DAPK1

Summary

DAPK1 (death associated protein kinase 1, HGNC:2674) is a protein-coding gene on chromosome 9q21.33, encoding Death-associated protein kinase 1 (P53355). Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy.

Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1612 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autism spectrum disorder (Limited, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 267 total
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2674
Approved symbol	DAPK1
Name	death associated protein kinase 1
Location	9q21.33
Locus type	gene with protein product
Status	Approved
Aliases	DAPK
Ensembl gene	ENSG00000196730
Ensembl biotype	protein_coding
OMIM	600831
Entrez	1612

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 22 protein_coding, 8 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000358077, ENST00000408954, ENST00000463069, ENST00000466188, ENST00000468482, ENST00000469067, ENST00000469640, ENST00000470267, ENST00000472284, ENST00000472344, ENST00000475804, ENST00000489291, ENST00000491893, ENST00000494010, ENST00000495182, ENST00000495281, ENST00000496522, ENST00000497743, ENST00000622514, ENST00000892177, ENST00000892178, ENST00000916389, ENST00000916390, ENST00000916391, ENST00000916392, ENST00000916393, ENST00000916394, ENST00000916395, ENST00000916396, ENST00000916397, ENST00000916398, ENST00000916399, ENST00000916400, ENST00000960309, ENST00000960310

RefSeq mRNA: 4 — MANE Select: NM_004938 NM_001288729, NM_001288730, NM_001288731, NM_004938

CCDS: CCDS43842

Canonical transcript exons

ENST00000408954 — 26 exons

Exon	Start	End
ENSE00001426275	87497867	87498107
ENSE00001536886	87706132	87708634
ENSE00003477002	87604954	87605175
ENSE00003485243	87681404	87681626
ENSE00003490924	87640802	87640847
ENSE00003495374	87697007	87697204
ENSE00003501071	87686551	87686739
ENSE00003503688	87668597	87668674
ENSE00003518230	87641969	87642058
ENSE00003529255	87648781	87648879
ENSE00003536985	87645895	87646014
ENSE00003538502	87639650	87639698
ENSE00003542522	87639789	87639815
ENSE00003557582	87649921	87650118
ENSE00003561408	87658029	87658127
ENSE00003595556	87643376	87643468
ENSE00003600575	87640298	87640450
ENSE00003610423	87639354	87639483
ENSE00003612446	87698656	87698794
ENSE00003614516	87651527	87651724
ENSE00003616132	87703029	87703217
ENSE00003643432	87700117	87700237
ENSE00003655088	87637943	87638081
ENSE00003660694	87646461	87646559
ENSE00003670343	87647305	87647403
ENSE00003689619	87498970	87499139

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 96.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.8500 / max 806.6993, expressed in 1465 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
97204	12.5228	1228
97202	10.1752	1374
97201	1.4170	603
97203	1.0304	588
97210	0.5411	328
97205	0.4855	313
97211	0.4508	253
97208	0.3242	132
97209	0.2607	126
205546	0.2038	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	96.30	gold quality
palpebral conjunctiva	UBERON:0001812	96.16	gold quality
placenta	UBERON:0001987	95.74	gold quality
left ovary	UBERON:0002119	95.28	gold quality
middle temporal gyrus	UBERON:0002771	95.24	gold quality
ovary	UBERON:0000992	95.21	gold quality
parietal pleura	UBERON:0002400	95.16	gold quality
corpus epididymis	UBERON:0004359	94.98	gold quality
pleura	UBERON:0000977	94.40	gold quality
gall bladder	UBERON:0002110	94.27	gold quality
pancreatic ductal cell	CL:0002079	94.15	gold quality
monocyte	CL:0000576	93.58	gold quality
right ovary	UBERON:0002118	93.54	gold quality
mononuclear cell	CL:0000842	93.42	gold quality
metanephros	UBERON:0000081	93.08	gold quality
visceral pleura	UBERON:0002401	92.97	gold quality
leukocyte	CL:0000738	92.90	gold quality
metanephros cortex	UBERON:0010533	92.83	gold quality
adrenal tissue	UBERON:0018303	92.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.64	gold quality
caput epididymis	UBERON:0004358	92.63	gold quality
renal medulla	UBERON:0000362	92.62	gold quality
lower lobe of lung	UBERON:0008949	92.48	gold quality
right lung	UBERON:0002167	92.43	gold quality
right uterine tube	UBERON:0001302	92.33	gold quality
body of pancreas	UBERON:0001150	92.23	gold quality
lung	UBERON:0002048	92.20	gold quality
metanephric glomerulus	UBERON:0004736	92.09	gold quality
mucosa of urinary bladder	UBERON:0001259	92.01	gold quality
pancreas	UBERON:0001264	91.98	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	26.28
E-ANND-3	yes	19.35
E-CURD-88	yes	4.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CTNNBL1, FOXO1, HOXB7, MBD2, NFKB2, NFKB, RARA, STAT3, TP53, TP73, WT1

miRNA regulators (miRDB)

79 targeting DAPK1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-8080	99.82	67.52	1342

Literature-anchored findings (GeneRIF, showing 40)

• To determine the extent of promoter hypermethylation in early lung tumorigenesis, we analyzed promoter methylation status of the p16, death-associated protein kinase (DAPK) and glutathione S-transferase P1 (GSTP1) genes (PMID:11809677)
• upregulated significantly in acute myeloid leukemia patients whose white blood cell count was higher than 100 x 10(9)/L cells (PMID:12031912)
• promoter methylation studied in 80 patients with head and neck squamous cell carcinoma (HNSCC) (PMID:12082610)
• Results indicate that DAP-kinase exerts apoptotic effects by suppressing integrin functions and integrin-mediated survival signals, thereby activating a p53-dependent apoptotic pathway. (PMID:12370243)
• Suppression of DAP kinase expression by DNA methylation might play a substantial role in the development of not only B-cell, but also T- and NK/T-cell lymphomas. (PMID:12708480)
• DAP kinase binds to syntaxin 1A in a signal transduction pathway (PMID:12730201)
• Frequent death-associated protein-kinase promoter hypermethylation is associated with brain metastases of solid tumors (PMID:12792765)
• Hepatoma cells may escape from apoptosis through the loss or reduction of DAP-kinase expression, while the block of IFN-gamma signal transduction as well as the methylation of promoter region may reduce the expression of DAP-kinase protein. (PMID:12820391)
• Loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia. (PMID:14504087)
• cellular activities of DAPK are critical for antagonizing caspase-dependent apoptosis to promote cell survival under normal cell growth conditions. (PMID:14530257)
• DAPK promoter methylation and down-regulation is tightly associated with gastric atrophy, often contributes to the preneoplastic changes in gastric carcinogenesis. (PMID:14612952)
• DAPK downregulation and methylation of the DAPK promoter may be involved in carcinogenesis of human uterine and ovarian tissues (PMID:14767518)
• the expression of DAP kinase, p19ARF, p53, and p21WAF1 was significantly down-regulated in the chronically HIV-1SF2-infected HUT78 T cells (PMID:15018706)
• Expression and phosphorylation of DAP kinase in hippocampus of patients with intractable temporal lobe epilepsy is significantly increased compared with autopsy controls. (PMID:15048887)
• although DAP kinase alteration was relatively rare, DAP kinase alteration and/or p53 mutation may associate with tumor progression in soft-tissue LMSs (PMID:15492995)
• DAP kinase is involved in TRAIL-mediated cell apoptosis and a demethylating agent may have a role in enhancing TRAIL-mediated apoptosis in some NSCLC cells by reactivation of DAP kinase (PMID:15634757)
• DAP-kinase promoter methylation may be a potential prognostic marker for gastric cancer patients (PMID:15809761)
• DAPK has a role as a sensor of mitochondrial membrane potential (PMID:16085644)
• DAPK does not regulate radiation-induced cell death (PMID:16142356)
• RSK-mediated phosphorylation of DAPK is a unique mechanism for suppressing the proapoptotic function of this death kinase in healthy cells as well as Ras/Raf-transformed cells. (PMID:16213824)
• These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD. (PMID:16847012)
• Aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression. (PMID:16858683)
• The promoter hypermethylation of DAPK-1 is a marker of aggressive renal cell carcinoma and provides independent prognostic information on disease outcome. (PMID:16951219)
• the apoptosis regulatory activities mediated by DAPK are controlled both by phosphorylation status and protein stability (PMID:17056602)
• TIMP3, DAPK1 and AKR1B10 are important for squamous cell lung cancer tumorogenesis while AKR1B10 is potential oncogene whereas TIMP3 and DAPK1 are potential tumor suppressor genes. (PMID:17209433)
• data highlight a naturally occurring DAPK-1 mutation that alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis (PMID:17244621)
• Aberrant hypermethylation on DAPK1 promoter is associated with the development of brain metastases from solid tumors (PMID:17319784)
• suggest that DAPK-1 forms a multiprotein survival complex with cathepsin B countering the rate of TNFR-1-dependent apoptosis (PMID:17324927)
• DAPK is found in two distinct immune complexes, one containing HSP90 and CHIP and a second complex containing only DIP1/Mib; strict modulation of DAPK activities by HSP90 heterocomplexes is critical for regulation of apoptosis and cellular homeostasis (PMID:17324930)
• results showed RASSF1A & DAPK genes’ promoter methylation occurred frequently in lung tumors, although prevalence of this alteration in these genes was not associated with smoking status of the patients or occurrence of mutations in K-ras, p53 & EGFR (PMID:17477876)
• Promoter hypermethylation of DAPK was observed. (PMID:17523078)
• Study shows that loss or reduced expression of DAPK1 underlies cases of heritable predisposition to chronic lymphocytic leukemia (CLL) and epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. (PMID:17540169)
• TIMP-3 promoter hypermethylation is elevated in HNSCC and is highly correlated with DAPK hypermethylation, implying a functional relationship between these genes. (PMID:17592394)
• Sodium arsenite caused DAPK promoter hypermethylation and gene silencing which may be involved in arsenic-induced carcinogenesis. (PMID:17683884)
• the DAPK gene epigenetically affected by methylation may be associated with the carcinogenesis of cholangiocarcinoma (PMID:17690039)
• these findings establish a major role for DAPk and its specific interaction with PKD in regulating the JNK signaling network under oxidative stress. (PMID:17703233)
• The promoter methylation of the DAPK gene is an important event during carcinogenesis and may have potential clinical application as a marker for the progression and prognosis of cancer. (PMID:17868341)
• study reports that DAP kinase 1 promotes in vitro & in vivo phosphorylation of tropomyosin-1 on Ser283 & that this phosphorylation is essential for the H2O2-induced organization of the assembly of actin stress fibers in endothelial cells (PMID:17895359)
• Exposure to arsenic may induce DAPK promoter hypermethylation and inactivate the function of DAPK in urothelial carcinoma. …a key molecular event …in the malignant phenotype of tumour arising in patients from arsenic-contaminated environments (PMID:17953697)
• Methylation of the DAPK gene is associated with cell transformation in HPV and EBV infection in cervical cells (PMID:18026971)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dapk1	ENSDARG00000060093
mus_musculus	Dapk1	ENSMUSG00000021559
rattus_norvegicus	Dapk1	ENSRNOG00000018198

Paralogs (4): DAPK2 (ENSG00000035664), MYLK (ENSG00000065534), NEXN (ENSG00000162614), DAPK3 (ENSG00000167657)

Protein

Protein identifiers

Death-associated protein kinase 1 — P53355 (reviewed: P53355)

All UniProt accessions (2): P53355, F8WCQ3

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition. Isoform 2 cannot induce apoptosis but can induce membrane blebbing.

Subunit / interactions. Interacts with KLHL20. Interacts (via death domain) with MAPK1 and MAPK3. Interacts with MAP1B (via N-terminus). Interacts with PRKD1 in an oxidative stress-regulated manner. Interacts with PIN1, PDCD6, BECN1, TSC2 and STX1A. Interacts (via kinase domain) with DAPK3 (via kinase domain). Interacts with GRINB. Interacts (via death domain) with UNC5B (via death domain). Interacts with UNC5C (via death domain).

Subcellular location. Cytoplasm. Cytoskeleton Cytoplasm. Cytoskeleton.

Tissue specificity. Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.

Post-translational modifications. Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome. Removal of the C-terminal tail of isoform 2 (corresponding to amino acids 296-337 of isoform 2) by proteolytic cleavage stimulates maximally its membrane-blebbing function. In response to mitogenic stimulation (PMA or EGF), phosphorylated at Ser-289; phosphorylation suppresses DAPK1 pro-apoptotic function. Autophosphorylation at Ser-308 inhibits its catalytic activity. Phosphorylation at Ser-734 by MAPK1 increases its catalytic activity and promotes cytoplasmic retention of MAPK1. Endoplasmic-stress can cause dephosphorylation at Ser-308.

Activity regulation. Activated by Ca(2+)/calmodulin. Regulated by a locking mechanism, involving autophosphorylation at Ser-308 and calmodulin binding. In the inactive state, Ser-308 is phosphorylated. Activation involves its dephosphorylation and a release-of-autoinhibition mechanism where binding of calmodulin induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain. Activity is modulated by UNC5B and NTN1. UNC5B activates it by inhibiting the phosphorylation at Ser-308, whereas NTN1 inhibits UNC5B-mediated activation of DAPK1. Endoplasmic-stress activates by causing Ser-308 dephosphorylation.

Domain organisation. The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.

Induction. Up-regulated following treatment with IFNG/IFN-gamma.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P53355-1	1, Alpha	yes
P53355-2	2, s-DAPK-1
P53355-3	3, Beta
P53355-4	4

RefSeq proteins (4): NP_001275658, NP_001275659, NP_001275660, NP_004929* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020676	DAPK1_cat	Domain
IPR020859	ROC	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF00069, PF00531, PF12796, PF13637

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (94 total): sequence variant 19, helix 16, strand 14, repeat 10, modified residue 6, mutagenesis site 6, binding site 5, splice variant 5, turn 4, domain 3, region of interest 2, sequence conflict 2, chain 1, active site 1

Structure

Experimental structures (PDB)

79 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6GY5	X-RAY DIFFRACTION	1.09
4PF4	X-RAY DIFFRACTION	1.13
2W4J	X-RAY DIFFRACTION	1.3
3GU4	X-RAY DIFFRACTION	1.35
9N2M	X-RAY DIFFRACTION	1.35
4YPD	X-RAY DIFFRACTION	1.4
5AV4	X-RAY DIFFRACTION	1.4
7CCW	X-RAY DIFFRACTION	1.4
9N1T	X-RAY DIFFRACTION	1.43
3GU6	X-RAY DIFFRACTION	1.49
9N2O	X-RAY DIFFRACTION	1.49
9O73	X-RAY DIFFRACTION	1.49
1JKS	X-RAY DIFFRACTION	1.5
5AUV	X-RAY DIFFRACTION	1.5
5AUW	X-RAY DIFFRACTION	1.5
5AUX	X-RAY DIFFRACTION	1.5
5AV1	X-RAY DIFFRACTION	1.5
9DUB	X-RAY DIFFRACTION	1.5
5AV2	X-RAY DIFFRACTION	1.5
9INW	X-RAY DIFFRACTION	1.52
3EHA	X-RAY DIFFRACTION	1.6
3GU8	X-RAY DIFFRACTION	1.6
4YO4	X-RAY DIFFRACTION	1.6
5AUZ	X-RAY DIFFRACTION	1.6
9INV	X-RAY DIFFRACTION	1.61
1JKL	X-RAY DIFFRACTION	1.62
7CCU	X-RAY DIFFRACTION	1.65
3GU5	X-RAY DIFFRACTION	1.65
9DUE	X-RAY DIFFRACTION	1.65
1YR5	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53355-F1	82.74	0.49

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 (1): 139 (proton acceptor)

Ligand- & substrate-binding residues (5): 19–27; 42; 94–96; 100; 161

Post-translational modifications (6): 289, 308, 319, 333, 734, 1115

Mutagenesis-validated functional residues (6):

Position	Phenotype
42	loss of activity, apoptotic function and of autophosphorylation.
289	loss of phosphorylation and significant increase in proapoptotic activity.
289	reduction in proapoptotic activity.
308	elevated ca(2+)-calmodulin binding and ca(2+)-calmodulin-independent kinase activity. increases apoptotic activity.
308	reduced ca(2+)-calmodulin binding and ca(2+)-calmodulin-independent kinase activity. decreases apoptotic activity.
313	minimal effect on activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand

MSigDB gene sets: 369 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GGTGTGT_MIR329, MODULE_169, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_RESPONSE_TO_PEPTIDE, PID_NETRIN_PATHWAY, TTTGTAG_MIR520D, LI_PROSTATE_CANCER_EPIGENETIC, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GCAAGGA_MIR502, MODULE_128, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN

GO Biological Process (20): defense response to tumor cell (GO:0002357), regulation of response to tumor cell (GO:0002834), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), regulation of autophagy (GO:0010506), positive regulation of autophagy (GO:0010508), negative regulation of translation (GO:0017148), intracellular signal transduction (GO:0035556), regulation of apoptotic process (GO:0042981), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), protein autophosphorylation (GO:0046777), cellular response to type II interferon (GO:0071346), cellular response to hydroperoxide (GO:0071447), apoptotic signaling pathway (GO:0097190), positive regulation of autophagic cell death (GO:1904094), regulation of NMDA receptor activity (GO:2000310), regulation of translation (GO:0006417), signal transduction (GO:0007165)

GO Molecular Function (13): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), calcium/calmodulin-dependent protein kinase activity (GO:0004683), calmodulin binding (GO:0005516), ATP binding (GO:0005524), GTP binding (GO:0005525), syntaxin-1 binding (GO:0017075), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), actin cytoskeleton (GO:0015629), glutamatergic synapse (GO:0098978), DAPK1-calmodulin complex (GO:1990722), cytoskeleton (GO:0005856), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Caspase activation via extrinsic apoptotic signalling pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	4
response to tumor cell	2
autophagy	2
translation	2
intracellular anatomical structure	2
signal transduction	2
regulation of apoptotic process	2
positive regulation of programmed cell death	2
protein kinase activity	2
protein binding	2
purine ribonucleoside triphosphate binding	2
cellular anatomical structure	2
defense response	1
regulation of response to biotic stimulus	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
extrinsic apoptotic signaling pathway	1
regulation of catabolic process	1
positive regulation of catabolic process	1
regulation of autophagy	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
regulation of programmed cell death	1
negative regulation of programmed cell death	1
protein phosphorylation	1
response to type II interferon	1
cellular response to cytokine stimulus	1
response to hydroperoxide	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
autophagic cell death	1
regulation of autophagic cell death	1
NMDA glutamate receptor activity	1
regulation of transmembrane transporter activity	1
regulation of neurotransmitter receptor activity	1
post-transcriptional regulation of gene expression	1

Protein interactions and networks

STRING

2703 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DAPK1	CALML3	P27482	896
DAPK1	CALML5	Q9NZT1	896
DAPK1	CALML6	Q8TD86	889
DAPK1	CALML4	Q96GE6	889
DAPK1	GRIN2B	Q13224	884
DAPK1	DAP	P51397	870
DAPK1	CALM1	P02593	867
DAPK1	BECN1	Q14457	831
DAPK1	TP53	P04637	815
DAPK1	RASSF1	Q9NS23	811
DAPK1	KLHL20	Q9Y2M5	794
DAPK1	MGMT	P16455	783
DAPK1	FADD	Q13158	738
DAPK1	UNC5B	Q8IZJ1	728
DAPK1	BCL2	P10415	726

IntAct

166 interactions, top by confidence:

A	B	Type	Score
BECN1	BCL2	psi-mi:“MI:0914”(association)	0.950
TSC1	TSC2	psi-mi:“MI:0914”(association)	0.930
KLHL20	DAPK1	psi-mi:“MI:0914”(association)	0.780
KLHL20	DAPK1	psi-mi:“MI:0915”(physical association)	0.780
KLHL20	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.780
DAPK1	DAPK1	psi-mi:“MI:0915”(physical association)	0.780
DAPK1	KLHL20	psi-mi:“MI:0915”(physical association)	0.780
DAPK1	DAPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.780
IFI30	DAPK1	psi-mi:“MI:0914”(association)	0.730
DAPK1	CALM1	psi-mi:“MI:0407”(direct interaction)	0.650
CALM1	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.650
DAPK1	CALM1	psi-mi:“MI:0915”(physical association)	0.650
CALM1	DAPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.650
DAPK1	MAPK3	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (264): DAPK1 (Biochemical Activity), BECN1 (Biochemical Activity), DAPK1 (Reconstituted Complex), DAPK1 (Affinity Capture-Western), DAPK1 (Two-hybrid), DAPK1 (Affinity Capture-Western), Mib1 (Affinity Capture-Western), DAPK1 (Affinity Capture-Western), DAPK1 (Biochemical Activity), DAPK1 (Affinity Capture-Western), DAPK1 (Affinity Capture-Western), PPP2R2D (Affinity Capture-Western), PPP2R5A (Affinity Capture-Western), DAPK1 (Biochemical Activity), DAPK1 (Biochemical Activity)

ESM2 similar proteins: A0PJZ0, A6NHY2, A7E2S9, C7B178, D3J162, G5E8K5, P42570, P42773, P53355, Q08E43, Q10311, Q14DN9, Q18297, Q2T9W8, Q3EC11, Q4R3S3, Q4R544, Q4UJC4, Q4UJJ2, Q5EFR1, Q5I126, Q5I148, Q5I155, Q5I159, Q5I160, Q5R6D7, Q5RCK5, Q5TYM7, Q5VYY1, Q60772, Q60773, Q6XJU9, Q80YE7, Q86WC6, Q91ZT9, Q91ZU0, Q92527, Q9BGT9, Q9CQM6, Q9D119

Diamond homologs: A0QQK3, A8WUG4, A8X5H5, A8X6H1, A8XJQ6, A8XW88, F1M7Y5, F4HYG2, F4J6F6, G4NH08, O02827, O76360, O88664, P00517, P0DPS8, P10421, P10830, P11799, P16054, P16912, P17612, P18431, P18654, P20911, P21137, P22216, P22694, P25321, P27636, P27791, P29294, P32490, P34099, P34103, P36887, P38070, P40376, P41743, P49673, P50613

SIGNOR signaling

33 interactions.

A	Effect	B	Mechanism
DAPK1	“down-regulates activity”	DAPK1	phosphorylation
DAPK1	down-regulates	CAMKK2	phosphorylation
DAPK1	unknown	CAMKK2	phosphorylation
DAPK1	down-regulates	MAPK1	binding
MAPK1	up-regulates	DAPK1	phosphorylation
DAPK1	up-regulates	TP53	phosphorylation
PTPRF	up-regulates	DAPK1	dephosphorylation
DAPK1	unknown	RPL5	phosphorylation
DAPK1	unknown	MCM3	phosphorylation
DAPK1	up-regulates	MAP1B	binding
DAPK1	up-regulates	BECN1	phosphorylation
DAPK1	“down-regulates activity”	STX1A	phosphorylation
DAPK1	“up-regulates activity”	MYL12A	phosphorylation
DAPK1	“up-regulates activity”	TPM1	phosphorylation
KLHL20	“down-regulates quantity by destabilization”	DAPK1	binding
MIB1	“down-regulates quantity by destabilization”	DAPK1	polyubiquitination
SRC	“down-regulates activity”	DAPK1	phosphorylation
PTPRF	“up-regulates activity”	DAPK1	dephosphorylation
DAPK1	“down-regulates activity”	DDX58	phosphorylation
DAPK1	“down-regulates quantity by destabilization”	PELI1	phosphorylation
DAPK1	“down-regulates activity”	PIN1	phosphorylation
DAPK1	“up-regulates activity”	GRIN2B	phosphorylation
DAPK1	“up-regulates quantity”	SNCA	phosphorylation
DAPK1	“up-regulates quantity”	APP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Response of endothelial cells to shear stress	5	19.8×	2e-03
Cellular responses to mechanical stimuli	5	17.1×	3e-03
Antimicrobial mechanism of IFN-stimulated genes	5	12.9×	6e-03
Mitotic G1 phase and G1/S transition	5	12.1×	6e-03
Leishmania infection	5	10.7×	7e-03
Parasitic Infection Pathways	5	10.7×	7e-03
Interferon Signaling	6	9.5×	6e-03
RHO GTPase Effectors	7	6.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
thymus development	5	15.6×	8e-03
positive regulation of protein ubiquitination	6	11.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	189
Likely benign	18
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

4995 predictions. Top by Δscore:

Variant	Effect	Δscore
9:87604949:TTCA:T	acceptor_loss	1.0000
9:87604952:A:AC	acceptor_loss	1.0000
9:87604952:A:AG	acceptor_gain	1.0000
9:87604952:AGT:A	acceptor_gain	1.0000
9:87604952:AGTG:A	acceptor_gain	1.0000
9:87604953:G:GA	acceptor_gain	1.0000
9:87604953:GT:G	acceptor_gain	1.0000
9:87604953:GTG:G	acceptor_gain	1.0000
9:87604953:GTGG:G	acceptor_gain	1.0000
9:87604953:GTGGA:G	acceptor_gain	1.0000
9:87605171:GAACT:G	donor_gain	1.0000
9:87605172:AACTG:A	donor_loss	1.0000
9:87605173:ACTGT:A	donor_loss	1.0000
9:87605174:CT:C	donor_gain	1.0000
9:87605175:TG:T	donor_loss	1.0000
9:87605176:G:GG	donor_gain	1.0000
9:87605176:GT:G	donor_loss	1.0000
9:87605177:T:G	donor_loss	1.0000
9:87605178:GAGT:G	donor_loss	1.0000
9:87639351:A:AG	acceptor_gain	1.0000
9:87639352:A:G	acceptor_gain	1.0000
9:87639353:G:GG	acceptor_gain	1.0000
9:87640293:A:AG	acceptor_gain	1.0000
9:87640296:A:AG	acceptor_gain	1.0000
9:87640297:G:GA	acceptor_gain	1.0000
9:87640297:GC:G	acceptor_gain	1.0000
9:87640297:GCC:G	acceptor_gain	1.0000
9:87640297:GCCT:G	acceptor_gain	1.0000
9:87640297:GCCTA:G	acceptor_gain	1.0000
9:87640449:AA:A	donor_gain	1.0000

AlphaMissense

9445 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:87604956:G:A	G22E	1.000
9:87604961:T:C	F24L	1.000
9:87604962:T:C	F24S	1.000
9:87604962:T:G	F24C	1.000
9:87604963:T:A	F24L	1.000
9:87604963:T:G	F24L	1.000
9:87605010:C:A	A40D	1.000
9:87605013:C:A	A41D	1.000
9:87605017:A:C	K42N	1.000
9:87605017:A:T	K42N	1.000
9:87605054:G:C	G55R	1.000
9:87605055:G:A	G55D	1.000
9:87605094:T:C	L68P	1.000
9:87638074:A:C	D139A	1.000
9:87638074:A:T	D139V	1.000
9:87638077:T:C	L140P	1.000
9:87639355:C:A	P142H	1.000
9:87639358:A:T	E143V	1.000
9:87639360:A:G	N144D	1.000
9:87639361:A:G	N144S	1.000
9:87639362:C:A	N144K	1.000
9:87639362:C:G	N144K	1.000
9:87639411:G:C	D161H	1.000
9:87639412:A:C	D161A	1.000
9:87639412:A:T	D161V	1.000
9:87639413:C:A	D161E	1.000
9:87639413:C:G	D161E	1.000
9:87639466:G:A	G179E	1.000
9:87639477:T:C	F183L	1.000
9:87639478:T:C	F183S	1.000

dbSNP variants (sampled 300 via entrez): RS1000007182 (9:87616223 C>G), RS1000011535 (9:87531022 T>C), RS1000047119 (9:87581928 C>T), RS1000048990 (9:87512184 C>A,T), RS1000061099 (9:87630486 G>T), RS1000066450 (9:87695362 C>A), RS1000072291 (9:87657218 A>G), RS1000092284 (9:87649796 T>C,G), RS1000092445 (9:87703928 G>A), RS1000103844 (9:87592146 C>G,T), RS1000118214 (9:87508384 C>G), RS1000125670 (9:87669317 T>C), RS1000183078 (9:87623862 C>T), RS1000188216 (9:87516058 C>T), RS1000201338 (9:87619281 G>A,C,T)

Disease associations

OMIM: gene MIM:600831 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
autism spectrum disorder	Limited	Autosomal dominant

Mondo (2): myoepithelial tumor (MONDO:0002380), autism spectrum disorder (MONDO:0005258)

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001390_2	Response to gemcitabine in pancreatic cancer	1.000000e-06
GCST001538_31	Immune reponse to smallpox (secreted IFN-alpha)	5.000000e-07
GCST002386_17	Cognitive function	4.000000e-06
GCST002497_2	Blood pressure	4.000000e-07
GCST002497_3	Blood pressure	7.000000e-06
GCST002497_4	Blood pressure	4.000000e-07
GCST003264_248	Post bronchodilator FEV1/FVC ratio	4.000000e-06
GCST003542_151	Night sleep phenotypes	5.000000e-06
GCST007239_16	Ovarian cancer	7.000000e-06
GCST008839_134	Height	1.000000e-12
GCST010397_113	Gut microbiota (bacterial taxa, rank normal transformation method)	3.000000e-07
GCST010397_93	Gut microbiota (bacterial taxa, rank normal transformation method)	3.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0003925	cognition
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0004713	FEV/FVC ratio
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2558 (SINGLE PROTEIN), CHEMBL3885543 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 281,558 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL50	QUERCETIN	3	74,559
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL1721885	SU-014813	2	363
CHEMBL44	GENISTEIN	2	44,212
CHEMBL475251	R-406	2	762
CHEMBL513909	BI-2536	2	895
CHEMBL521851	PICTILISIB	2	6,071
CHEMBL150	KAEMPFEROL	1	25,940
CHEMBL1908394	GSK-461364	1	1,093
CHEMBL1908397	KW-2449	1	622
CHEMBL494089	GSK-690693	1	2,061

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11141915	Toxicity	3	gemcitabine	Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11141915	DAPK1	3	0.00	1	gemcitabine

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Death-associated kinase (DAPK) family

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

Ligand	Action	Affinity	Parameter
staurosporine	Inhibition	9.3	pIC50

Binding affinities (BindingDB)

9 measured of 9 human assays (9 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
HS38	IC50	200 nM
CPR005231 (6)	IC50	247 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
HS43	KD	1500 nM
3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenol	KD	2400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

89 potent at pChembl≥5 of 100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	STAUROSPORINE
8.85	Kd	1.4	nM	STAUROSPORINE
8.72	IC50	1.9	nM	CHEMBL4568087
8.05	IC50	8.88	nM	STAUROSPORINE
8.03	IC50	9.4	nM	STAUROSPORINE
7.98	IC50	10.4	nM	STAUROSPORINE
7.92	IC50	12	nM	CHEMBL3735890
7.88	IC50	13.08	nM	STAUROSPORINE
7.88	IC50	13.1	nM	STAUROSPORINE
7.80	IC50	15.7	nM	STAUROSPORINE
7.80	Kd	16	nM	FEDRATINIB
7.64	IC50	23	nM	CHEMBL4764610
7.58	IC50	26	nM	CHEMBL4552628
7.27	Kd	54	nM	CHEMBL4060481
7.26	Kd	55	nM	R-406
7.23	Kd	59	nM	CHEMBL4576489
7.16	Kd	69	nM	CHEMBL4465866
7.14	Kd	72	nM	RUXOLITINIB
7.10	Kd	80	nM	LESTAURTINIB
7.01	Kd	97	nM	CHEMBL1241674
6.92	Kd	120	nM	SUNITINIB
6.85	IC50	140	nM	CHEMBL3799389
6.70	IC50	200	nM	CHEMBL5303531
6.69	IC50	203	nM	CHEMBL4439133
6.61	IC50	247	nM	CHEMBL5407750
6.57	Kd	270	nM	SU-014813
6.52	Kd	300	nM	CHEMBL5303531
6.46	Kd	346	nM	CHEMBL6149465
6.44	Kd	360	nM	KW-2449
6.43	IC50	370	nM	CHEMBL5433785
6.42	Kd	380	nM	CHEMBL2425628
6.38	Kd	420	nM	CHEMBL2048872
6.35	IC50	450	nM	CHEMBL3797466
6.29	IC50	510	nM	CHEMBL3799585
6.27	Kd	540	nM	BI-2536
6.25	IC50	560	nM	CHEMBL5202142
6.24	Ki	581	nM	CHEMBL4461911
6.21	Kd	620	nM	CHEMBL464552
6.20	Kd	625	nM	CHEMBL6165977
6.16	IC50	700	nM	CHEMBL513703
6.12	Kd	767	nM	CHEMBL6134160
6.09	IC50	810	nM	CHEMBL5205578
6.05	IC50	890	nM	PURPURIN
6.04	IC50	920	nM	CHEMBL4461911
6.01	Kd	970	nM	RUBOXISTAURIN
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.90	IC50	1250	nM	CHEMBL4461911
5.85	IC50	1400	nM	CHEMBL3622137

PubChem BioAssay actives

91 with measured affinity, of 857 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,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	350261: Inhibition of DAPK1	ic50	0.0005	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637070: Inhibition of recombinant human GST-tagged DAPK1 catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0019	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637070: Inhibition of recombinant human GST-tagged DAPK1 catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0100	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637070: Inhibition of recombinant human GST-tagged DAPK1 catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0100	uM
6-methoxy-7-(1-piperazin-1-ylethyl)-2-[(Z)-pyrazolo[3,4-b]pyridin-3-ylidenemethyl]-1-benzofuran-3-ol	1262526: Inhibition of DAPK1 (unknown origin) by electrophoretic mobility shift assay	ic50	0.0120	uM
Fedratinib	624971: Binding constant for DAPK1 kinase domain	kd	0.0160	uM
4-fluoro-2-methoxy-11-oxo-5-propan-2-yl-3-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-6H-indolo[2,3-b]quinoline-8-carbonitrile	1700700: Inhibition of human DAPK1	ic50	0.0230	uM
N-[(1R,6R)-6-amino-2,2-difluorocyclohexyl]-4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophene-2-carboxamide	1637070: Inhibition of recombinant human GST-tagged DAPK1 catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0260	uM
5-(3-amino-5-thiophen-3-ylthieno[2,3-b]pyridin-2-yl)-3H-1,3,4-oxadiazole-2-thione	1446749: Binding affinity to DAPK1 (unknown origin)	kd	0.0540	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624971: Binding constant for DAPK1 kinase domain	kd	0.0550	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526262: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged DAPK1 (unknown origin) (1 to 289 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0590	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526262: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged DAPK1 (unknown origin) (1 to 289 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0690	uM
Ruxolitinib	624971: Binding constant for DAPK1 kinase domain	kd	0.0720	uM
2-[[1-(3-chlorophenyl)-4-oxo-5H-pyrazolo[5,4-d]pyrimidin-6-yl]sulfanyl]propanamide	1800106: Kinome Profiling from Article 10.1021/cb400407c: “Fluorescence Linked Enzyme Chemoproteomic Strategy for Discovery of a Potent and Selective DAPK1 and ZIPK Inhibitor.”	kd	0.0790	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507892: Binding affinity to DAPK1	kd	0.0800	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624971: Binding constant for DAPK1 kinase domain	kd	0.0970	uM
Sunitinib	435283: Binding constant for DAPK1 kinase domain	kd	0.1200	uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]cyclopropanecarboxamide	1298195: Inhibition of DAPK1 (unknown origin)	ic50	0.1400	uM
6-(5-methyl-1H-pyrazol-4-yl)-2-[(2S)-piperidin-2-yl]-3H-thieno[3,2-d]pyrimidin-4-one;dihydrochloride	1528743: Inhibition of recombinant human N-terminal GST-tagged DAPK1 catalytic domain (1 to 363 residues) expressed in baculovirus expression system by Adapta kinase assay	ic50	0.2030	uM
N-[2-(dimethylamino)ethyl]-3-[2-(4-hydroxy-3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-7-yl]benzamide	1801001: DAPK1 Isothermal Titration Calorimetry from Article 10.1002/cbic.201402512: “Identification and characterization of a small-molecule inhibitor of death-associated protein kinase 1.”	kd	0.2400	uM
N-[2-(dimethylamino)ethyl]-4-[6-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl]benzamide	1966657: Inhibition of DAPK1 (unknown origin)	ic50	0.2470	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435283: Binding constant for DAPK1 kinase domain	kd	0.2700	uM
1-(3-chlorophenyl)-6-(2-hydroxyethylsulfanyl)-5H-pyrazolo[5,4-d]pyrimidin-4-one	1800106: Kinome Profiling from Article 10.1021/cb400407c: “Fluorescence Linked Enzyme Chemoproteomic Strategy for Discovery of a Potent and Selective DAPK1 and ZIPK Inhibitor.”	kd	0.3200	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624971: Binding constant for DAPK1 kinase domain	kd	0.3600	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-methoxy-2-N-[4-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine	1966657: Inhibition of DAPK1 (unknown origin)	ic50	0.3700	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769525: Binding affinity to DAPK1 (unknown origin)	kd	0.3800	uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]-3-methylbut-2-enamide	1298195: Inhibition of DAPK1 (unknown origin)	ic50	0.4500	uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]butanamide	1298195: Inhibition of DAPK1 (unknown origin)	ic50	0.5100	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624971: Binding constant for DAPK1 kinase domain	kd	0.5400	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-(difluoromethyl)-2-pyridinyl]-2-pyridinyl]carbamate	1904666: Inhibition of DAPK1 (unknown origin)	ic50	0.5600	uM
3,5-dimethoxy-N-[4-(4-methoxyphenoxy)-2-[(6-morpholin-4-yl-3-pyridinyl)amino]pyrimidin-5-yl]benzamide	1585374: Inhibition of human DAPK1 (1 to 363 residues) using KKLNRTLSFAEPG as substrate after 120 mins [gamma-33P]-ATP by filtration method	ki	0.5810	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624971: Binding constant for DAPK1 kinase domain	kd	0.6200	uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]-2,2-dimethylpropanamide	1298195: Inhibition of DAPK1 (unknown origin)	ic50	0.7000	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-chloro-2-pyridinyl]-2-pyridinyl]carbamate	1904666: Inhibition of DAPK1 (unknown origin)	ic50	0.8100	uM
1,2,4-trihydroxyanthracene-9,10-dione	1966663: Inhibition of DAPK1 (1 to 285 residues) (unknown origin) expressed in Escherichia coli using KKLNRTLSFAEPG as substrate in presence of ATP by fluoro-spark kinase assay	ic50	0.8900	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	435283: Binding constant for DAPK1 kinase domain	kd	0.9700	uM
(4Z)-2-[(E)-2-phenylethenyl]-4-(pyridin-3-ylmethylidene)-1,3-oxazol-5-one	443270: Inhibition of DAPK1	ic50	1.0000	uM
methyl N-[4-[5-[(2S)-2-amino-2,4-dimethylpentoxy]-6-methyl-2-pyridinyl]-2-pyridinyl]carbamate	1904666: Inhibition of DAPK1 (unknown origin)	ic50	1.4000	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	624971: Binding constant for DAPK1 kinase domain	kd	1.4000	uM
N,N-dicyclopropyl-7-[(4,5-dimethyl-1,3-thiazol-2-yl)amino]-10-ethyl-3-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaene-11-carboxamide	1249772: Inhibition of recombinant DAPK1 (unknown origin) using fluoresceinated peptide as substrate after 60 mins by HTRF assay	ic50	1.4000	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624971: Binding constant for DAPK1 kinase domain	kd	1.6000	uM
2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one	1247840: Displacement of ANS from DAPK1 catalytic domain (1 to 285) (unknown origin) after 30 mins by fluorescence assay	ic50	1.6000	uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]pentanamide	1298195: Inhibition of DAPK1 (unknown origin)	ic50	1.8000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624971: Binding constant for DAPK1 kinase domain	kd	1.8000	uM
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol	435283: Binding constant for DAPK1 kinase domain	kd	2.4000	uM
9-tert-butyl-8-phenyl-6-phenylmethoxypurine	1966662: Inhibition of DAPK1 (unknown origin) in presence of 33P-ATP radiolabeled kinase assay	ic50	2.5000	uM
N-[4-(4-methoxyphenoxy)-2-(4-morpholin-4-ylanilino)pyrimidin-5-yl]-3-(trifluoromethyl)benzamide	1585370: Inhibition of human DAPK1 (1 to 363 residues) using KKLNRTLSFAEPG as substrate after 120 mins in presence of 10 uM [gamma-33P]-ATP by filtration method	ic50	2.6100	uM
3,5-dimethoxy-N-[4-(4-methoxyphenoxy)-2-[(6-piperidin-1-yl-3-pyridinyl)amino]pyrimidin-5-yl]benzamide	1585370: Inhibition of human DAPK1 (1 to 363 residues) using KKLNRTLSFAEPG as substrate after 120 mins in presence of 10 uM [gamma-33P]-ATP by filtration method	ic50	2.6900	uM
3,5-dimethoxy-N-[4-(4-methoxyphenoxy)-2-(4-morpholin-4-ylanilino)pyrimidin-5-yl]benzamide	1585370: Inhibition of human DAPK1 (1 to 363 residues) using KKLNRTLSFAEPG as substrate after 120 mins in presence of 10 uM [gamma-33P]-ATP by filtration method	ic50	2.7700	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	624971: Binding constant for DAPK1 kinase domain	kd	3.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, decreases reaction, increases expression, affects cotreatment, increases abundance (+1 more)	7
Decitabine	decreases methylation, increases expression, affects expression, decreases expression, decreases reaction	6
Air Pollutants	decreases expression, increases abundance, decreases methylation, increases expression	5
Arsenic	increases abundance, decreases expression, increases methylation, affects cotreatment, affects expression	4
Estradiol	decreases expression, increases expression, affects cotreatment	4
Particulate Matter	increases expression, decreases expression, increases abundance, decreases methylation	4
Benzo(a)pyrene	decreases expression, increases methylation	3
Valproic Acid	affects expression, increases expression	3
bisphenol A	increases expression, affects cotreatment, increases methylation	2
arsenite	increases expression, increases methylation, decreases reaction, decreases expression, affects binding (+1 more)	2
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	2
Resveratrol	decreases expression, increases activity, increases expression, affects cotreatment	2
Calcitriol	decreases expression, affects cotreatment	2
Copper	affects binding, affects expression, affects cotreatment, decreases expression	2
Hydrogen Peroxide	affects expression, decreases expression	2
Smoke	decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	increases expression, decreases expression	2
Sodium Selenite	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
urushiol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects cotreatment, increases expression	1

ChEMBL screening assays

332 unique, capped per target: 330 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1034093	Binding	Inhibition of DAPK1 at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem
CHEMBL4687855	ADMET	Inhibition of human DAPK1 assessed as residual activity at 10 uM relative to control	Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B2VK	Abcam HEK293T DAPK1 KO	Transformed cell line	Female
CVCL_D7NC	Ubigene A-549 DAPK1 KO	Cancer cell line	Male
CVCL_SK31	HAP1 DAPK1 (-) 1	Cancer cell line	Male
CVCL_SK32	HAP1 DAPK1 (-) 2	Cancer cell line	Male
CVCL_YP14	ZSSYe001-A	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder