PDK4

Summary

PDK4 (pyruvate dehydrogenase kinase 4, HGNC:8812) is a protein-coding gene on chromosome 7q21.3, encoding [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial (Q16654). Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2.

This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin.

Source: NCBI Gene 5166 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 72 total
• Druggable target: yes
• MANE Select transcript: NM_002612

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8812
Approved symbol	PDK4
Name	pyruvate dehydrogenase kinase 4
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000004799
Ensembl biotype	protein_coding
OMIM	602527
Entrez	5166

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 4 retained_intron

ENST00000005178, ENST00000468445, ENST00000473301, ENST00000473796, ENST00000498190, ENST00000886049, ENST00000886050, ENST00000886051, ENST00000943768, ENST00000943769, ENST00000943770, ENST00000943771, ENST00000943772, ENST00000943773, ENST00000943774

RefSeq mRNA: 1 — MANE Select: NM_002612 NM_002612

CCDS: CCDS5643

Canonical transcript exons

ENST00000005178 — 11 exons

Exon	Start	End
ENSE00000706266	95592511	95592597
ENSE00000706268	95592760	95592944
ENSE00000706269	95593699	95593770
ENSE00000706270	95595023	95595164
ENSE00001133344	95596164	95596516
ENSE00001267271	95583499	95585781
ENSE00003551716	95587418	95587528
ENSE00003624438	95587727	95587825
ENSE00003662285	95591988	95592065
ENSE00003670922	95589640	95589716
ENSE00003687176	95587010	95587123

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.0129 / max 12965.8185, expressed in 923 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84979	72.4770	872
84976	0.6605	136
84974	0.5848	168
84975	0.3252	112
84983	0.2142	97
84968	0.1974	78
84977	0.1751	64
84978	0.1596	65
84981	0.0826	32
84966	0.0447	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	99.81	gold quality
mucosa of stomach	UBERON:0001199	99.73	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.60	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.45	gold quality
pericardium	UBERON:0002407	99.40	gold quality
heart right ventricle	UBERON:0002080	99.36	gold quality
right lung	UBERON:0002167	99.20	gold quality
diaphragm	UBERON:0001103	99.18	gold quality
left adrenal gland cortex	UBERON:0035825	99.07	gold quality
adrenal cortex	UBERON:0001235	99.03	gold quality
tibialis anterior	UBERON:0001385	99.00	gold quality
left adrenal gland	UBERON:0001234	98.97	gold quality
gastrocnemius	UBERON:0001388	98.94	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.89	gold quality
omental fat pad	UBERON:0010414	98.87	gold quality
peritoneum	UBERON:0002358	98.86	gold quality
jejunal mucosa	UBERON:0000399	98.82	gold quality
right adrenal gland cortex	UBERON:0035827	98.81	gold quality
right ovary	UBERON:0002118	98.80	gold quality
right adrenal gland	UBERON:0001233	98.77	gold quality
left ovary	UBERON:0002119	98.74	gold quality
adrenal gland	UBERON:0002369	98.62	gold quality
adipose tissue	UBERON:0001013	98.52	gold quality
muscle of leg	UBERON:0001383	98.19	gold quality
connective tissue	UBERON:0002384	98.18	gold quality
body of pancreas	UBERON:0001150	98.17	gold quality
islet of Langerhans	UBERON:0000006	98.11	gold quality
superficial temporal artery	UBERON:0001614	98.10	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.05	gold quality
tibial nerve	UBERON:0001323	98.03	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	3193.61
E-ENAD-27	yes	1659.30
E-HCAD-38	yes	1572.60
E-GEOD-81608	yes	1523.99
E-MTAB-10287	yes	37.38
E-HCAD-31	yes	30.15
E-CURD-46	yes	26.83
E-MTAB-8410	yes	22.06
E-HCAD-9	yes	18.20
E-MTAB-10137	yes	9.35
E-CURD-10	no	1109.82
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL3, CEBPB, CREBZF, E2F1, ESRRA, ESRRG, FLCN, FOXO1, FOXO3, HAND2, HNF4A, NCOR1, NFKB1, NFKB, NR0B2, NR1H4, NR3C1, PPARA, PPARD, PPARG, RELA, SIRT1, SP1, STAT5A

miRNA regulators (miRDB)

116 targeting PDK4, 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-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3163	100.00	77.23	8605
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-3667-3P	99.99	67.17	1636
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-205-3P	99.92	69.92	3165

Literature-anchored findings (GeneRIF, showing 40)

• The expression of the pyruvate dehydrogenase kinase 4 was downregulated in the failing heart. (PMID:12145475)
• results support the concept that a reduced tissue availability of fatty acids consequent to a massive lipid malabsorption influences glucose metabolism acting through the regulation of pyruvate dehydrogenase kinase 4 (PMID:12582211)
• mRNA levels are increased in skeletal muscle during fasting (PMID:14966024)
• Expression of constitutively active PKB alpha abrogates dexamethasone stimulation of hPDK4 promoter activity. (PMID:15047604)
• Gene expression regulation is affected by retinoic acid and histone acetyation (review). (PMID:15581486)
• activation of FXR may suppress glycolysis and enhance oxidation of fatty acids via inactivation of the pyruvate dehydrogenase complex by increasing PDK4 expression (PMID:15721319)
• in human muscle, hormonal and nutritional conditions may control PDK2 and PDK4 mRNA expression via a common signalling mechanism. (PMID:15955060)
• retinoic acids (RA) as well as Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), regulate PDK4 gene expression (PMID:16757381)
• Accumulation of im lipids plays a more important role than impaired activation of Akt-mediated pathways in the regulation of muscle PDK4 gene expression in lipid-induced acute insulin-resistant states (PMID:17652214)
• PDK2, PDK3 and PDK4 are primary PPARbeta/delta target genes in humans underlining the importance of the receptor in the control of metabolism (PMID:17669420)
• PDK4 upregulation in adipocytes participates in the hypolipidemic effect of thiazolidinediones through modulation of glyceroneogenesis (PMID:18519799)
• PDK4 with bound ADP exists in equilibrium between the open and the closed conformations (PMID:18658136)
• PDK4 gene is downregulated in colic adenocarcinoma. (PMID:20715114)
• Data show that overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner. (PMID:21852536)
• mRNA of PGC-1alpha and PDK4 increases markedly in both type I and type II skeletal muscle after either continuous or interval exercise (PMID:21883960)
• The present structures demonstrate the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4. (PMID:21904029)
• PDK4 polymorphisms may not be associated with type 2 diabetes or metabolic syndrome. (PMID:22019269)
• Data show that the orphan nuclear receptor estrogen related receptor gamma (ERRgamma) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. (PMID:23050013)
• Methylation increased in PDK4, IL1 B, IL6, and TNF promoters 12 months after gastric bypass. (PMID:24837562)
• PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade. (PMID:25164809)
• Fatty acids induce the expression of PDK4 mRNA, which was increased in myotubes cultured from obese and T2DM donors. (PMID:25311062)
• ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression (PMID:25609694)
• Swiss PDB Viewer identifies NFkappaB subunit p100/p49 as a potential interacting partner for PDK4. Relationship between PDK4 and apoptosis is suggested. (PMID:25794976)
• High PDK4 expression is associated with hepatocellular cancer. (PMID:26506419)
• upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification. (PMID:26560812)
• FXR may promote the proliferation of tumor cells and the hepatocytes in the process of liver regeneration by activating the PDK4-mediated metabolic reprogramming to generate glycolytic intermediates essential for rapid biomass generation, establishing a mechanistic link between cell proliferation and metabolic switch. (PMID:26728993)
• Inhibition of CK2 increased the expression of metabolic regulators, PDK4 and AMPK along with the key cellular energy sensor CREB. (PMID:27001465)
• Results show that PDK4-specific 5’UTR DNA methylation is positively associated with eicosapentaenoic and arachidonic acid in adult males. (PMID:27181711)
• We found that PDK4 gene and protein expression was significantly elevated in pulmonary arterial hypertension pericytes and correlated with reduced mitochondrial metabolism, higher rates of glycolysis, and hyperproliferation (PMID:27456128)
• Combined speed endurance and endurance exercise amplify the exercise-induced PGC-1alpha and PDK4 mRNA response in trained human muscle. (PMID:27456910)
• Low PDK4 expression is associated with lung tumorigenesis. (PMID:27641336)
• inhibition of PDK4 activity in Hepatocellular carcinoma cells increased cyclin E1, cyclin A2, and E2F1 proteins. (PMID:28003426)
• Increased PDK4 expression is associated with colon cancer. (PMID:28208156)
• it was found that low expression of FAM210B was significantly correlated with decreased survival and enhanced metastasis in vivo and in vitro, and the loss of FAM210B led to an increased mitochondrial respiratory capacity and reduced glycolysis through the downregulation of pyruvate dehydrogenase kinase 4 (PDK4). (PMID:28594398)
• down-regulation of PDK4 is critical for the metabolic shift from glycolysis to oxidative phosphorylation during syncytialization, which may be a prerequisite for the proper implementation of syncytiotrophoblast functions (PMID:28814762)
• In conclusion, our data indicated that PDK4 potentially contributes to the hepatic steatosis in NASH via regulating several signaling pathway and PDK4 may be a new therapeutic strategy against NAFLD. (PMID:29128353)
• miR-15b-5p acted as a tumor suppressor in osteosarcoma by directly targeting PDK4 and inhibiting its expression. (PMID:30093112)
• Up-regulation of miR-23a played an important role in colorectal cancer cell proliferation through direct repressing PDK4. (PMID:30342991)
• lncRNA PCAT19 promotes the proliferation of laryngocarcinoma cells via modulation of the miR-182/PDK4 axis. (PMID:30868666)
• Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease. (PMID:31099942)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdk4	ENSDARG00000054848
mus_musculus	Pdk4	ENSMUSG00000019577
rattus_norvegicus	Pdk4	ENSRNOG00000009565
drosophila_melanogaster	Pdk	FBGN0017558
caenorhabditis_elegans		WBGENE00022719

Paralogs (4): PDK2 (ENSG00000005882), PDK3 (ENSG00000067992), BCKDK (ENSG00000103507), PDK1 (ENSG00000152256)

Protein

Protein identifiers

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial — Q16654 (reviewed: Q16654)

Alternative names: Pyruvate dehydrogenase kinase isoform 4

All UniProt accessions (2): Q16654, A4D1H4

UniProt curated annotations — full annotation on UniProt →

Function. Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.

Subunit / interactions. Homodimer. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3).

Subcellular location. Mitochondrion matrix.

Tissue specificity. Ubiquitous; highest levels of expression in heart and skeletal muscle.

Induction. Up-regulated by prolonged fasting, in glucose-deprived cells and in response to a high-fat diet. Down-regulated by insulin. Up-regulated by PPARD.

Similarity. Belongs to the PDK/BCKDK protein kinase family.

RefSeq proteins (1): NP_002603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003594	HATPase_dom	Domain
IPR005467	His_kinase_dom	Domain
IPR018955	BCDHK/PDK_N	Domain
IPR036784	AK/P_DHK_N_sf	Homologous_superfamily
IPR036890	HATPase_C_sf	Homologous_superfamily
IPR039028	BCKD/PDK	Family

Pfam: PF02518, PF10436

Enzyme classification (BRENDA):

• EC 2.7.11.2 — [pyruvate dehydrogenase (acetyl-transferring)] kinase (BRENDA: 19 organisms, 106 substrates, 260 inhibitors, 52 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.006–1.5	26
PYRUVATE DEHYDROGENASE	0.05–3.5	7
[PYRUVATE DEHYDROGENASE (ACETYL-TRANSFERRING)]	0.0006–0.02	6
MG2+	0.02	5
[PYRUVATE DEHYDROGENASE (LIPOAMIDE)]	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-seryl-[pyruvate dehydrogenase E1 alpha subunit] + ATP = O-phospho-L-seryl-[pyruvate dehydrogenase E1 alpha subunit] + ADP + H(+) (RHEA:23052)

UniProt features (46 total): helix 14, strand 10, turn 5, mutagenesis site 4, binding site 4, sequence variant 3, site 3, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
2E0A	X-RAY DIFFRACTION	1.86
7EBB	X-RAY DIFFRACTION	1.9
7EBG	X-RAY DIFFRACTION	1.95
2ZKJ	X-RAY DIFFRACTION	2
3D2R	X-RAY DIFFRACTION	2.03
7EAT	X-RAY DIFFRACTION	2.1
2ZDY	X-RAY DIFFRACTION	2.4
2ZDX	X-RAY DIFFRACTION	2.54

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16654-F1	89.68	0.78

Functional residue map

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

Catalytic / active sites (3): 157 (interaction with the other subunit in the homodimer); 161 (interaction with the other subunit in the homodimer); 395 (interaction with the other subunit in the homodimer)

Ligand- & substrate-binding residues (4): 254–261; 293; 312–313; 329–334

Mutagenesis-validated functional residues (4):

Position	Phenotype
157	loss of activity.
161	loss of activity.
394	loss of activity; when associated with a-395.
395	loss of activity; when associated with a-394.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

MSigDB gene sets: 354 (showing top): GOBP_LIPID_MODIFICATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, WALLACE_PROSTATE_CANCER_RACE_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS

GO Biological Process (15): regulation of pH (GO:0006885), insulin receptor signaling pathway (GO:0008286), cellular response to starvation (GO:0009267), regulation of pyruvate decarboxylation to acetyl-CoA (GO:0010510), regulation of ketone metabolic process (GO:0010565), regulation of glucose metabolic process (GO:0010906), regulation of fatty acid biosynthetic process (GO:0042304), glucose homeostasis (GO:0042593), response to starvation (GO:0042594), regulation of bone resorption (GO:0045124), regulation of fatty acid oxidation (GO:0046320), cellular response to fatty acid (GO:0071398), cellular response to stress (GO:0033554), reactive oxygen species metabolic process (GO:0072593), negative regulation of anoikis (GO:2000811)

GO Molecular Function (7): protein kinase activity (GO:0004672), pyruvate dehydrogenase (acetyl-transferring) kinase activity (GO:0004740), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of fatty acid metabolic process	2
response to stress	2
monoatomic cation homeostasis	1
biological regulation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
pyruvate decarboxylation to acetyl-CoA	1
regulation of acyl-CoA biosynthetic process	1
regulation of metabolic process	1
ketone metabolic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
fatty acid biosynthetic process	1
regulation of lipid biosynthetic process	1
carbohydrate homeostasis	1
response to nutrient levels	1
bone resorption	1
regulation of bone remodeling	1
fatty acid oxidation	1
response to fatty acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular response to stimulus	1
metabolic process	1
negative regulation of apoptotic process	1
anoikis	1
regulation of anoikis	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1

Protein interactions and networks

STRING

4040 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDK4	HSPA9	P30036	902
PDK4	VDAC1	P21796	821
PDK4	ITPR1	Q14643	821
PDK4	ITPR3	Q14573	818
PDK4	INS	P01308	777
PDK4	PPARGC1A	Q9UBK2	764
PDK4	SLC2A4	P14672	749
PDK4	PPARA	Q07869	738
PDK4	UCP3	P55916	735
PDK4	CPT1B	Q92523	708
PDK4	ANGPTL4	Q9BY76	708
PDK4	PPARD	Q03181	703
PDK4	PDP2	Q9P2J9	692
PDK4	IRS1	P35568	660
PDK4	CPT1A	P50416	640

IntAct

15 interactions, top by confidence:

A	B	Type	Score
PDK4	PDK2	psi-mi:“MI:0914”(association)	0.640
PDK4	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
DOK2	NCK2	psi-mi:“MI:0914”(association)	0.530
PDK4	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDHA1	PDK4	psi-mi:“MI:0844”(phosphotransfer reaction)	0.440
PDK4	THRAP3	psi-mi:“MI:0915”(physical association)	0.400
PDK4		psi-mi:“MI:0914”(association)	0.350
PDK3	HSP90AA1	psi-mi:“MI:0914”(association)	0.350
PDK4	CNOT1	psi-mi:“MI:0914”(association)	0.350
PDK4	PDK1	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
PDK4	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.000
PDK4		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (56): PDK2 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), PLEKHF2 (Two-hybrid), THRAP3 (Proximity Label-MS), PDK2 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), PDK4 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), NARS2 (Affinity Capture-MS), PDK4 (Two-hybrid), PDK4 (Affinity Capture-MS), CNOT1 (Affinity Capture-MS), AIP (Affinity Capture-MS)

ESM2 similar proteins: B6JWC1, B9FK36, O01757, O02623, O14874, O42895, O54937, O55028, O70571, O88345, P36617, P37221, P37224, P37225, P39864, P40530, P48009, P78820, P78875, P78963, P91622, Q00972, Q02332, Q09116, Q10299, Q15118, Q15119, Q15120, Q16654, Q17828, Q1KMR4, Q2KJG8, Q38970, Q61SU7, Q63065, Q64536, Q8BFP9, Q8S6N5, Q922H2, Q9BGQ3

Diamond homologs: A0A0H2ZNH9, A0QR01, A1A699, A3PDI2, A5A2P0, A5INR0, A6QD58, A6TXG9, A7WWQ7, A8YYU2, O34638, O69729, O88345, P0A4I5, P0A4I6, P0A601, P23545, P30847, P35164, P39664, P54576, P54883, P73276, P94414, P94608, P9WGK4, P9WGK5, Q04943, Q16654, Q1KMR4, Q2FH24, Q2FKN7, Q2G2U4, Q2YUQ2, Q2YY04, Q31AE8, Q45614, Q49XM6, Q49ZT9, Q4A159

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
PDK4	down-regulates	PDHA2	phosphorylation
PDK4	down-regulates	PDHA1	phosphorylation
PDK4	“down-regulates activity”	PC	phosphorylation
PDK4	“down-regulates activity”	PDHA1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

789 predictions. Top by Δscore:

Variant	Effect	Δscore
7:95585777:AAAGC:A	acceptor_gain	1.0000
7:95585778:AAGC:A	acceptor_gain	1.0000
7:95585780:GC:G	acceptor_gain	1.0000
7:95585781:CC:C	acceptor_gain	1.0000
7:95585782:C:CC	acceptor_gain	1.0000
7:95585783:T:A	acceptor_loss	1.0000
7:95587005:GATAC:G	donor_loss	1.0000
7:95587006:ATAC:A	donor_loss	1.0000
7:95587007:TACCT:T	donor_loss	1.0000
7:95587008:A:AT	donor_loss	1.0000
7:95587039:AT:A	donor_gain	1.0000
7:95587119:CCAGC:C	acceptor_gain	1.0000
7:95587120:CAGCC:C	acceptor_gain	1.0000
7:95587124:C:CC	acceptor_gain	1.0000
7:95587412:TCTTA:T	donor_loss	1.0000
7:95587413:CTTAC:C	donor_loss	1.0000
7:95587414:TTAC:T	donor_loss	1.0000
7:95587415:TA:T	donor_loss	1.0000
7:95587416:A:AC	donor_gain	1.0000
7:95587416:ACC:A	donor_loss	1.0000
7:95587417:C:CA	donor_gain	1.0000
7:95587417:CCAA:C	donor_gain	1.0000
7:95587524:GAAAT:G	acceptor_gain	1.0000
7:95587526:AAT:A	acceptor_gain	1.0000
7:95587527:AT:A	acceptor_gain	1.0000
7:95587528:TC:T	acceptor_loss	1.0000
7:95587529:C:CC	acceptor_gain	1.0000
7:95587535:C:CT	acceptor_gain	1.0000
7:95587721:GGTTA:G	donor_loss	1.0000
7:95587722:GTTA:G	donor_loss	1.0000

AlphaMissense

2704 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:95589640:C:A	K257N	1.000
7:95589640:C:G	K257N	1.000
7:95593758:G:C	S95R	1.000
7:95593758:G:T	S95R	1.000
7:95593760:T:G	S95R	1.000
7:95587104:A:G	L334S	0.999
7:95587113:C:T	G331D	0.999
7:95587815:C:G	R261P	0.999
7:95587822:C:G	A259P	0.999
7:95589647:A:G	L255P	0.999
7:95589650:T:A	E254V	0.999
7:95589668:A:G	L248P	0.999
7:95592552:C:T	G192E	0.999
7:95592780:C:G	R170P	0.999
7:95592786:G:A	S168F	0.999
7:95592786:G:T	S168Y	0.999
7:95592792:C:G	R166P	0.999
7:95592807:C:G	R161P	0.999
7:95592880:C:G	G137R	0.999
7:95592880:C:T	G137R	0.999
7:95592930:A:G	L120P	0.999
7:95593756:A:G	L96P	0.999
7:95595098:G:T	A66D	0.999
7:95595099:C:G	A66P	0.999
7:95595103:T:A	R64S	0.999
7:95595103:T:G	R64S	0.999
7:95595104:C:G	R64T	0.999
7:95595105:T:C	R64G	0.999
7:95595127:A:C	F56L	0.999
7:95595127:A:T	F56L	0.999

dbSNP variants (sampled 300 via entrez): RS1000065458 (7:95588427 C>T), RS1000216785 (7:95589370 T>C), RS1000219296 (7:95595959 G>A), RS1000270274 (7:95595344 C>T), RS1000286675 (7:95596135 C>T), RS1000335690 (7:95596337 G>A), RS1000481111 (7:95587984 A>G), RS1000621137 (7:95594582 T>A), RS1000714090 (7:95588969 G>T), RS1000873074 (7:95583218 T>C), RS1000953195 (7:95587616 T>C), RS1001123300 (7:95589811 G>A,T), RS1001895452 (7:95594086 A>C), RS1002347790 (7:95593196 C>A,T), RS1002442622 (7:95592869 C>G,T)

Disease associations

OMIM: gene MIM:602527 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_258	Refractive error	8.000000e-13

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096665 (PROTEIN FAMILY), CHEMBL4141 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — PDHK family

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

Ligand	Action	Affinity	Parameter
VER-246608	Inhibition	7.04	pIC50

Binding affinities (BindingDB)

6 measured of 7 human assays (7 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
PA1	KD	6 nM
DC23	KD	25 nM
PA7	KD	27.3 nM
PS10	KD	47000 nM
PS2	KD	50900 nM
PS8	KD	60100 nM

ChEMBL bioactivities

506 potent at pChembl≥5 of 547 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL4591977
8.15	IC50	7.1	nM	CHEMBL73068
8.10	IC50	8	nM	CHEMBL4551410
8.10	IC50	8	nM	CHEMBL74582
8.08	IC50	8.4	nM	CHEMBL73204
8.00	IC50	10	nM	CHEMBL3718383
8.00	IC50	10	nM	CHEMBL3719344
8.00	IC50	10	nM	CHEMBL3717579
8.00	IC50	10	nM	CHEMBL3716924
8.00	IC50	10	nM	CHEMBL3716176
8.00	IC50	10	nM	CHEMBL3719004
8.00	IC50	10	nM	CHEMBL3715313
8.00	IC50	10	nM	CHEMBL3716404
8.00	IC50	10	nM	CHEMBL3719305
8.00	IC50	10	nM	CHEMBL3717052
8.00	IC50	10	nM	CHEMBL3715598
8.00	IC50	10	nM	CHEMBL3714928
8.00	IC50	10	nM	CHEMBL3717436
8.00	IC50	10	nM	CHEMBL3717459
8.00	IC50	10	nM	CHEMBL3717764
8.00	IC50	10	nM	CHEMBL3718319
8.00	IC50	10	nM	CHEMBL3717613
8.00	IC50	10	nM	CHEMBL3715330
8.00	IC50	10	nM	CHEMBL3715072
8.00	IC50	10	nM	CHEMBL3717025
8.00	IC50	10	nM	CHEMBL3715512
8.00	IC50	10	nM	CHEMBL3716740
8.00	IC50	10	nM	CHEMBL3715842
8.00	IC50	10	nM	CHEMBL3715757
8.00	IC50	10	nM	CHEMBL3717836
8.00	IC50	10	nM	CHEMBL3715049
8.00	IC50	10	nM	CHEMBL3715972
8.00	IC50	10	nM	CHEMBL3715771
8.00	IC50	10	nM	CHEMBL3716746
8.00	IC50	10	nM	CHEMBL3717827
8.00	IC50	10	nM	CHEMBL3717940
8.00	IC50	10	nM	CHEMBL3714889
8.00	IC50	10	nM	CHEMBL3717799
8.00	IC50	10	nM	CHEMBL3719348
8.00	IC50	10	nM	CHEMBL3715964
8.00	IC50	10	nM	CHEMBL3719035
8.00	IC50	10	nM	CHEMBL3719333
8.00	IC50	10	nM	CHEMBL3715044
8.00	IC50	10	nM	CHEMBL3719351
8.00	IC50	10	nM	CHEMBL3714823
8.00	IC50	10	nM	CHEMBL3716865
8.00	IC50	10	nM	CHEMBL3715674
8.00	IC50	10	nM	CHEMBL3717530
8.00	IC50	10	nM	CHEMBL75821
7.96	IC50	11	nM	CHEMBL4519504

PubChem BioAssay actives

179 with measured affinity, of 372 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(4-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0050	uM
(2R)-N-[2-chloro-4-(cyclopropylmethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0071	uM
(2R)-N-[2-chloro-4-(prop-2-enylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0080	uM
N-[(5-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0080	uM
(2R)-N-[4-[(3-aminocyclohexyl)sulfamoyl]-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0084	uM
(2R)-N-[2-chloro-4-(2-morpholin-4-ylethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0100	uM
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(5-iodofuran-2-yl)methyl]benzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0110	uM
5-[(3S,5S)-1-(8-cyclopropyl-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl]-1H-pyrrole-2-carboxylic acid	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0122	uM
N-[(5-bromofuran-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0130	uM
(2R)-N-[2-chloro-4-(2-methylpropylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0130	uM
(2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-4-phenylbutanoic acid	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0150	uM
(2R)-N-[2-chloro-4-[3-(2-oxopyrrolidin-1-yl)propylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0160	uM
(2R)-N-[4-[[4-(2-aminoethyl)phenyl]sulfonylsulfamoyl]-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0160	uM
4-[(2R,5S)-2,5-dimethyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carbonyl]benzonitrile	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0165	uM
5-[(3S,5S)-1-(8-cyclopropyl-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl]-1H-pyrrole-2-carboxamide	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0178	uM
(2R)-N-[2-chloro-4-(3-ethoxypropylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0190	uM
(2R)-N-[2-chloro-4-(pyridin-2-ylmethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0200	uM
(2R)-N-[2-chloro-4-(3,3-dimethylbutylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0200	uM
N-[(5-bromo-1,3-thiazol-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0200	uM
benzyl (2R)-2-methyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carboxylate	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0210	uM
N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-[[4-[[(2,2-difluoroacetyl)amino]methyl]phenyl]methyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0210	uM
(2R)-N-[4-(3-aminopyrrolidin-1-yl)sulfonyl-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0230	uM
N-[1-[5-(8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indol-3-yl)-1,3,4-oxadiazol-2-yl]-2-methylpropyl]-3-phenylpropanamide	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0241	uM
(2R)-N-[2-chloro-4-(3-hydroxypropylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0290	uM
(2R)-N-[2-chloro-4-[2-(dimethylamino)ethylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0320	uM
N-benzyl-3-[5-(8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indol-3-yl)-1,3,4-oxadiazol-2-yl]-4-methylpentanamide	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0329	uM
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(4-hydroxyphenyl)methyl]benzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0340	uM
sodium (2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-3-phenylpropanoate	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0340	uM
(2R)-N-[2-chloro-4-[2-(4-fluorophenyl)ethylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0350	uM
5-[(3S,5R)-1-(8-cyclopropyl-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-ethylpyrrolidin-3-yl]-1H-pyrrole-2-carboxylic acid	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0406	uM
3-chloro-N-(3-hydroxypropyl)-N-methyl-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0470	uM
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(5-methylfuran-2-yl)methyl]benzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0520	uM
N-[4-(dimethylcarbamoyl)phenyl]-N-[(4-fluorophenyl)methyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0520	uM
(2R)-N-(2-chloro-4-piperazin-1-ylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0550	uM
(2R)-N-[2-chloro-4-(diethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0610	uM
(3S)-3-[5-(8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indol-3-yl)-1,3,4-oxadiazol-2-yl]-4-methyl-N-[(1R)-1-phenylethyl]pentanamide	1833815: Inhibition of human recombinant PDHK4 co-complexed with porcine PDH using sodium pyruvate, coenzymeA and NAD as substrates preincubated with enzyme complex for 45 mins followed by substrates addition and further incubated for 90 mins in presence of ATP at Km concentration by spectrophotometric assay	ic50	0.0615	uM
(2R)-N-[2-chloro-4-[3-(diethylamino)propylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0660	uM
N-benzyl-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0660	uM
N-[4-(dimethylcarbamoyl)phenyl]-N-(furan-2-ylmethyl)-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0690	uM
(2R)-N-(2-chloro-4-methylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0700	uM
(2R)-N-[2-chloro-4-(4-pyridin-2-ylpiperazin-1-yl)sulfonylphenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0730	uM
3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzenesulfonyl fluoride	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0770	uM
(2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-3-(4-phenylphenyl)propanoic acid	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0770	uM
3-chloro-4-[(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)amino]benzenesulfonyl fluoride	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0770	uM
4-[(2R)-2-methyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carbonyl]benzonitrile	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0790	uM
(2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropan-1-one	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0820	uM
N-[(5-chlorofuran-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0820	uM
1-(1-piperidin-4-ylpyrazol-4-yl)anthracene-9,10-dione;hydrochloride	1536189: Inhibition of PDK4 (unknown origin)	ic50	0.0840	uM
3-chloro-N-(3-hydroxypropyl)-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0870	uM
N-[(2-bromo-1,3-thiazol-5-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604073: Inhibition of PDHK4 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0870	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	affects expression, affects cotreatment, increases expression	6
pirinixic acid	affects binding, increases activity, increases expression	5
sodium arsenite	increases expression, decreases expression, affects binding, decreases reaction, increases reaction	5
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	4
perfluorooctane sulfonic acid	affects cotreatment, increases expression, affects expression	4
Rosiglitazone	increases expression	4
Estradiol	decreases expression, affects expression, increases reaction, increases expression, affects cotreatment	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	4
methylmercuric chloride	decreases expression, increases expression, affects expression	3
perfluoro-n-nonanoic acid	affects cotreatment, affects expression, increases expression	3
Troglitazone	increases expression	3
Bezafibrate	increases expression, decreases reaction	3
Valproic Acid	decreases expression, increases expression	3
Cyclosporine	decreases expression, increases expression	3
trichostatin A	increases reaction, increases expression, affects binding	2
GW 7647	increases expression	2
perfluorohexanesulfonic acid	increases expression, affects cotreatment, affects expression	2
bisphenol S	increases expression	2
Resveratrol	increases expression, increases reaction	2
Zoledronic Acid	decreases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Cisplatin	decreases expression, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Lipopolysaccharides	decreases expression, affects expression, affects response to substance, increases expression, affects cotreatment	2
Fenofibrate	increases expression	2
Rotenone	affects expression, increases expression	2
Silicon Dioxide	affects expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2

ChEMBL screening assays

94 unique, capped per target: 93 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3721114	Binding	Inhibition of pyruvate dehydrogenase kinase (unknown origin) assessed as reduction in E1 phosphorylation incubated for 1 hr by DELFIA method	Tetrahydroisoquinoline compounds and their use as pyruvate dehydrogenase kinase inhibitors
CHEMBL767695	Functional	In vivo inhibion of pyruvate dehydrogenase kinase, increased oxidation of lactate	(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionamides are orally active inhibitors of pyruvate dehydrogenase kinase. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2AE	Abcam HeLa PDK4 KO	Cancer cell line	Female
CVCL_D9MJ	Ubigene HEK293 PDK4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer