PDK1

Summary

PDK1 (pyruvate dehydrogenase kinase 1, HGNC:8809) is a protein-coding gene on chromosome 2q31.1, encoding [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial (Q15118). 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.

Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 5163 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 67 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002610

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8809
Approved symbol	PDK1
Name	pyruvate dehydrogenase kinase 1
Location	2q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000152256
Ensembl biotype	protein_coding
OMIM	602524
Entrez	5163

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000282077, ENST00000392571, ENST00000410055, ENST00000416991, ENST00000431718, ENST00000436490, ENST00000439519, ENST00000443353, ENST00000466437, ENST00000851218, ENST00000851219, ENST00000939646, ENST00000957078, ENST00000957079

RefSeq mRNA: 2 — MANE Select: NM_002610 NM_001278549, NM_002610

CCDS: CCDS2250, CCDS63059

Canonical transcript exons

ENST00000282077 — 11 exons

Exon	Start	End
ENSE00001004281	172568741	172568817
ENSE00001004287	172570726	172570824
ENSE00001341369	172595829	172608669
ENSE00001930036	172556090	172556346
ENSE00003475061	172564503	172564687
ENSE00003496230	172592935	172593048
ENSE00003519110	172562220	172562291
ENSE00003603823	172558708	172558849
ENSE00003628173	172566856	172566933
ENSE00003652206	172586278	172586388
ENSE00003787538	172564978	172565073

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3578 / max 294.3793, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23711	23.8956	1805
23710	0.5966	334
23709	0.5278	308
23708	0.3377	136

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.45	gold quality
oocyte	CL:0000023	97.09	gold quality
adrenal tissue	UBERON:0018303	95.04	gold quality
skin of hip	UBERON:0001554	92.36	gold quality
heart right ventricle	UBERON:0002080	92.09	gold quality
upper leg skin	UBERON:0004262	91.38	gold quality
cartilage tissue	UBERON:0002418	91.23	gold quality
colonic epithelium	UBERON:0000397	89.89	gold quality
jejunal mucosa	UBERON:0000399	89.33	gold quality
esophagus squamous epithelium	UBERON:0006920	88.96	gold quality
tonsil	UBERON:0002372	88.83	gold quality
endothelial cell	CL:0000115	88.48	silver quality
mucosa of sigmoid colon	UBERON:0004993	88.18	gold quality
trabecular bone tissue	UBERON:0002483	87.40	gold quality
colonic mucosa	UBERON:0000317	87.08	gold quality
tibia	UBERON:0000979	86.89	gold quality
penis	UBERON:0000989	86.61	gold quality
oral cavity	UBERON:0000167	86.53	gold quality
bone marrow	UBERON:0002371	86.34	gold quality
pylorus	UBERON:0001166	86.20	gold quality
parietal pleura	UBERON:0002400	86.06	gold quality
skin of leg	UBERON:0001511	85.93	gold quality
skin of abdomen	UBERON:0001416	85.79	gold quality
ventricular zone	UBERON:0003053	85.75	gold quality
sperm	CL:0000019	85.54	gold quality
epithelium of nasopharynx	UBERON:0001951	85.54	gold quality
zone of skin	UBERON:0000014	85.31	gold quality
rectum	UBERON:0001052	85.11	gold quality
blood	UBERON:0000178	85.04	gold quality
cardiac ventricle	UBERON:0002082	84.96	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	42.19
E-CURD-46	yes	34.15
E-MTAB-8410	yes	28.68
E-ANND-3	yes	28.58
E-HCAD-11	yes	20.20
E-MTAB-9543	yes	13.86
E-MTAB-10553	yes	9.51
E-GEOD-124858	no	747.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF1, HIF1A, JUN, MEIS3, MYC, NFKB, PPARA, RELA, TP53

miRNA regulators (miRDB)

135 targeting PDK1, 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-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• mRNA levels not changed in skeletal muscle during fasting (PMID:14966024)
• In summary, PDK activity is decreased after a high-fat diet that is rich in n-3 fatty acids, although PDHa activity was unaltered. (PMID:15591305)
• HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). (PMID:16517405)
• Distinct structural mechanisms for inhibition of PDK1 by AZD7545, dichloroacetate, and radicol. (PMID:17683942)
• HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2 and pyruvate dehydrogenase kinase 1. (PMID:17785433)
• HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects (PMID:18542064)
• Data show that PDK1 and HIF prolyl hydroxylase 3 expressions are lowest in children of chronic mountain sickness fathers at altitude. (PMID:18954447)
• Pyruvate dehydrogenase kinase 1 is an important regulator of pyruvate dehydrogenase in clonal pancreatic beta-cells. (PMID:20415663)
• post-mortem brain extracts from patients with Alzheimer disease exhibited a decrease in PDK1 expression compared with nondemented patients. (PMID:22948140)
• High expression of pyruvate dehydrogenase kinase-1 is associated with gastric cancer. (PMID:23135628)
• Accordingly, elevated levels of PDK1, PDK3, and PKM2 and reduced PK activity could be observed in iPSCs and human embryonic stem cells in the undifferentiated state (PMID:24123565)
• NOR1 expression causes apoptosis of tumor cells in hypoxia by altering the expression of PDK1 expression and mitochondrial Bax-Bcl2 balance thus suppress tumor cell adaptation to hypoxia (PMID:24788728)
• Follow-up replication analyses in up to an additional 21,345 participants identified three new fasting plasma glucose loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. (PMID:25187374)
• Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1. (PMID:25301052)
• both PDK 1 and 2 isoforms are overexpressed in cutaneous melanoma compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status (PMID:25976231)
• PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. (PMID:26365179)
• Dichloroacetate, an Iihibitor of PDK1, can reverse the mitochondrial suppression of renal cell carcinoma and decrease HIF transcriptional activity, decreasing tumor growth and angiogenesis. (PMID:26433571)
• High expression of PDK1 is associated with Colon Cancer. (PMID:26439504)
• Our results demonstrated that down-regulation of SDHB and up-regulation of PDK1 may be novel biomarkers for predicting advanced tumor progression and unfavorable prognosis in recurrent nasopharyngeal carcinoma patients (PMID:26547584)
• Tergeting PDK1 with dichloroacetophenone inhibited acute myeloid leukemia cell growth via multiple signaling pathways. (PMID:26593251)
• n the conditon of miR- 128b over-expression, we also observed spontaneous inactivation of the Akt/NF-kappaB signalling, implying PDK1 was a potential regulator of this pathway. In conclusion, our study shed some novel light on miR-128b-PDK1/Akt/NF-kappaB axis onGastric cancer (GC) progression (PMID:26949090)
• The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. (PMID:27626669)
• A new function for PDK1 in metabolic reprogramming, which could be used to indicate the prognosis of Non small cell lung cancer and provide targeted therapeutic strategy for clinical treatment. (PMID:27878287)
• PDK1 is frequently upregulated in primary nasopharyngeal carcinoma and may serve as a prognostic marker. (PMID:28029432)
• These results also suggest that inhibition of HIF-1a with 2-MeOE2 sensitizes radioresistant melanoma cells 435R to X-ray irradiation through targeting the glycolysis that is regulated by PDK1 (PMID:28339028)
• The importance of PDK1 in tumor growth and progression.A role of PDK1 in tumor microenvironment.[review] (PMID:28473254)
• dicumarol potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. (PMID:28617852)
• MiR-138 inhibits glycolysis but promotes mitochondrial respiration through directly targetting PDK1, and that contributes to cardiac cells’ survival. (PMID:28899927)
• High PDK1 expression promotes breast cancer stemness. (PMID:29106390)
• These results indicate that the immunohistochemistry analysis of the protein expression of PDK1, PHD3, and HIF-1alpha defines the hypoxic status of Neuroblastoma tumors. (PMID:29117193)
• mir-138-5p could repress the development of Retinoblastoma (RB) via suppressing PDK1, which may offer a new vision for interpreting the mechanism of RB tumorigenesis. (PMID:29271995)
• data indicate that ectopic endometriotic cells may adapt to hypoxic microenvironment via upregulating pyruvate dehydrogenase kinase 1( PDK1) and reprogramming metabolism (PMID:30092712)
• miR-375 and its probable PDK1 target may be utilized for the management of Kidney cancer. (PMID:30098579)
• These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR (PMID:30229902)
• This study confirmed that the PDK-1 is involved in non-small cell lung cancer cells apoptosis, the underlying mechanism is related to Hippo-YAP/IRS2 signaling network. (PMID:30988063)
• Ku80 promoted melanoma growth and regulated antitumor activity of melatonin by targeting HIF1-alpha dependent PDK-1 signaling pathway. (PMID:31023624)
• Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers. (PMID:31461649)
• we demonstrated that the clinically approved drug metformin sensitizes chemoresistant ovarian cancer (OVCA) cells to cisplatin (CDDP) via PDK1-HKII pathway. Collectively, our data implicate that p53–PDK1-HKII axis is a central regulatory component of metabolism conferring chemoresistance in OVCA. (PMID:31486135)
• These findings highlight the potential use of PGK1 mRNA level, PGK1 promoter hypomethylation, and PGK1 pS203 and PDHK1 pT338 levels as biomarkers for cancer progression and prognosis, and the promising significance of PGK1 as a target in cancer treatment. (PMID:31578148)
• Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma. (PMID:31578313)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdk1	ENSDARG00000013128
mus_musculus	Pdk1	ENSMUSG00000006494
rattus_norvegicus	Pdk1	ENSRNOG00000001517
drosophila_melanogaster	Pdk	FBGN0017558
caenorhabditis_elegans		WBGENE00022719

Paralogs (4): PDK4 (ENSG00000004799), PDK2 (ENSG00000005882), PDK3 (ENSG00000067992), BCKDK (ENSG00000103507)

Protein

Protein identifiers

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial — Q15118 (reviewed: Q15118)

Alternative names: Pyruvate dehydrogenase kinase isoform 1

All UniProt accessions (5): Q15118, C9IYB4, C9JKT3, F8WC75, F8WEJ6

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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia.

Subunit / interactions. Homodimer, and heterodimer with PDK2. 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). Interacts with phosphoglycerate kinase PGK1; the interaction is direct, occurs under hypoxic conditions and leads to PDK1-mediated inhibition of pyruvate dehydrogenase complex activity.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas.

Post-translational modifications. Phosphorylated by constitutively activated ABL1, FGFR1, FLT3 and JAK2 (in vitro), and this may also occur in cancer cells that express constitutively activated ABL1, FGFR1, FLT3 and JAK2. Phosphorylation at Tyr-243 and Tyr-244 strongly increases kinase activity, while phosphorylation at Tyr-136 has a lesser effect. Phosphorylated under hypoxic conditions at Thr-338 by phosphoglycerate kinase PGK1 which has an activating effect.

Activity regulation. Activity is enhanced by binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity. Inhibited by dichloroacetate and radicicol. Activated under hypoxic conditions by phosphoglycerate kinase PGK1-mediated phosphorylation at Thr-338.

Induction. Up-regulated via the HIF1A signaling pathway in response to hypoxia.

Miscellaneous. Exposure of cancer cells to severe hypoxia induces translocation of AKT to the mitochondrion, leading to AKT-mediated phosphorylation of PDK1 at Thr-346 which supports tumor cell survival and proliferation during hypoxia.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q15118-1	1	yes
Q15118-2	2

RefSeq proteins (2): NP_001265478, NP_002601* (*=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 9, modified residue 5, turn 5, binding site 4, sequence conflict 3, sequence variant 2, transit peptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9M3O	X-RAY DIFFRACTION	1.76
2Q8G	X-RAY DIFFRACTION	1.9
2Q8H	X-RAY DIFFRACTION	2
9M3P	X-RAY DIFFRACTION	2.01
2Q8F	X-RAY DIFFRACTION	2.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15118-F1	86.94	0.74

Functional residue map

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

Ligand- & substrate-binding residues (4): 279–286; 318; 337–338; 354–359

Post-translational modifications (5): 338, 405, 136, 243, 244

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-9837999	Mitochondrial protein degradation

MSigDB gene sets: 385 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, MENSE_HYPOXIA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (7): glucose metabolic process (GO:0006006), cell population proliferation (GO:0008283), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), regulation of pyruvate decarboxylation to acetyl-CoA (GO:0010510), regulation of glucose metabolic process (GO:0010906), hypoxia-inducible factor-1alpha signaling pathway (GO:0097411), cellular response to stress (GO:0033554)

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 (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), pyruvate dehydrogenase complex (GO:0045254)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hexose metabolic process	1
cellular process	1
intrinsic apoptotic signaling pathway	1
pyruvate decarboxylation to acetyl-CoA	1
regulation of acyl-CoA biosynthetic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
intracellular signal transduction	1
cellular response to hypoxia	1
response to stress	1
cellular response to stimulus	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
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
acetyltransferase complex	1

Protein interactions and networks

STRING

3476 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDK1	LDHA	P00338	828
PDK1	HK2	P52789	739
PDK1	SLC2A1	P11166	733
PDK1	HIF1A	Q16665	725
PDK1	PKM	P14618	716
PDK1	PDHA1	P08559	715
PDK1	PDK2	Q15119	650
PDK1	PGK1	P00558	622
PDK1	PFKM	P08237	616
PDK1	SLC16A4	O15374	611
PDK1	SLC2A3	P11169	610
PDK1	PFKFB3	Q16875	608
PDK1	ARNT	P27540	606
PDK1	AKT1	P31749	596
PDK1	SLC16A3	O15427	589

IntAct

96 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PDK1	PDK2	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
PDK1	PDHA1	psi-mi:“MI:0217”(phosphorylation reaction)	0.570
APP	PDK1	psi-mi:“MI:0915”(physical association)	0.560
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PDK3	PDHX	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
SGK3	PDK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.490
SGK3	PDK1	psi-mi:“MI:0403”(colocalization)	0.490
TRMT61B	GLS	psi-mi:“MI:0914”(association)	0.480
PDK1	MT-CO2	psi-mi:“MI:0403”(colocalization)	0.460
PDK1	MT-CO2	psi-mi:“MI:0915”(physical association)	0.460
PDK1	PDK1	psi-mi:“MI:0407”(direct interaction)	0.440
EPAS1	PDK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDK1	RPS6KB1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PDK1	PKN2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (442): PDK1 (Two-hybrid), PDK1 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), PDHX (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), PDK1 (Affinity Capture-Western), RPTOR (Affinity Capture-Western), MTOR (Affinity Capture-Western), PDK1 (Affinity Capture-Western), PDK1 (Affinity Capture-Western), COL4A5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U3BRC5, A0A2L0VXR5, A2AIL4, A7YVD7, A9UMP7, C5Y210, D3ZN43, E7FCP8, F4I1L3, K2SUY0, M2U578, O43824, O95822, Q08BC6, Q15118, Q16854, Q1LXS2, Q28205, Q2KHV5, Q2QMG2, Q330K2, Q39108, Q4KM93, Q53S58, Q5ZM96, Q6DCC6, Q6JQN1, Q7XYS8, Q8BPE4, Q8K370, Q8N159, Q8R4H7, Q8RWT8, Q8S6N5, Q920F5, Q96RQ3, Q99J39, Q99MR8, Q9BTW9, Q9CWG8

Diamond homologs: O02623, O14874, O54937, O55028, O70571, O88345, P91622, Q00972, Q02332, Q15118, Q15119, Q15120, Q16654, Q1KMR4, Q2KJG8, Q63065, Q64536, Q8BFP9, Q922H2, Q9JK42, Q9P6P9, Q9SBJ1, Q4LAJ8, Q5HK19, Q8CU87, Q9RDT3, A5INR0, A6QD58, A6TXG9, A7WWQ7, A8YYU2, Q2FKN7, Q2G2U4, Q2YUQ2, Q5HJX6, Q6GD71, Q6GKS6, Q7A215, Q7A305, Q7A8E0

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
PDK1	down-regulates	PDHA2	phosphorylation
FGFR1	up-regulates	PDK1	phosphorylation
PDK1	“up-regulates activity”	PKN2	phosphorylation
HIF1A	“up-regulates quantity by expression”	PDK1	“transcriptional regulation”
PDK1	“down-regulates activity”	PDH	phosphorylation
“HIF-1 complex”	“up-regulates quantity by expression”	PDK1	“transcriptional regulation”
PGK1	“up-regulates activity”	PDK1	phosphorylation
PDK1	“up-regulates activity”	AKT1	phosphorylation
PDK1	“up-regulates activity”	AKT2	phosphorylation
“HIF-1 complex”	“up-regulates quantity”	PDK1	“transcriptional regulation”
PDK1	“down-regulates activity”	PDHA1	phosphorylation
PDK1	“down-regulates activity”	ITGB3	phosphorylation
AKT2	“up-regulates activity”	PDK1	phosphorylation
AKT1	“up-regulates activity”	PDK1	phosphorylation
PDK1	down-regulates	PDHA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
Regulation of pyruvate dehydrogenase (PDH) complex	6	60.3×	2e-07
Signaling by Retinoic Acid	6	34.5×	5e-06
Complex I biogenesis	5	11.7×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2295 predictions. Top by Δscore:

Variant	Effect	Δscore
2:172556347:G:A	donor_loss	1.0000
2:172556347:G:GG	donor_gain	1.0000
2:172556348:T:A	donor_loss	1.0000
2:172558846:GCTG:G	donor_gain	1.0000
2:172558850:G:GG	donor_gain	1.0000
2:172562213:A:AG	acceptor_gain	1.0000
2:172562215:TTTA:T	acceptor_gain	1.0000
2:172562215:TTTAG:T	acceptor_loss	1.0000
2:172562217:TA:T	acceptor_loss	1.0000
2:172562219:GGT:G	acceptor_gain	1.0000
2:172562287:TATGA:T	donor_gain	1.0000
2:172562288:ATGA:A	donor_gain	1.0000
2:172562288:ATGAG:A	donor_loss	1.0000
2:172562289:TGA:T	donor_gain	1.0000
2:172562289:TGAG:T	donor_loss	1.0000
2:172562290:GA:G	donor_gain	1.0000
2:172562290:GAG:G	donor_gain	1.0000
2:172562290:GAGTA:G	donor_loss	1.0000
2:172562291:AGTAA:A	donor_loss	1.0000
2:172562292:G:GG	donor_gain	1.0000
2:172562292:GTAA:G	donor_loss	1.0000
2:172562293:T:G	donor_loss	1.0000
2:172562294:AA:A	donor_loss	1.0000
2:172562295:AGTT:A	donor_loss	1.0000
2:172564502:G:GT	acceptor_gain	1.0000
2:172564502:GC:G	acceptor_gain	1.0000
2:172564625:A:AG	donor_gain	1.0000
2:172564626:G:GG	donor_gain	1.0000
2:172564683:GCACT:G	donor_gain	1.0000
2:172564684:CACT:C	donor_gain	1.0000

AlphaMissense

2860 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:172556343:T:C	F65L	1.000
2:172556345:C:A	F65L	1.000
2:172556345:C:G	F65L	1.000
2:172558743:T:C	F78L	1.000
2:172558744:T:C	F78S	1.000
2:172558745:T:A	F78L	1.000
2:172558745:T:G	F78L	1.000
2:172558768:G:C	R86T	1.000
2:172558769:A:C	R86S	1.000
2:172558769:A:T	R86S	1.000
2:172562230:A:C	S117R	1.000
2:172562232:T:A	S117R	1.000
2:172562232:T:G	S117R	1.000
2:172564535:G:C	R148P	1.000
2:172564640:G:C	R183P	1.000
2:172592966:G:C	R363P	1.000
2:172592990:G:A	G371E	1.000
2:172558708:G:A	G66E	0.999
2:172558734:T:C	S75P	0.999
2:172558744:T:G	F78C	0.999
2:172558747:T:C	L79P	0.999
2:172558750:G:C	R80P	0.999
2:172558755:G:A	E82K	0.999
2:172558757:G:C	E82D	0.999
2:172558757:G:T	E82D	0.999
2:172558765:T:A	V85D	0.999
2:172558767:A:G	R86G	0.999
2:172558771:T:C	L87P	0.999
2:172558773:G:C	A88P	0.999
2:172558774:C:A	A88E	0.999

dbSNP variants (sampled 300 via entrez): RS1000102160 (2:172582259 G>A), RS1000102590 (2:172625568 T>C), RS1000132456 (2:172570178 G>A,C,T), RS1000133253 (2:172581922 G>T), RS1000147853 (2:172640820 A>G), RS1000156854 (2:172616748 A>G), RS1000187111 (2:172569965 A>G), RS1000202145 (2:172634256 CTATTTATA>C), RS1000214416 (2:172593585 T>C), RS1000218650 (2:172719855 C>G), RS1000231076 (2:172628464 G>C), RS1000244363 (2:172619867 A>C), RS1000261303 (2:172673668 C>T), RS1000287218 (2:172706169 A>G), RS1000297039 (2:172575783 T>C)

Disease associations

OMIM: gene MIM:602524 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001572_2	Erectile dysfunction in type 1 diabetes	2.000000e-06
GCST002586_1	Fasting plasma glucose	7.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2096665 (PROTEIN FAMILY), CHEMBL3885616 (PROTEIN FAMILY), CHEMBL4766 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,861 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL362558	LY-2090314	2	108
CHEMBL3673096	JTT-251	2	22
CHEMBL495727	AT-9283	2	1,376
CHEMBL565612	SOTRASTAURIN	2	1,355

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
VER-246608	Inhibition	7.46	pIC50
AZD7545	Inhibition	7.43	pIC50

Binding affinities (BindingDB)

27 measured of 29 human assays (29 total across all organisms); most potent 27 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(5-cyclopropyl-1H-pyrazol-3-yl)-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl]methanone	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
(4-chloro-5-cyclopropyl-1H-pyrazol-3-yl)-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl]methanone	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
2-[4-[(9R)-9-hydroxy-2-(4-hydroxy-4-methylpentoxy)-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-2-methylpropanamide	IC50	3.5 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
1H-indazol-4-yl-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl]methanone	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
(5-fluoro-1H-indazol-3-yl)-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl]methanone	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
2-[4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutoxy)-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-2-methylpropanamide	IC50	4.7 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
2-methyl-1-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridin-6-yl]-2-[4-(2H-tetrazol-5-yl)phenyl]propan-1-one	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[5-(4-fluorophenyl)pyrazolidin-3-yl]-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl]methanone	IC50	10 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
CHEMBL5424355	EC50	68 nM
CHEMBL5422377	EC50	190 nM
CHEMBL5402490	EC50	620 nM
CHEMBL5425301	EC50	650 nM
CHEMBL5417465	EC50	930 nM
CHEMBL5436563	EC50	1000 nM
CHEMBL5439850	EC50	1200 nM
CHEMBL5405743	EC50	1300 nM
CHEMBL5419996	EC50	1600 nM
CHEMBL5394529	EC50	1900 nM
CHEMBL5419257	EC50	1900 nM
CHEMBL5423077	EC50	2600 nM
CHEMBL5423379	EC50	2900 nM
CHEMBL5423915	EC50	3200 nM
CHEMBL5403973	EC50	4700 nM
CHEMBL5440159	EC50	9600 nM
CHEMBL5289763	EC50	17000 nM
PS10	KD	47000 nM
PS8	KD	60100 nM

ChEMBL bioactivities

1315 potent at pChembl≥5 of 1368 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.506	nM	STAUROSPORINE
9.27	IC50	0.538	nM	STAUROSPORINE
9.00	Kd	1	nM	CHEMBL3731789
8.60	IC50	2.5	nM	CHEMBL1765740
8.52	IC50	3	nM	CHEMBL5782152
8.52	IC50	3	nM	CHEMBL5820129
8.52	IC50	3	nM	CHEMBL5967251
8.52	IC50	3	nM	CHEMBL5768930
8.52	IC50	3	nM	CHEMBL5863265
8.52	IC50	3	nM	CHEMBL5880436
8.52	IC50	3	nM	CHEMBL5746971
8.52	IC50	3	nM	CHEMBL5749526
8.52	IC50	3	nM	CHEMBL5833861
8.52	IC50	3	nM	CHEMBL5751502
8.52	IC50	3	nM	CHEMBL5746482
8.52	IC50	3	nM	CHEMBL5750845
8.52	IC50	3	nM	CHEMBL6193469
8.46	IC50	3.5	nM	CHEMBL3673097
8.40	Kd	4	nM	CHEMBL4576489
8.40	IC50	4	nM	CHEMBL228804
8.40	IC50	4	nM	CHEMBL5915744
8.40	IC50	4	nM	CHEMBL5966862
8.40	IC50	4	nM	CHEMBL5741827
8.40	IC50	4	nM	CHEMBL5963093
8.40	IC50	4	nM	CHEMBL5912949
8.40	IC50	4	nM	CHEMBL6052495
8.40	IC50	4	nM	CHEMBL5956732
8.40	IC50	4	nM	CHEMBL5938067
8.40	IC50	4	nM	CHEMBL6024658
8.40	IC50	4	nM	CHEMBL5798373
8.40	IC50	4	nM	CHEMBL5911723
8.40	IC50	4	nM	CHEMBL5872700
8.40	IC50	4	nM	CHEMBL5878931
8.40	IC50	4	nM	CHEMBL5897540
8.40	IC50	4	nM	CHEMBL5932414
8.40	IC50	4	nM	CHEMBL5900406
8.40	IC50	4	nM	CHEMBL5871755
8.40	IC50	4	nM	CHEMBL6008639
8.40	IC50	4	nM	CHEMBL6058366
8.40	IC50	4	nM	CHEMBL6193076
8.33	IC50	4.7	nM	JTT-251
8.30	Kd	5	nM	CHEMBL4465866
8.30	IC50	5	nM	CHEMBL6041978
8.30	IC50	5	nM	CHEMBL5943434
8.30	IC50	5	nM	CHEMBL5973489
8.30	IC50	5	nM	CHEMBL5844120
8.30	IC50	5	nM	CHEMBL6012529
8.30	IC50	5	nM	CHEMBL6025353
8.30	IC50	5	nM	CHEMBL5875090
8.30	IC50	5	nM	CHEMBL5887885

PubChem BioAssay actives

368 with measured affinity, of 1535 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1531826: Inhibition of human PDK1 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0005	uM
N-benzyl-2,4-dihydroxy-N-[4-[methyl(quinoxalin-6-ylmethyl)carbamoyl]phenyl]benzamide	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0010	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526292: Binding affinity to recombinant human full length N-terminal his-tagged PDK1 expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0040	uM
3-[5-[(Z)-[5-(carbamoylamino)-2-oxo-1H-indol-3-ylidene]methyl]-1H-pyrrol-3-yl]-N-[2-(dimethylamino)ethyl]benzamide	1866040: Inhibition of PDK1 (unknown origin)	ic50	0.0040	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526292: Binding affinity to recombinant human full length N-terminal his-tagged PDK1 expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0050	uM
N-[[5-[(1Z)-1-[5-(carbamoylamino)-2-oxo-1H-indol-3-ylidene]ethyl]-1H-pyrrol-3-yl]methyl]piperidine-4-carboxamide	1866040: Inhibition of PDK1 (unknown origin)	ic50	0.0060	uM
(2S)-1-(2,4-dihydroxybenzoyl)-N,2-dimethyl-N-(quinoxalin-6-ylmethyl)-3,4-dihydro-2H-quinoline-6-carboxamide	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0060	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
[(3Z)-2-oxo-3-[(4-pyridin-2-yl-1H-pyrrol-2-yl)methylidene]-1H-indol-5-yl]urea	1866040: Inhibition of PDK1 (unknown origin)	ic50	0.0080	uM
(3Z)-3-[[5-(2-nitrophenyl)-1H-pyrazol-4-yl]methylidene]-1H-indol-2-one	739584: Inhibition of PDK1 (unknown origin) after 10 mins by mobility shift assay	ic50	0.0083	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
[(2S)-6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(2,4-dihydroxyphenyl)methanone	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0090	uM
N-[(4-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604074: Inhibition of PDHK1 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0090	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-benzyl-2,4-dihydroxy-N-[4-[(4-methoxyphenyl)methyl-methylcarbamoyl]phenyl]benzamide	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0100	uM
[(2S)-6-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(2,4-dihydroxyphenyl)methanone	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0100	uM
[(2R)-6-(2-chloro-5-methylpyrimidin-4-yl)-2-pyridin-3-yl-3,4-dihydro-2H-quinolin-1-yl]-(2,4-dihydroxyphenyl)methanone	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	0.0100	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	412616: Inhibition of PDK1	ic50	0.0100	uM
5-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1,2-oxazole-3-carboxamide	2130574: Inhibition of PDHK1 (unknown origin)	ic50	0.0100	uM
(3S,6R)-1-[6-(3-amino-1H-indazol-6-yl)-2-(methylamino)pyrimidin-4-yl]-N-cyclohexyl-6-methylpiperidine-3-carboxamide	1994240: Inhibition of PDK1 (unknown origin)	ic50	0.0100	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
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(5-iodofuran-2-yl)methyl]benzamide	1604074: Inhibition of PDHK1 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0140	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
N-benzyl-N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-dihydroxybenzamide	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	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-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-9-(trifluoromethyl)fluoren-9-ol	2112530: Inhibition of PDHK1 (unknown origin)	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
(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
[(2S)-6-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(2,4-dihydroxyphenyl)methanone	1441274: Binding affinity to PDHK1 (unknown origin) by surface plasmon resonance method	kd	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
[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-5-yl]urea	1866040: Inhibition of PDK1 (unknown origin)	ic50	0.0200	uM
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(5-methylfuran-2-yl)methyl]benzamide	1604074: Inhibition of PDHK1 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0200	uM
N-[(5-bromo-1,3-thiazol-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604074: Inhibition of PDHK1 (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
(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
[(3R)-3-(methoxymethyl)morpholine-4-carbothioyl]sulfanyl (3R)-3-(methoxymethyl)morpholine-4-carbodithioate	1442053: Inhibition of full length His6-tagged PDK1 (unknown origin) expressed in Escherichia coli using full length His6-tagged PDHA1 as substrate after 30 mins by ELISA	ic50	0.0240	uM
N-[(5-chlorofuran-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604074: Inhibition of PDHK1 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0240	uM
N-[(2-bromo-1,3-thiazol-5-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604074: Inhibition of PDHK1 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0240	uM
N-(1-benzylpiperidin-4-yl)-5-(5-chloro-2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)-1,2-oxazole-3-carboxamide	1170877: Inhibition of recombinant PDHK1 (unknown origin) expressed in Escherichia coli incubated for 1 hr by ELISA	ic50	0.0250	uM
1,4-oxazepane-4-carbothioylsulfanyl 1,4-oxazepane-4-carbodithioate	1442053: Inhibition of full length His6-tagged PDK1 (unknown origin) expressed in Escherichia coli using full length His6-tagged PDHA1 as substrate after 30 mins by ELISA	ic50	0.0260	uM
5-(5-chloro-2,4-dihydroxyphenyl)-N-[1-(cyclopropylmethyl)piperidin-4-yl]-4-(4-methoxyphenyl)-1,2-oxazole-3-carboxamide	1170877: Inhibition of recombinant PDHK1 (unknown origin) expressed in Escherichia coli incubated for 1 hr by ELISA	ic50	0.0280	uM
N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-[[4-[[(2,2-difluoroacetyl)amino]methyl]phenyl]methyl]-2,4-dihydroxybenzamide	1441271: Inhibition of fluorescein-labelled VER160364 binding to PDHK1 (unknown origin) after 90 mins by fluorescence polarization assay	ki	0.0280	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
[(3S)-3-(methoxymethyl)morpholine-4-carbothioyl]sulfanyl (3S)-3-(methoxymethyl)morpholine-4-carbodithioate	1442053: Inhibition of full length His6-tagged PDK1 (unknown origin) expressed in Escherichia coli using full length His6-tagged PDHA1 as substrate after 30 mins by ELISA	ic50	0.0300	uM
5-(5-bromo-1-methylpyrrolo[2,3-b]pyridin-3-yl)-6-(5-methoxy-1H-indol-3-yl)-1,2,4-triazin-3-amine	1995118: Inhibition of PDK1 (unknown origin) incubated for 30 mins followed by substrate addition measured after 60 mins in presence of ATP by ADP-Glo luminescent assay	ic50	0.0300	uM
5-(5-bromo-1-methylpyrrolo[2,3-b]pyridin-3-yl)-6-(5-fluoro-1H-indol-3-yl)-1,2,4-triazin-3-amine	2140018: Inhibition of PDK1 (unknown origin) incubated for 30 mins followed by substrate addition measured after 60 mins in presence of ATP by ADP-Glo luminescent assay	ic50	0.0300	uM
5-(5-bromo-1H-indol-3-yl)-6-(5-bromo-1-methylpyrrolo[2,3-b]pyridin-3-yl)-1,2,4-triazin-3-amine	2140018: Inhibition of PDK1 (unknown origin) incubated for 30 mins followed by substrate addition measured after 60 mins in presence of ATP by ADP-Glo luminescent assay	ic50	0.0300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	decreases reaction, increases activity, increases expression, affects reaction, increases reaction (+1 more)	12
Acetylcysteine	decreases reaction, increases expression, increases phosphorylation	5
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
sodium arsenite	decreases expression, increases methylation, decreases reaction, increases phosphorylation, affects reaction (+1 more)	4
cobaltous chloride	increases expression, decreases reaction	4
Cadmium Chloride	decreases expression, increases abundance, increases expression	4
bisphenol A	affects cotreatment, decreases expression, affects expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
methylmercuric chloride	decreases expression	2
manganese chloride	increases abundance, increases expression	2
ochratoxin A	affects expression, affects phosphorylation	2
mercuric bromide	decreases expression, affects cotreatment	2
2,3’,4,4’,5-pentachlorobiphenyl	increases expression, decreases reaction, affects reaction	2
Vorinostat	decreases reaction, increases expression, decreases expression	2
Cadmium	increases abundance, increases expression, increases reaction	2
Cisplatin	decreases expression	2
Cobalt	affects binding, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Manganese	increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
VER-246608	decreases activity	1
bisphenol F	increases expression	1
PF-06840003	decreases reaction, decreases expression	1
WZ35 compound	decreases expression	1

ChEMBL screening assays

529 unique, capped per target: 527 binding, 1 functional, 1 admet

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
CHEMBL4407591	ADMET	Inhibition of recombinant human full-length His-tagged PDK1 expressed in baculovirus expression system at 25 uM using FRET-labeled Ser/Thr 07 peptide as substrate measured after 1 hr by Z’-lyte assay relative to control	Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D7WR	Ubigene A-549 PDK1 KO	Cancer cell line	Male
CVCL_D8S4	Ubigene HCT 116 PDK1 KO	Cancer cell line	Male
CVCL_D9MI	Ubigene HEK293 PDK1 KO	Transformed cell line	Female
CVCL_E0JW	Ubigene HeLa PDK1 KO	Cancer cell line	Female
CVCL_TC78	HAP1 PDK1 (-) 1	Cancer cell line	Male
CVCL_TC79	HAP1 PDK1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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