8.66	Ki	2.2	nM	CHEMBL1214943
8.66	Ki	2.2	nM	CHEMBL1215018
8.64	Ki	2.3	nM	CHEMBL2441837
8.64	Ki	2.3	nM	CHEMBL2441830
8.60	Ki	2.5	nM	CHEMBL1215163
8.60	Ki	2.5	nM	CHEMBL1215166
8.59	Ki	2.6	nM	CHEMBL494497
8.55	IC50	2.8	nM	CHEMBL63860
8.55	Ki	2.8	nM	CHEMBL2441847
8.54	Ki	2.9	nM	CHEMBL2441841
8.52	Ki	3	nM	CHEMBL94278
8.52	IC50	3	nM	CHEMBL5402430

PubChem BioAssay actives

560 with measured affinity, of 1996 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-[2-[(3-hydroxy-1-adamantyl)amino]acetyl]pyrrolidine-2-carbonitrile	1781440: Inhibition of human recombinant DPP9 using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition and measured for 20 mins by fluorescence based microplate reader assay	ic50	0.0001	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(2-pyridin-2-ylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0002	uM
3-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]propanoic acid	778686: Inhibition of DPP9 (unknown origin)	ki	0.0003	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(2-pyridin-3-ylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0003	uM
1-[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-2-[(6-methyl-2-pyridinyl)methylamino]ethanone	499234: Inhibition of human DPP9	ki	0.0003	uM
[(2R,4S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]-4-hydroxypyrrolidin-2-yl]boronic acid	675170: Inhibition of human DPP9 expressed in HEK293 cells using Ala-Pro-p-nitroanilide hydrochloride salt as substrate preincubated for 10 mins prior to addition of substrate measured after 30 mins	ic50	0.0003	uM
[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]boronic acid	390966: Inhibition of human recombinant DPP9 expressed in HEK293T cells	ki	0.0004	uM
[(2R)-1-[(2S)-2-aminopropanoyl]pyrrolidin-2-yl]boronic acid	390966: Inhibition of human recombinant DPP9 expressed in HEK293T cells	ki	0.0005	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-6-[[(2S)-oxolan-2-yl]methyl]-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0005	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(pyridin-3-ylmethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0006	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-pyridin-2-ylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0006	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-6-(2-oxo-2-piperidin-1-ylethyl)-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0008	uM
[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-(4-methylsulfonylpiperazin-1-yl)methanone	499234: Inhibition of human DPP9	ki	0.0008	uM
[(2R)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid	390966: Inhibition of human recombinant DPP9 expressed in HEK293T cells	ki	0.0008	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-6-(2-oxo-2-pyrrolidin-1-ylethyl)-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0009	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(2,5-dimethylpyrazol-3-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0009	uM
[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-(4,4-dimethyl-1,3-oxazolidin-3-yl)methanone	499234: Inhibition of human DPP9	ki	0.0009	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(2-ethylpyrazol-3-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0009	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0009	uM
2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]acetic acid	778686: Inhibition of DPP9 (unknown origin)	ki	0.0009	uM
[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-pyrrolidin-1-ylmethanone	499234: Inhibition of human DPP9	ki	0.0010	uM
(2S)-2-amino-1-(1,3-dihydroisoindol-2-yl)-2-(4-hydroxycyclohexyl)ethanone	2015042: Inhibition of DPP9 (unknown origin)	ic50	0.0010	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-6-(1-methylpyrazol-3-yl)-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0012	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-2-methyl-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0013	uM
2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]-N,N-diethylacetamide	778686: Inhibition of DPP9 (unknown origin)	ki	0.0013	uM
[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methanone	499234: Inhibition of human DPP9	ki	0.0013	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,N-diethyl-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0014	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(oxan-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0015	uM
2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]-N-methyl-N-propylacetamide	778686: Inhibition of DPP9 (unknown origin)	ki	0.0018	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyethyl)-2-methyl-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0019	uM
4-[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carbonyl]piperazin-2-one	499234: Inhibition of human DPP9	ki	0.0019	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(4-pyridin-3-yl-1,3-thiazol-2-yl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0019	uM
[(2S)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid	255020: Inhibitory concentration against human dipeptidylpeptidase 9 using FP-TAMRA incubated for 30 min	ic50	0.0020	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-N,7-dimethyl-N-(2-methylsulfonylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0020	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(2-pyridin-4-ylethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0021	uM
[(2R,4S)-4-hydroxy-1-[(2S)-pyrrolidine-2-carbonyl]pyrrolidin-2-yl]boronic acid	675170: Inhibition of human DPP9 expressed in HEK293 cells using Ala-Pro-p-nitroanilide hydrochloride salt as substrate preincubated for 10 mins prior to addition of substrate measured after 30 mins	ic50	0.0021	uM
[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl]-morpholin-4-ylmethanone	499234: Inhibition of human DPP9	ki	0.0022	uM
N-[(3S)-1-[6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carbonyl]pyrrolidin-3-yl]methanesulfonamide	499234: Inhibition of human DPP9	ki	0.0022	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-(2-methoxyphenyl)-2-methyl-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0023	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-6-[(2S)-1-methoxypropan-2-yl]-2-methyl-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0023	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(1,3-oxazol-2-ylmethyl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0025	uM
6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methyl-N-(1,2-oxazol-3-yl)imidazo[1,2-a]pyrimidine-2-carboxamide	499234: Inhibition of human DPP9	ki	0.0025	uM
(4S)-4-amino-5-[(2R)-2-boronopyrrolidin-1-yl]-5-oxopentanoic acid	390966: Inhibition of human recombinant DPP9 expressed in HEK293T cells	ki	0.0026	uM
3-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]-N,N-diethylpropanamide	778686: Inhibition of DPP9 (unknown origin)	ki	0.0028	uM
3-(aminomethyl)-6-[[(2S)-1-cyclopropylsulfonylpyrrolidin-2-yl]methyl]-4-(2,4-dichlorophenyl)-2-methyl-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0029	uM
tert-butyl N-[3-[[2-(5,6-difluoro-1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl]carbamate	2015034: Inhibition of N-terminal human recombinant DPP9 expressed in Sf9 insect cells using Ala-Pro-paranitroanilide as substrate incubated for 15 mins by fluorescence based analysis	ic50	0.0030	uM
(2S)-1-[(2S)-2-amino-2-cyclopentylacetyl]pyrrolidine-2-carbonitrile	1796928: DPPIV Inhibition Assay from Article 10.1021/jm060777o: “Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]-4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.”	ki	0.0030	uM
3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-6-[[(2R)-oxolan-2-yl]methyl]-7H-pyrrolo[3,4-b]pyridin-5-one	778686: Inhibition of DPP9 (unknown origin)	ki	0.0031	uM
2-[3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]-N,N-dimethylacetamide	778686: Inhibition of DPP9 (unknown origin)	ki	0.0032	uM
ethyl 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate	499234: Inhibition of human DPP9	ki	0.0033	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation, increases mutagenesis	3
Estradiol	affects expression, affects cotreatment, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
bisphenol S	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
chloroacetaldehyde	increases expression	1
daidzein	affects cotreatment, decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
decabromobiphenyl ether	decreases expression	1
daidzin	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
genistin	affects cotreatment, decreases expression	1
glycylproline 4-nitroanilide	affects cotreatment, decreases activity, decreases cleavage	1
alanylproline-4-nitroanilide	decreases activity, decreases cleavage, affects cotreatment	1
glycitein	affects cotreatment, decreases expression	1
glycitin	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
UAMC00132	affects cotreatment, decreases activity, decreases cleavage	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1

ChEMBL screening assays

160 unique, capped per target: 154 binding, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3873291	Binding	Inhibition of full length recombinant human DPP-8/9 expressed in HEK293 cells at 10 uM incubated for 1 hr	Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents. — *Eur J Med Chem*
CHEMBL4683607	ADMET	Inhibition of recombinant human DPP8/9 expressed in Rosetta cells at 10 uM using Gly-Pro-p-nitroanilide as substrate incubated for 1 hr relative to control	The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119. — *Eur J Med Chem*

Clinical trials (associated diseases)

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

4 trials:

NCT	Phase	Status	Title
NCT00442182	Phase 2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DPP9 across ~30M SureChEMBL compounds — explore on Sugi Predict.