DGKZ

Summary

DGKZ (diacylglycerol kinase zeta, HGNC:2857) is a protein-coding gene on chromosome 11p11.2, encoding Diacylglycerol kinase zeta (Q13574). Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.

The protein encoded by this gene belongs to the eukaryotic diacylglycerol kinase family. It may attenuate protein kinase C activity by regulating diacylglycerol levels in intracellular signaling cascade and signal transduction. Alternative splicing occurs at this locus and multiple transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 8525 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 575 total — 1 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_001199267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2857
Approved symbol	DGKZ
Name	diacylglycerol kinase zeta
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	DAGK5, hDGKzeta, DGK-ZETA, DAGK6
Ensembl gene	ENSG00000149091
Ensembl biotype	protein_coding
OMIM	601441
Entrez	8525

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 28 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000318201, ENST00000343674, ENST00000421244, ENST00000454345, ENST00000456247, ENST00000524448, ENST00000524869, ENST00000524984, ENST00000525242, ENST00000525434, ENST00000527211, ENST00000527674, ENST00000527903, ENST00000527911, ENST00000528173, ENST00000528615, ENST00000529660, ENST00000529698, ENST00000531879, ENST00000532868, ENST00000532941, ENST00000533376, ENST00000534215, ENST00000534802, ENST00000878698, ENST00000878699, ENST00000878700, ENST00000878701, ENST00000878702, ENST00000878703, ENST00000878704, ENST00000878705, ENST00000926265, ENST00000926266, ENST00000926267, ENST00000926268, ENST00000926269, ENST00000926270, ENST00000946824, ENST00000946825, ENST00000946826

RefSeq mRNA: 7 — MANE Select: NM_001199267 NM_001105540, NM_001199266, NM_001199267, NM_001199268, NM_003646, NM_201532, NM_201533

CCDS: CCDS41640, CCDS44579, CCDS44580, CCDS55757, CCDS55758, CCDS55759, CCDS7918

Canonical transcript exons

ENST00000456247 — 31 exons

Exon	Start	End
ENSE00001238291	46368005	46368079
ENSE00002144719	46347463	46347820
ENSE00003465254	46378991	46379111
ENSE00003478562	46378198	46378229
ENSE00003488571	46379203	46379236
ENSE00003494074	46377073	46377212
ENSE00003504936	46376328	46376397
ENSE00003506259	46374157	46374235
ENSE00003512444	46372075	46372170
ENSE00003516892	46376524	46376564
ENSE00003521545	46374604	46374666
ENSE00003526927	46371487	46371603
ENSE00003535641	46367291	46367399
ENSE00003538571	46374766	46374839
ENSE00003552560	46367652	46367747
ENSE00003552843	46369494	46369550
ENSE00003554217	46372961	46373101
ENSE00003559793	46379469	46379568
ENSE00003591398	46375432	46375631
ENSE00003607026	46374399	46374454
ENSE00003614954	46372771	46372884
ENSE00003618408	46375851	46375951
ENSE00003637395	46369941	46370009
ENSE00003639841	46378457	46378500
ENSE00003642840	46371704	46371775
ENSE00003663961	46372617	46372677
ENSE00003666474	46376066	46376145
ENSE00003672524	46374934	46375045
ENSE00003673844	46372428	46372510
ENSE00003787908	46371313	46371384
ENSE00003964298	46379831	46380551

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.9259 / max 418.4610, expressed in 1810 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114114	16.8893	1785
114115	8.0265	1684
114119	4.0923	702
114110	3.4835	671
114104	0.7214	255
114111	0.2996	134
114109	0.2901	119
114103	0.2062	100
114113	0.1909	73
114102	0.1332	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.08	gold quality
anterior cingulate cortex	UBERON:0009835	98.86	gold quality
granulocyte	CL:0000094	98.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.61	gold quality
gastrocnemius	UBERON:0001388	97.55	gold quality
apex of heart	UBERON:0002098	97.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.19	gold quality
adenohypophysis	UBERON:0002196	97.17	gold quality
prefrontal cortex	UBERON:0000451	97.03	gold quality
right atrium auricular region	UBERON:0006631	96.95	gold quality
muscle of leg	UBERON:0001383	96.63	gold quality
cerebellar hemisphere	UBERON:0002245	96.56	gold quality
cerebellar cortex	UBERON:0002129	96.40	gold quality
bone marrow cell	CL:0002092	95.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.91	gold quality
cardiac atrium	UBERON:0002081	94.56	gold quality
leukocyte	CL:0000738	94.54	gold quality
monocyte	CL:0000576	94.30	gold quality
amygdala	UBERON:0001876	94.02	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.95	gold quality
vermiform appendix	UBERON:0001154	93.69	gold quality
body of stomach	UBERON:0001161	93.44	gold quality
body of pancreas	UBERON:0001150	93.34	gold quality
spleen	UBERON:0002106	93.25	gold quality
heart left ventricle	UBERON:0002084	93.24	gold quality
lower esophagus mucosa	UBERON:0035834	93.20	gold quality
pituitary gland	UBERON:0000007	93.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.08	gold quality
metanephros cortex	UBERON:0010533	93.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-4448	97.04	66.22	752
HSA-MIR-500B-3P	96.49	65.40	1087

Literature-anchored findings (GeneRIF, showing 37)

• structural domain requirements for translocation and activity (PMID:12015310)
• Negative regulation of T cell receptor induced activation of the Ras-Erk1/2-AP1 pathway by DGKz (PMID:12070163)
• PKC alpha phosphorylates diacylglycerol kinase zeta in cells, and this phosphorylation inhibits its kinase activity to remove cellular diacylglycerol, thereby affecting cell growth. (PMID:12890670)
• role in controlling the induction of luteinizing hormone beta transcription by ERK1/2 (PMID:14707140)
• DGKzeta generating PA, stimulates PIP5KIalpha activity to increase local PIP2, which regulates actin polymerization. (PMID:15157668)
• DGKzeta-derived phosphatidic acid acts as a mediator of mTOR signaling (PMID:15632115)
• DGKzeta may act in vivo as a downstream effector of pRB to regulate nuclear levels of diacylglycerol and phosphatidic acid (PMID:16286473)
• 2,3-dioleoylglycerol binds to a site on the alpha and zeta isoforms of diacylglycerol kinase that is exposed as a consequence of the substrate binding to the active site. (PMID:18004883)
• PKD activation is induced by DGKzeta, suggesting DGK is an upstream regulator of oxidative stress-induced activation of the PKD signaling pathway in intestinal epithelial cells. (PMID:18694729)
• In DGKzeta-deficient fibroblasts PAK1 phosphorylation and Rac1-RhoGDI dissociation were attenuated, leading to reduced Rac1 activation after platelet-derived growth factor stimulation. (PMID:19211846)
• None of SNPs of diacylglycerol kinase zeta tested showed association with bipolar disorder in Sardinian sample. (PMID:19308020)
• Data show that Diacylglycerol that 2-arachidonoyl glycerol is a very poor substrate for either the epsilon or the zeta isoforms of diacylglycerol kinases. (PMID:21194521)
• DGK-zeta translocated rapidly to the plasma membrane at early stages of immunological synapse (IS) formation independent of enzyme activity; study highlights a DGKzeta-specific function for local diacylglycerol metabolism at the IS and offers new clues to its mode of regulation (PMID:21937721)
• Nucleosome assembly protein (NAP) 1-like 1 (NAP1L1) and NAP1-like 4 (NAP1L4) are identified as novel DGKzeta binding partners. (PMID:21996351)
• Antigen-specific CD8-positive T cells from DGKzeta-deficient transgenic mice show enhanced expansion and increased cytokine production after lymphocytic choriomeningitis virus infection, yet DGK-deficient memory CD8+ T cells exhibit impaired expansion. (PMID:22271650)
• DGK regulates melanogenesis via modulation of the posttranslational processing of tyrosinase, which may be related with the protein degradation machinery. (PMID:22895365)
• Data indicate that after P2Y6 receptor stimulation both phospholipase D (PLD) and DGKzeta enzymes are responsible for producing phosphatidic acid (PA). (PMID:23723068)
• Elevated DGKzeta expression contributes to increased Rho GTPase activation and the enhanced motility of metastatic cancer cells. (PMID:24646293)
• This study shows that DGKzeta knockdown facilitates degradation of IkappaB, followed by nuclear translocation of NF-kappaB p65 subunit. (PMID:25450975)
• Redundant and specialized roles for diacylglycerol kinases alpha and zeta in the control of T cell functions. (PMID:25921290)
• These results established the positive correlation between DGKzeta expression and gliomagrade. (PMID:26452358)
• DGKzeta knockdown engenders enhancement of NF-kappaB pathway in response to TNF-alpha. [review] (PMID:26521214)
• Diacylglycerol kinases alpha and zeta are up-regulated in cancer in cancer, and contribute towards tumor immune evasion and T cells clonal anergy. (Review) (PMID:27697466)
• these data suggest that the activation of DGKzeta downstream of antigen recognition provides a mechanism that ensures the activation of PA-dependent signaling as a direct result of the strength of TCR-dependent DAG mobilization. (PMID:27999176)
• Results show that DGKzeta is downregulated in bone marrow mononuclear cells and associated with the severity of aplastic anemia (AA). Also, DGKzeta is a downstream target gene of miR34a. Their dysregulation enhances T-cell activation in AA cells. (PMID:28008152)
• we showed that rs7951870-TT genotype was strongly associated with increased DGKZ expression level (P = 0.038). In conclusion, our findings revealed dysregulation of DGKZ in SCZ patients and a significant correction between the gene expression and DGKZ variant rs7951870. (PMID:31087244)
• knockdown of DGKZ can induce apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells through the MAPK/survivin/caspase pathway. (PMID:31288898)
• Characterization of alpha-synuclein N-terminal domain as a novel cellular phosphatidic acid sensor. (PMID:31722116)
• DGKzeta depletion attenuates HIF-1alpha induction and SIRT1 expression, but enhances TAK1-mediated AMPKalpha phosphorylation under hypoxia. (PMID:32224048)
• Diacylglycerol kinase zeta limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes. (PMID:33246984)
• Regulation of p53 and NF-kappaB transactivation activities by DGKzeta in catalytic activity-dependent and -independent manners. (PMID:33450306)
• Downregulation of Diacylglycerol kinase zeta (DGKZ) suppresses tumorigenesis and progression of cervical cancer by facilitating cell apoptosis and cell cycle arrest. (PMID:33926342)
• DGKZ promotes TGFbeta signaling pathway and metastasis in triple-negative breast cancer by suppressing lipid raft-dependent endocytosis of TGFbetaR2. (PMID:35115500)
• Identification and characterization of diacylglycerol kinase zeta as a novel enzyme producing ceramide-1-phosphate. (PMID:36906254)
• Diacylglycerol kinase zeta interacts with sphingomyelin synthase 1 and sphingomyelin synthase-related protein via different regions. (PMID:37166445)
• Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease. (PMID:37347142)
• Differential expression of diacylglycerol kinase zeta is involved in inferior parietal lobule-related dysfunction in schizophrenia with cognitive impairments. (PMID:37479996)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	dgkza	ENSDARG00000014439
danio_rerio	dgkzb	ENSDARG00000076025
mus_musculus	Dgkz	ENSMUSG00000040479
rattus_norvegicus	Dgkz	ENSRNOG00000017737
drosophila_melanogaster	CG34384	FBGN0085413
drosophila_melanogaster	rdgA	FBGN0261549
caenorhabditis_elegans		WBGENE00006483
caenorhabditis_elegans		WBGENE00019428

Paralogs (9): DGKG (ENSG00000058866), DGKA (ENSG00000065357), DGKD (ENSG00000077044), DGKH (ENSG00000102780), DGKB (ENSG00000136267), DGKQ (ENSG00000145214), DGKE (ENSG00000153933), DGKI (ENSG00000157680), DGKK (ENSG00000274588)

Protein

Protein identifiers

Diacylglycerol kinase zeta — Q13574 (reviewed: Q13574)

Alternative names: Diglyceride kinase zeta

All UniProt accessions (7): Q13574, E9PK94, E9PKT3, E9PNL8, E9PNZ3, H0YDN6, H0YEG2

UniProt curated annotations — full annotation on UniProt →

Function. Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids. Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes. Also plays an important role in the biosynthesis of complex lipids. Does not exhibit an acyl chain-dependent substrate specificity among diacylglycerol species. Can also phosphorylate 1-alkyl-2-acylglycerol in vitro but less efficiently and with a preference for alkylacylglycerols containing an arachidonoyl group. The biological processes it is involved in include T cell activation since it negatively regulates T-cell receptor signaling which is in part mediated by diacylglycerol. By generating phosphatidic acid, stimulates PIP5KIA activity which regulates actin polymerization. Through the same mechanism could also positively regulate insulin-induced translocation of SLC2A4 to the cell membrane. Regulates RASGRP1 activity. Does not regulate RASGRP1 activity.

Subunit / interactions. Interacts (via PDZ-binding motif) with the PDZ domain of the syntrophin SNTG1 and that of SNX27. Interacts with IRS1 in the absence of insulin; insulin stimulation decreases this interaction. Found in a ternary complex with IRS1 and PIP5K1A in the absence of insulin. Interacts with PIP5K1A. Forms a signaling complex with RASGRP1 and HRAS.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Cell membrane. Cell projection. Lamellipodium.

Tissue specificity. Highest levels in brain, and substantial levels in skeletal muscle, heart, and pancreas. Predominantly expressed in muscle.

Post-translational modifications. Phosphorylation of the MARCKS homology domain by PKC reduces nuclear accumulation of DGK-zeta.

Activity regulation. Activated by 1,2-diacyl-sn-glycero-3-phosphate/phosphatidic acid irrespective of its acyl chain composition.

Domain organisation. The PDZ-binding motif mediates interaction with PDZ domain-containing proteins like SNTG1 and SNX27.

Pathway. Lipid metabolism; glycerolipid metabolism.

Miscellaneous. Minor isoform. Major isoform.

Similarity. Belongs to the eukaryotic diacylglycerol kinase family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q13574-2	1, Short	yes
Q13574-1	2, Long, zeta2
Q13574-3	3
Q13574-4	4
Q13574-5	5
Q13574-6	6
Q13574-7	7

RefSeq proteins (7): NP_001099010, NP_001186195, NP_001186196, NP_001186197, NP_003637, NP_963290, NP_963291 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000756	Diacylglycerol_kin_accessory	Domain
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR002219	PKC_DAG/PE	Domain
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037607	DGK	Family
IPR047484	C1_DGKzeta_rpt2	Domain
IPR047485	C1_DGKzeta_rpt1	Domain
IPR056383	DGKI-like_dom	Domain

Pfam: PF00130, PF00609, PF00781, PF12796, PF23578

Enzyme classification (BRENDA):

• EC 2.7.1.107 — diacylglycerol kinase (ATP) (BRENDA: 27 organisms, 171 substrates, 108 inhibitors, 81 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.05–4.8	46
GTP	0.03–8.7	5
DIOLEIN	0.05–0.08	3
1,2-DIARACHIDONOYL-GLYCEROL	0.09–0.14	2
1-STEAROYL-2-ARACHIDONOYL-SN-GLYCEROL	0.07–0.09	2
SN-1,2-DIOLEOYLGLYCEROL	0.1–0.125	2
1,2-DIACYL-SN-GLYCEROL	0.25	1
1,2-DIOLEIN	0.45	1
1,2-DIOLEOYL-SN-GLYCEROL	0.125	1
2’-DEOXY-ATP	4.2	1
ADP	1	1
CERAMIDE	0.23	1
DIOLEOYLGLYCEROL	0.9	1
ITP	5.9	1
1-STEAROYL-2-LINOLEOYL-SN-GLYCEROL	—	0

Catalyzed reactions (Rhea), 12 shown:

• a 1,2-diacyl-sn-glycerol + ATP = a 1,2-diacyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:10272)
• a 1-O-alkyl-sn-glycerol + ATP = a 1-O-alkyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:16937)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40323)
• 1,2-di-(9Z-octadecenoyl)-sn-glycerol + ATP = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40327)
• 1-eicosanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycerol + ATP = 1-eicosanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40331)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40335)
• 1,2-di-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycerol + ATP = 1,2-di-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40351)
• 1-octadecanoyl-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycerol + ATP = 1-octadecanoyl-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40359)
• 1-O-hexadecyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-O-hexadecyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40403)
• 1-O-hexadecyl-2-(9Z-octadecenoyl)-sn-glycerol + ATP = 1-O-hexadecyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40407)
• 1-O-hexadecyl-sn-glycerol + ATP = 1-O-hexadecyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:41672)
• 1-O-hexadecyl-2-acetyl-sn-glycerol + ATP = 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:41676)

UniProt features (35 total): splice variant 7, region of interest 6, compositionally biased region 5, sequence conflict 3, short sequence motif 2, modified residue 2, repeat 2, sequence variant 2, zinc finger region 2, chain 1, domain 1, mutagenesis site 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5ELQ	X-RAY DIFFRACTION	1.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13574-F1	77.94	0.45

Functional residue map

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

Post-translational modifications (2): 705, 781

Mutagenesis-validated functional residues (1):

Position	Phenotype
926–927	loss of interaction with sntg1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis

MSigDB gene sets: 312 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_LIPID_MODIFICATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, MODY_HIPPOCAMPUS_POSTNATAL, WANG_CLIM2_TARGETS_UP, MYOGENIN_Q6, PAX4_01, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, AREB6_03, GOBP_CELL_CYCLE_PHASE_TRANSITION, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MORF_HDAC1

GO Biological Process (12): phosphatidic acid biosynthetic process (GO:0006654), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), cell migration (GO:0016477), platelet activation (GO:0030168), mitotic G1 DNA damage checkpoint signaling (GO:0031571), intracellular signal transduction (GO:0035556), diacylglycerol metabolic process (GO:0046339), glycerolipid metabolic process (GO:0046486), lipid phosphorylation (GO:0046834), negative regulation of T cell receptor signaling pathway (GO:0050860), lipid metabolic process (GO:0006629), signal transduction (GO:0007165)

GO Molecular Function (10): lipid kinase activity (GO:0001727), ATP-dependent diacylglycerol kinase activity (GO:0004143), ATP binding (GO:0005524), zinc ion binding (GO:0008270), kinase activity (GO:0016301), alkylglycerol kinase activity (GO:0047649), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear speck (GO:0016607), lamellipodium (GO:0030027), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
kinase activity	2
phosphotransferase activity, alcohol group as acceptor	2
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic process	1
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
cell motility	1
cell activation	1
blood coagulation	1
mitotic G1 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G1/S transition checkpoint signaling	1
signal transduction	1
acylglycerol metabolic process	1
lipid metabolic process	1
phosphorylation	1
lipid modification	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
primary metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lipid kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
transferase activity, transferring phosphorus-containing groups	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1

Protein interactions and networks

STRING

1036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DGKZ	SNX27	Q96L92	975
DGKZ	MARCKS	P29966	845
DGKZ	DLG4	P78352	799
DGKZ	ARRB1	P49407	767
DGKZ	ARRB2	P32121	737
DGKZ	ARHGDIA	P52565	729
DGKZ	CYTIP	O60759	713
DGKZ	ANK3	Q12955	692
DGKZ	ANK2	Q01484	690
DGKZ	ANK1	P16157	683
DGKZ	NAP1L4	Q99733	666
DGKZ	SERPINB3	P29508	663
DGKZ	DDX5	P17844	647
DGKZ	SNTG1	Q9NSN8	621
DGKZ	RASGRP1	O95267	613

IntAct

305 interactions, top by confidence:

A	B	Type	Score
DLG4	DGKZ	psi-mi:“MI:0407”(direct interaction)	0.610
DGKZ	DLG4	psi-mi:“MI:0915”(physical association)	0.610
DGKZ	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.610
DGKZ	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.610
DGKZ	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.610
DGKZ	MAST2	psi-mi:“MI:0407”(direct interaction)	0.610
DGKZ	DLG4	psi-mi:“MI:0407”(direct interaction)	0.610
SCRIB	DGKZ	psi-mi:“MI:0407”(direct interaction)	0.610
MAGI2	DGKZ	psi-mi:“MI:0407”(direct interaction)	0.610
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
PTGES3	AIP	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
DGKZ	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (96): DGKZ (Affinity Capture-MS), DGKZ (Affinity Capture-Western), TP53 (Affinity Capture-Western), DGKZ (Reconstituted Complex), DGKZ (Affinity Capture-MS), DGKZ (Biochemical Activity), PIK3CA (Affinity Capture-Western), PLCG1 (Affinity Capture-Western), DGKZ (Affinity Capture-MS), DGKZ (Affinity Capture-MS), DGKZ (Two-hybrid), DGKZ (Two-hybrid), DGKZ (Affinity Capture-Western), SNTA1 (Reconstituted Complex), SNTB1 (Reconstituted Complex)

ESM2 similar proteins: A0A096MJN4, A0JND4, A1CPP3, A2CI35, A2WYE9, A2YU42, A8HYJ1, A8JAM0, B4HWV2, B4Q9T2, B6QIM3, B7PXE3, B9FS74, C4JQN4, D3ZKV9, F4IAE9, K7WCC7, O23702, O43236, O46080, P09758, P28661, P54816, Q0JGK4, Q13574, Q2QNS6, Q3HRN7, Q4R4X5, Q53JI9, Q552Z6, Q5I3B1, Q5R6R7, Q67WN8, Q6DN07, Q6GZW6, Q6P9Z6, Q6YYZ1, Q6Z690, Q753S8, Q758T2

Diamond homologs: A0JN54, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D3YWQ0, D3ZEY4, F1MAB7, O08560, O75912, O88673, P0CM54, P0CM55, P20192, P23743, P25296, P34057, P34125, P35243, P49619, P49620, P49621, P51556, P52429, P52824, P87072, Q01583, Q03603, Q09103, Q10024, Q13574, Q39017, Q6BWS8, Q6CGE6, Q6DT37, Q6FLU4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCA	unknown	DGKZ	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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
Ras activation upon Ca2+ influx through NMDA receptor	5	35.2×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	33.6×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	33.6×	1e-05
Assembly and cell surface presentation of NMDA receptors	10	31.3×	8e-11
Dopamine Neurotransmitter Release Cycle	5	30.6×	2e-05
Long-term potentiation	5	29.4×	2e-05
Neurexins and neuroligins	11	26.7×	7e-11
Protein-protein interactions at synapses	7	22.9×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	55.1×	2e-14
receptor clustering	8	43.0×	3e-09
protein localization to synapse	6	39.6×	1e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	8	34.2×	2e-08
positive regulation of receptor internalization	5	30.3×	4e-05
establishment of cell polarity	5	16.5×	7e-04
bicellular tight junction assembly	5	14.2×	1e-03
cell-cell adhesion	11	9.6×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	316
Likely benign	187
Benign	33

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
431728	NM_001199267.2(DGKZ):c.162-921dup	Pathogenic

SpliceAI

5076 predictions. Top by Δscore:

Variant	Effect	Δscore
11:46367286:TCTA:T	acceptor_loss	1.0000
11:46367288:TA:T	acceptor_loss	1.0000
11:46367289:A:AG	acceptor_gain	1.0000
11:46367289:AG:A	acceptor_gain	1.0000
11:46367290:G:A	acceptor_loss	1.0000
11:46367290:G:GG	acceptor_gain	1.0000
11:46367290:GG:G	acceptor_gain	1.0000
11:46367290:GGA:G	acceptor_gain	1.0000
11:46367290:GGAA:G	acceptor_gain	1.0000
11:46367290:GGAAA:G	acceptor_gain	1.0000
11:46367395:GGAGC:G	donor_gain	1.0000
11:46367396:GAGC:G	donor_gain	1.0000
11:46367396:GAGCG:G	donor_gain	1.0000
11:46367398:GC:G	donor_gain	1.0000
11:46367400:G:GG	donor_gain	1.0000
11:46367645:T:TA	acceptor_gain	1.0000
11:46367646:G:A	acceptor_gain	1.0000
11:46367647:GCTA:G	acceptor_loss	1.0000
11:46367650:A:AG	acceptor_gain	1.0000
11:46367651:G:A	acceptor_loss	1.0000
11:46367651:G:GG	acceptor_gain	1.0000
11:46367651:GGA:G	acceptor_gain	1.0000
11:46367748:G:GG	donor_gain	1.0000
11:46367997:TGCA:T	acceptor_loss	1.0000
11:46367998:GCAG:G	acceptor_loss	1.0000
11:46367999:CA:C	acceptor_loss	1.0000
11:46368000:A:AG	acceptor_gain	1.0000
11:46368001:G:GA	acceptor_gain	1.0000
11:46368001:GC:G	acceptor_gain	1.0000
11:46368001:GCA:G	acceptor_gain	1.0000

AlphaMissense

6064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:46367679:T:A	W100R	1.000
11:46367679:T:C	W100R	1.000
11:46367709:T:C	C110R	1.000
11:46367710:G:A	C110Y	1.000
11:46367711:C:G	C110W	1.000
11:46367732:T:G	C117W	1.000
11:46368026:T:C	C130R	1.000
11:46368028:C:G	C130W	1.000
11:46368035:T:C	C133R	1.000
11:46368036:G:A	C133Y	1.000
11:46368059:T:C	C141R	1.000
11:46368061:C:G	C141W	1.000
11:46369506:T:C	C152R	1.000
11:46369507:G:A	C152Y	1.000
11:46369508:T:G	C152W	1.000
11:46369956:C:G	H172D	1.000
11:46369962:T:A	W174R	1.000
11:46369962:T:C	W174R	1.000
11:46369963:G:C	W174S	1.000
11:46369964:G:C	W174C	1.000
11:46369964:G:T	W174C	1.000
11:46369992:T:A	C184S	1.000
11:46369992:T:C	C184R	1.000
11:46369993:G:C	C184S	1.000
11:46369994:T:G	C184W	1.000
11:46370001:T:C	C187R	1.000
11:46370002:G:A	C187Y	1.000
11:46370003:T:G	C187W	1.000
11:46371356:C:A	A204D	1.000
11:46371364:T:C	C207R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002643 (11:46380726 C>A,T), RS1000018838 (11:46342300 T>A,C), RS1000059396 (11:46375070 G>C,T), RS1000097772 (11:46351619 C>G), RS1000258452 (11:46341981 C>A,T), RS1000269356 (11:46380390 T>A,G), RS1000283590 (11:46354127 G>C), RS1000355309 (11:46353912 C>A,G,T), RS1000419131 (11:46354385 G>A,C), RS1000480797 (11:46346363 C>T), RS1000513074 (11:46346159 A>G), RS1000596637 (11:46367225 A>C,G), RS1000596744 (11:46348136 G>A), RS1000806613 (11:46334756 T>A), RS1000847024 (11:46341236 T>C)

Disease associations

OMIM: gene MIM:601441 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (1): autism (MONDO:0005260)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000763_2	Immunoglobulin A	2.000000e-06
GCST004521_122	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004946_84	Schizophrenia	7.000000e-12
GCST006268_465	Reaction time	2.000000e-09
GCST006803_20	Schizophrenia	3.000000e-13
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST010989_97	Body size at age 10	5.000000e-10
GCST90000046_4	Age at first sexual intercourse	9.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0008393	reaction time measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4105942 (SINGLE PROTEIN), CHEMBL4630754 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Diacylglycerol kinases

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

Ligand	Action	Affinity	Parameter
BMS-502	Inhibition	8.68	pIC50
alcudacigib	Inhibition	8.05	pIC50

Binding affinities (BindingDB)

549 measured of 589 human assays (589 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US20250223301, Compound 39	IC50	1 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-2,5-diethyl-4-[(1S)-1-(4-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	1 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-(7-((2S,5R)-2,5-diethyl-4-(1-(7-fluorobenzo[d]thiazol-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	1.6 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
6-chloro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-7-(oxolan-3-yloxy)quinazolin-2-one	IC50	2 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-5-ethyl-2-methyl-4-[(1S)-1-(4-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	2 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
5-[(2S,5R)-2,5-diethyl-4-[1-(4-methylphenyl)propyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a][1,5]naphthyridine-7-carbonitrile	IC50	2 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 41	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 42	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 43	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 115	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250215014, Compound 119	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
4-[(2S,5R)-4-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-(4-methylphenyl)methyl]-2,5-diethylpiperazin-1-yl]-1-methyl-2-oxopyrido[3,2-d]pyrimidine-6-carbonitrile	IC50	3 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-(7-((2S,5R)-4-(1-(3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2,5-dimethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile	IC50	3 nM	US-20250353858: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
US20250223301, Compound 23	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
(4R,7S)-4-ethyl-12-methyl-11-oxo-5-[1-[4-(trifluoromethyl)phenyl]propyl]-9-oxa-2,5,12,17-tetrazatetracyclo[8.8.0.02,7.013,18]octadeca-1(10),13(18),14,16-tetraene-16-carbonitrile	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-5-ethyl-2-methyl-4-[1-(4-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
6-chloro-4-[(2R,4R)-2-ethyl-4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-1-methyl-7-(oxolan-3-yloxy)quinazolin-2-one	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
4-[(2S,5R)-4-[(S)-(4-cyclopropyl-1,3-thiazol-2-yl)-[4-(pentafluoro-lambda6-sulfanyl)phenyl]methyl]-2,5-diethylpiperazin-1-yl]-1-methyl-2-oxopyrido[3,2-d]pyrimidine-6-carbonitrile	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-2,5-diethyl-4-[(1S)-1-(3-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	4 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-[7-[(2S,5R)-2,5-diethyl-4-[1-(4-fluoro-2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl]-4-methyl-5-oxopyrazolo[4,3-b]pyridin-2-yl]acetonitrile	IC50	4 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
US20250223301, Compound 22	IC50	5 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 46	IC50	5 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-2,5-diethyl-4-[(1R)-1-(4-methylphenyl)ethyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	5 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-2,5-diethyl-4-[(1S)-1-(4-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	5 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
6-chloro-4-[(2R,4S)-2-ethyl-4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-1-methyl-7-(oxolan-3-yloxy)quinazolin-2-one	IC50	5 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-[7-[(2S,5R)-4-[1-(3,3-dimethyl-2H-1,4-benzodioxin-6-yl)ethyl]-2,5-dimethylpiperazin-1-yl]-4-methyl-5-oxopyrazolo[1,5-a]pyrimidin-2-yl]acetonitrile	IC50	5 nM	US-20250353858: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
US20250223301, Compound 109	IC50	6 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 110	IC50	6 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
8-[(2S,5R)-5-ethyl-2-methyl-4-[(1R)-1-(4-methylphenyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	6 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
(4R,7S)-4-ethyl-12-methyl-11-oxo-5-[(1R)-1-[4-(trifluoromethyl)phenyl]propyl]-9-oxa-2,5,12,17-tetrazatetracyclo[8.8.0.02,7.013,18]octadeca-1(10),13(18),14,16-tetraene-16-carbonitrile	IC50	6 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile	IC50	6 nM	US-20250353858: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(7-((2S,5R)-2,5-diethyl-4-(1-(6-(2-fluoropropan-2-yl)pyridin-3-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	6.4 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(7-((2S,5R)-5-ethyl-4-(1-(7-fluoro-2-methylbenzo[d]thiazol-6-yl)ethyl)-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	6.5 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
8-[(2S,5R)-2,5-diethyl-4-[(1S)-1-(6-methyl-3-pyridinyl)propyl]piperazin-1-yl]-2,4,5,7,10-pentazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene-11-carbonitrile	IC50	7 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-(7-((2S,5R)-2,5-diethyl-4-(1-(3-methylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	7.5 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-[7-[(2S,5R)-2,5-diethyl-4-[1-(6-fluoro-3,3-dimethyl-2H-1,4-benzodioxin-7-yl)ethyl]piperazin-1-yl]-4-methyl-5-oxopyrazolo[4,3-b]pyridin-2-yl]acetonitrile	IC50	7.8 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(7-((2S,5R)-2,5-dimethyl-4-(1-(3-methylquinoxalin-6-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-2-yl)acetonitrile	IC50	8.2 nM	US-20250353858: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(7-((2S,5R)-2,5-diethyl-4-(1-(thiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	8.6 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(4-((2S,5R)-2,5-diethyl-4-(1-(2-methylthiazolo[5,4-b]pyridin-5-yl)ethyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrazolo[1,5-a][1,3,5]triazin-7-yl)acetonitrile	IC50	8.7 nM	US-20250353858: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(N-[5-[4-[2-[2-(1-adamantyl)ethylamino]-2-oxoethoxy]benzoyl]-4-amino-1,3-thiazol-2-yl]-4-fluoroanilino)propanamide	IC50	8.79 nM	US-11964953: Substituted aminothiazoles as DGKzeta inhibitors for immune activation
2-(7-((2S,5R)-4-(1-(3-chloroimidazo[1,2-b]pyridazin-6-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl)acetonitrile	IC50	8.9 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
US20250223301, Compound 84	IC50	9 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250215014, Compound 107	IC50	9 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
6-chloro-1-methyl-4-[4-(5-methyl-1,3-benzoxazol-2-yl)piperidin-1-yl]-7-(oxolan-3-yloxy)quinazolin-2-one	IC50	9 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
4-[(2S,5R)-4-[(S)-(4-cyclopropyl-1,3-thiazol-2-yl)-(4-methylphenyl)methyl]-2,5-diethylpiperazin-1-yl]-1-methyl-2-oxopyrido[3,2-d]pyrimidine-6-carbonitrile	IC50	9 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
5-[(2S,5R)-2,5-diethyl-4-[1-(4-methylphenyl)propyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a][1,5]naphthyridine-7-carbonitrile	IC50	9 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
2-(7-((2S,5R)-4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)-2,5-diethylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	9 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
2-(7-((2S,5R)-4-(1-(benzo[d]thiazol-6-yl)ethyl)-5-ethyl-2-methylpiperazin-1-yl)-4-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridin-2-yl)acetonitrile	IC50	9.1 nM	US-20250346597: CONDENSED HETEROCYCLIC COMPOUNDS AS INHIBITOR OF DIACYLGLYCEROL KINASES
US20250223301, Compound 64	IC50	10 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF
US20250223301, Compound 74	IC50	10 nM	US-20250223301: KINASE INHIBITORS, PREPARATION METHODS AND USES THEREOF

ChEMBL bioactivities

405 potent at pChembl≥5 of 436 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5424446
8.70	IC50	2	nM	CHEMBL5768187
8.40	IC50	4	nM	CHEMBL6044573
8.40	IC50	4	nM	CHEMBL5851336
8.22	IC50	6	nM	CHEMBL5921368
8.02	IC50	9.6	nM	CHEMBL4633304
8.00	IC50	10	nM	CHEMBL5868935
7.96	IC50	11	nM	CHEMBL5860953
7.92	IC50	12	nM	CHEMBL5828405
7.89	IC50	13	nM	CHEMBL5931568
7.89	IC50	13	nM	CHEMBL5906768
7.85	IC50	14	nM	CHEMBL5996929
7.85	IC50	14	nM	CHEMBL5916345
7.85	IC50	14	nM	CHEMBL5941027
7.80	IC50	16	nM	CHEMBL5858446
7.77	IC50	17	nM	CHEMBL5798900
7.77	IC50	17	nM	CHEMBL5973282
7.77	IC50	17	nM	CHEMBL5973971
7.75	IC50	18	nM	CHEMBL5762768
7.75	IC50	18	nM	CHEMBL5824753
7.75	IC50	18	nM	CHEMBL5750453
7.68	IC50	21	nM	CHEMBL5894838
7.68	IC50	21	nM	CHEMBL5915810
7.68	IC50	21	nM	CHEMBL5887438
7.68	IC50	21	nM	CHEMBL5988633
7.66	IC50	22	nM	CHEMBL6050801
7.66	IC50	22	nM	CHEMBL5794331
7.66	IC50	22	nM	CHEMBL5755234
7.66	IC50	22	nM	CHEMBL5900198
7.66	IC50	22	nM	CHEMBL5953259
7.66	IC50	22	nM	CHEMBL5995415
7.64	IC50	23	nM	CHEMBL5816364
7.64	IC50	23	nM	CHEMBL5900061
7.60	IC50	25	nM	CHEMBL5771377
7.58	IC50	26	nM	CHEMBL4648848
7.58	IC50	26	nM	CHEMBL5757875
7.57	IC50	27	nM	CHEMBL5793843
7.55	IC50	28	nM	CHEMBL4647083
7.55	IC50	28	nM	CHEMBL5828074
7.55	IC50	28	nM	CHEMBL5955850
7.55	IC50	28	nM	CHEMBL5754718
7.54	IC50	29	nM	CHEMBL5948984
7.54	IC50	29	nM	CHEMBL5849375
7.51	IC50	31	nM	CHEMBL5742891
7.51	IC50	31	nM	CHEMBL5990111
7.50	IC50	32	nM	CHEMBL5950211
7.48	IC50	33	nM	CHEMBL6028934
7.48	IC50	33	nM	CHEMBL5816364
7.48	IC50	33	nM	CHEMBL5849375
7.48	IC50	33	nM	CHEMBL5816604

PubChem BioAssay actives

23 with measured affinity, of 34 total; 10 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
8-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-5-methyl-7-nitro-6-oxo-1,5-naphthyridine-2-carbonitrile	2010064: Inhibition of human DGK zeta using 1, 2-Dilauroyl-sn-glycerol as substrate by ADP-Glo kinase assay	ic50	0.0020	uM
8-[(3R)-4-[(4-chlorophenyl)-phenylmethyl]-3-methylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2,7-dicarbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.0096	uM
8-[(2S,5R)-4-[(2-fluorophenyl)-(4-fluorophenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.0260	uM
8-[(3R)-4-[bis(4-chlorophenyl)methyl]-3-methylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2,7-dicarbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.0280	uM
8-[(2S,5R)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.0390	uM
8-[(2S,5R)-4-[bis(4-fluorophenyl)methyl]-2,5-dimethylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.0430	uM
8-[(2R)-4-[bis(4-fluorophenyl)methyl]-2-ethylpiperazin-1-yl]-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	0.1900	uM
8-[(3S)-4-[bis(4-fluorophenyl)methyl]-3-methylpiperazin-1-yl]-7-chloro-5-methyl-6-oxo-1,5-naphthyridine-2-carbonitrile	1658256: Inhibition of DGKA/DGKZ in human CD8 cells assessed as induction of CD8 activation by measuring IFNgamma level after 20 hrs by AlphaLISA assay	ic50	1.2000	uM
4-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-1-methyl-3-nitro-1,5-naphthyridin-2-one	2010064: Inhibition of human DGK zeta using 1, 2-Dilauroyl-sn-glycerol as substrate by ADP-Glo kinase assay	ic50	2.7000	uM
4-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-1-methyl-3-nitro-2-oxoquinoline-6-carbonitrile	2010064: Inhibition of human DGK zeta using 1, 2-Dilauroyl-sn-glycerol as substrate by ADP-Glo kinase assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	3
Valproic Acid	increases methylation, affects expression, increases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Acetaminophen	increases expression	2
Arsenic	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases methylation, affects cotreatment	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
beta-lapachone	increases expression, decreases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	decreases methylation	1
cupric chloride	increases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Caffeine	increases phosphorylation	1
Camptothecin	decreases response to substance	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lead	affects methylation	1
Methapyrilene	decreases methylation	1
Pesticides	affects methylation	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4015090	Binding	Inhibition of human DGKzeta (1 to 929 residues) by ADP Glo HTS assay	Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7NP	Ubigene A-549 DGKZ KO	Cancer cell line	Male
CVCL_D8K2	Ubigene HCT 116 DGKZ KO	Cancer cell line	Male
CVCL_D9DC	Ubigene HEK293 DGKZ KO	Transformed cell line	Female
CVCL_E0BQ	Ubigene HeLa DGKZ KO	Cancer cell line	Female
CVCL_E0WH	Ubigene Jurkat, Clone E6-1 DGKZ KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms