PDK2

Summary

PDK2 (pyruvate dehydrogenase kinase 2, HGNC:8810) is a protein-coding gene on chromosome 17q21.33, encoding [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial (Q15119). Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2.

This gene encodes a member of the pyruvate dehydrogenase kinase family. The encoded protein phosphorylates pyruvate dehydrogenase, down-regulating the activity of the mitochondrial pyruvate dehydrogenase complex. Overexpression of this gene may play a role in both cancer and diabetes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 5164 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8810
Approved symbol	PDK2
Name	pyruvate dehydrogenase kinase 2
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	PDHK2
Ensembl gene	ENSG00000005882
Ensembl biotype	protein_coding
OMIM	602525
Entrez	5164

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000007708, ENST00000503076, ENST00000503176, ENST00000503614, ENST00000505440, ENST00000505897, ENST00000506242, ENST00000506647, ENST00000508030, ENST00000508960, ENST00000510219, ENST00000511026, ENST00000512204, ENST00000512238, ENST00000515040, ENST00000614357, ENST00000892665, ENST00000892666, ENST00000892667, ENST00000892668, ENST00000892669, ENST00000892670, ENST00000892671, ENST00000930435, ENST00000969548, ENST00000969549, ENST00000969550

RefSeq mRNA: 4 — MANE Select: NM_002611 NM_001199898, NM_001199899, NM_001199900, NM_002611

CCDS: CCDS11559, CCDS56039

Canonical transcript exons

ENST00000503176 — 11 exons

Exon	Start	End
ENSE00000736618	50108156	50108232
ENSE00002040192	50109957	50112152
ENSE00002078252	50095351	50095553
ENSE00003460887	50106794	50106883
ENSE00003465791	50109287	50109400
ENSE00003480424	50105885	50106069
ENSE00003561449	50097423	50097564
ENSE00003595845	50105371	50105442
ENSE00003609313	50107076	50107153
ENSE00003679731	50108319	50108417
ENSE00003789605	50108612	50108719

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.0353 / max 546.5870, expressed in 1767 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161581	35.3454	1766
161580	2.6424	1450
161582	0.0476	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.43	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.42	gold quality
cerebellar hemisphere	UBERON:0002245	98.35	gold quality
cerebellar cortex	UBERON:0002129	98.30	gold quality
apex of heart	UBERON:0002098	98.23	gold quality
gastrocnemius	UBERON:0001388	97.72	gold quality
cerebellum	UBERON:0002037	97.53	gold quality
right atrium auricular region	UBERON:0006631	97.42	gold quality
muscle of leg	UBERON:0001383	97.28	gold quality
left adrenal gland cortex	UBERON:0035825	97.16	gold quality
heart left ventricle	UBERON:0002084	97.15	gold quality
cardiac atrium	UBERON:0002081	97.09	gold quality
right adrenal gland cortex	UBERON:0035827	97.05	gold quality
right adrenal gland	UBERON:0001233	96.99	gold quality
cardiac ventricle	UBERON:0002082	96.93	gold quality
left adrenal gland	UBERON:0001234	96.89	gold quality
muscle organ	UBERON:0001630	96.36	gold quality
adrenal cortex	UBERON:0001235	96.28	gold quality
heart	UBERON:0000948	96.18	gold quality
mucosa of stomach	UBERON:0001199	96.12	gold quality
right frontal lobe	UBERON:0002810	96.04	gold quality
prefrontal cortex	UBERON:0000451	95.65	gold quality
paraflocculus	UBERON:0005351	95.43	gold quality
adrenal gland	UBERON:0002369	95.33	gold quality
nucleus accumbens	UBERON:0001882	95.29	gold quality
diaphragm	UBERON:0001103	95.20	gold quality
popliteal artery	UBERON:0002250	94.85	gold quality
tibial artery	UBERON:0007610	94.83	gold quality
right coronary artery	UBERON:0001625	94.80	gold quality
right ovary	UBERON:0002118	94.54	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PPARG

miRNA regulators (miRDB)

47 targeting PDK2, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-500A-5P	98.76	69.13	1241

Literature-anchored findings (GeneRIF, showing 32)

• study of facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase (PMID:12816949)
• The increased PDK activity was independent of changes in intra-mitochondrial effectors, and PDK-2 and PDK-4 protein content, suggesting that it was caused by a change in the specific activity of the existing kinases. (PMID:15169745)
• A mechanism for pyruvate dehydrogenase kinase isoform 2 regulation is supported in which kinase activity is limited by ADP dissociation and pyruvate binding. (PMID:15491150)
• Reductive acetylation stimulates activity of pyruvate dehydrogenase kinase isoform 2 by speeding up ADP dissociation. (PMID:15491151)
• in human muscle, hormonal and nutritional conditions may control PDK2 and PDK4 mRNA expression via a common signalling mechanism. (PMID:15955060)
• Crystallographic studies reveal several PDHK2 structures with C-terminal cross arms that span a large trough region between the N-terminal regulatory (R) domains of the PDHK2 dimers. Three novel ligand binding sites are located in the R domain of PDHK2. (PMID:16401071)
• analysis of ligand induced effects on pyruvate dehydrogenase kinase isoform 2 (PMID:16517984)
• These studies identify ORP9 as a PDK-2 substrate and negative regulator of Akt phosphorylation at the PDK-2 site. (PMID:16962287)
• 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)
• Critical role of specific ions for ligand-induced changes regulating pyruvate dehydrogenase kinase isoform 2. (PMID:18220414)
• Pi is suggested to facilitate transmission within PDHK2 of the stimulatory signal of acetylation from the distal lipoyl-group binding site to the active site. (PMID:18220415)
• mitochondrial ND2 mutation contributes to HIF1alpha accumulation via increased ROS production, up-regulation of PDK2, attenuating PDH activity, thereby increasing pyruvate, resulting in HIF1alpha stabilization (PMID:19147752)
• PKD1 children have more and larger renal cysts, larger kidneys and higher ambulatory BP than do PKD2 children. (PMID:19194729)
• the DW-motif has a pivotal role in mediating communications between the DCA-, the nucleotide-, and the lipoyl domain-binding sites of PDK2 (PMID:19833728)
• PKD2 mutations are associated with autosomal dominant polycystic kidney disease. (PMID:21115670)
• Results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2. These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism. (PMID:22123926)
• Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. (PMID:22614004)
• Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species. (PMID:22910903)
• Germline mutations in PKD2 gene is associated with autosomal-dominant polycystic kidney disease. (PMID:23300259)
• we for the first time demonstrated that a low-nutrient condition drives cancer cells to utilize glycolysis to produce ATP, and this increases the Warburg effect through a novel mechanism involving ROS/AMPK-dependent activation of PDK. (PMID:23376776)
• The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 muM for PDK2. (PMID:24356970)
• 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)
• The findings of the present study reveal a novel survival pathway that functionally couples the unique glycolytic phenotype in cancer cells to hypoxia resistance via a PDK2-dependent mechanism that switches Bnip3 from cell death to survival. (PMID:26416963)
• High glycolysis and PDK2 overexpression are closely linked to cisplatin resistance in head and neck cancer cells, which can be reversed by PDK2 nhibition. (PMID:26607904)
• The data demonstrate potential roles of PDK2 and ABCG2 polymorphisms in the metabolic phenotypes of Tibetan gout patients. (PMID:26909964)
• PDK2/PARL senses defects in mitochondrial bioenergetics. (PMID:28178523)
• MiR-422a regulates cellular metabolism and malignancy by targeting PDK2 in gastric cancer. (PMID:29725130)
• we identified PDK2 as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma and PDK2-dependent Cisplatin-resistance promotes tumour growth of lung adenocarcinoma mainly through transcriptional regulation of CNNM3 (PMID:30457021)
• Overexpression of PDK2 and PDK3 reflects poor prognosis in acute myeloid leukemia. (PMID:30578412)
• [Expression Level of Protein Kinase D in Oral Squamous Cell Carcinoma with Diverse Differentiation]. (PMID:33236596)
• Circular RNA hsa_circ_0005397 promotes hepatocellular carcinoma progression by regulating the miR-326/PDK2 axis. (PMID:33783904)
• PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma. (PMID:34464482)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdk2a	ENSDARG00000020876
danio_rerio	pdk2b	ENSDARG00000059054
mus_musculus	Pdk2	ENSMUSG00000038967
rattus_norvegicus	Pdk2	ENSRNOG00000004172
drosophila_melanogaster	Pdk	FBGN0017558
caenorhabditis_elegans		WBGENE00022719

Paralogs (4): PDK4 (ENSG00000004799), PDK3 (ENSG00000067992), BCKDK (ENSG00000103507), PDK1 (ENSG00000152256)

Protein

Protein identifiers

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial — Q15119 (reviewed: Q15119)

Alternative names: Pyruvate dehydrogenase kinase isoform 2

All UniProt accessions (6): Q15119, D6R983, D6RDN9, D6RGV8, D6RHG2, D6RJH7

UniProt curated annotations — full annotation on UniProt →

Function. Kinase that plays a key role in the 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. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. 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. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.

Subunit / interactions. Homodimer, and heterodimer with PDK1. 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. Expressed in many tissues, with the highest level in heart and skeletal muscle, intermediate levels in brain, kidney, pancreas and liver, and low levels in placenta and lung.

Activity regulation. Activity is enhanced by binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by ADP and pyruvate; these compounds interfere with DLAT binding and thereby inhibit kinase activity. Inhibited by dichloroacetate. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity.

Induction. Down-regulated by insulin. Up-regulated by reactive oxygen species and cigarette smoke extract. Up-regulated by PPARD.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q15119-1	1	yes
Q15119-2	2

RefSeq proteins (3): NP_001186827, NP_001186828, NP_002602* (*=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 (50 total): helix 18, strand 12, turn 6, binding site 4, modified residue 3, sequence conflict 2, transit peptide 1, chain 1, splice variant 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5J71	X-RAY DIFFRACTION	1.65
4MPC	X-RAY DIFFRACTION	1.7
4MP2	X-RAY DIFFRACTION	1.75
4MPN	X-RAY DIFFRACTION	1.75
6LIO	X-RAY DIFFRACTION	1.76
6TN2	X-RAY DIFFRACTION	1.77
4MP7	X-RAY DIFFRACTION	1.8
7VBU	X-RAY DIFFRACTION	1.89
6TN0	X-RAY DIFFRACTION	1.91
9M3U	X-RAY DIFFRACTION	1.92
6LIL	X-RAY DIFFRACTION	1.93
4MPE	X-RAY DIFFRACTION	1.95
7EBH	X-RAY DIFFRACTION	1.96
7EAS	X-RAY DIFFRACTION	1.97
5J6A	X-RAY DIFFRACTION	2.04
6TMP	X-RAY DIFFRACTION	2.08
9M3T	X-RAY DIFFRACTION	2.08
6TMQ	X-RAY DIFFRACTION	2.11
9M3R	X-RAY DIFFRACTION	2.14
2BTZ	X-RAY DIFFRACTION	2.2
7VBV	X-RAY DIFFRACTION	2.21
5M4P	X-RAY DIFFRACTION	2.3
7EA0	X-RAY DIFFRACTION	2.34
8ZM2	X-RAY DIFFRACTION	2.34
2BU5	X-RAY DIFFRACTION	2.35
8ZM1	X-RAY DIFFRACTION	2.35
2BU2	X-RAY DIFFRACTION	2.4
2BU6	X-RAY DIFFRACTION	2.4
2BU7	X-RAY DIFFRACTION	2.4
5M4M	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15119-F1	91.16	0.80

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): 251–258; 290; 309–310; 325–330

Post-translational modifications (3): 215, 216, 376

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517	Signaling by Retinoic Acid

MSigDB gene sets: 218 (showing top): BIOCARTA_PTEN_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GTTAAAG_MIR302B, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, USF_C, GOBP_KETONE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (13): glucose metabolic process (GO:0006006), regulation of gluconeogenesis (GO:0006111), regulation of pH (GO:0006885), insulin receptor signaling pathway (GO:0008286), regulation of pyruvate decarboxylation to acetyl-CoA (GO:0010510), regulation of ketone metabolic process (GO:0010565), regulation of glucose metabolic process (GO:0010906), cellular response to nutrient (GO:0031670), cellular response to reactive oxygen species (GO:0034614), glucose homeostasis (GO:0042593), regulation of calcium-mediated signaling (GO:0050848), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), cellular response to stress (GO:0033554)

GO Molecular Function (8): protein kinase activity (GO:0004672), pyruvate dehydrogenase (acetyl-transferring) kinase activity (GO:0004740), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), pyruvate dehydrogenase complex (GO:0045254)

Reactome top-level categories

Rollup of top-2 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoplasm	2
hexose metabolic process	1
gluconeogenesis	1
regulation of glucose metabolic process	1
regulation of carbohydrate biosynthetic process	1
monoatomic cation homeostasis	1
biological regulation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	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
response to nutrient	1
cellular response to nutrient levels	1
cellular response to chemical stimulus	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
carbohydrate homeostasis	1
calcium-mediated signaling	1
regulation of intracellular signal transduction	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	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
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1

Protein interactions and networks

STRING

3144 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDK2	AKT1	P31749	763
PDK2	PDP2	Q9P2J9	706
PDK2	RICTOR	Q6R327	691
PDK2	MTOR	P42345	669
PDK2	PDHX	O00330	662
PDK2	PDK1	Q15118	650
PDK2	KIF3C	O14782	638
PDK2	TP53	P04637	615
PDK2	PDHA1	P08559	605
PDK2	DLAT	P10515	596
PDK2	KIF3B	O15066	588
PDK2	PRKD1	Q15139	579
PDK2	PPP1R15A	O75807	572
PDK2	PDP1	Q9P0J1	570
PDK2	PDPK1	O15530	563

IntAct

48 interactions, top by confidence:

A	B	Type	Score
PDK1	PDK2	psi-mi:“MI:0914”(association)	0.710
FECH	PGRMC1	psi-mi:“MI:0914”(association)	0.700
HTT	PDK2	psi-mi:“MI:0915”(physical association)	0.670
STAT5A	PDHA1	psi-mi:“MI:0914”(association)	0.640
PDK4	PDK2	psi-mi:“MI:0914”(association)	0.640
SYT12	B4GALT5	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
SYT12	PDK2	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
VSIG4	PDK2	psi-mi:“MI:0915”(physical association)	0.370
SPG11	PDK2	psi-mi:“MI:0915”(physical association)	0.370
Hdac6	TDG	psi-mi:“MI:0914”(association)	0.350
PDK1	VWA8	psi-mi:“MI:0914”(association)	0.350
ACAD9	A2ML1	psi-mi:“MI:0914”(association)	0.350
FOXD4		psi-mi:“MI:0914”(association)	0.350
PDHB		psi-mi:“MI:0914”(association)	0.350
PDK3		psi-mi:“MI:0914”(association)	0.350

BioGRID (55): PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK2 (Positive Genetic)

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: 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

9 interactions.

A	Effect	B	Mechanism
PDK2	down-regulates	PDHA2	phosphorylation
PDK2	down-regulates	PDHA1	phosphorylation
PDK2	“up-regulates activity”	PARL	phosphorylation
PDK2	“down-regulates activity”	PDHA1	phosphorylation
PDK2	“up-regulates activity”	AKT1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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	186.2×	4e-11
Signaling by Retinoic Acid	6	106.4×	9e-10
Mitochondrial protein degradation	5	24.8×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
425666	Single allele	Pathogenic

SpliceAI

1469 predictions. Top by Δscore:

Variant	Effect	Δscore
17:50097561:GCTG:G	donor_gain	1.0000
17:50105369:A:T	acceptor_loss	1.0000
17:50105370:GGT:G	acceptor_gain	1.0000
17:50105438:AGCCA:A	donor_gain	1.0000
17:50105439:GCCA:G	donor_gain	1.0000
17:50105439:GCCAG:G	donor_gain	1.0000
17:50105440:CCA:C	donor_gain	1.0000
17:50105441:CA:C	donor_gain	1.0000
17:50105442:AG:A	donor_loss	1.0000
17:50105443:G:GG	donor_gain	1.0000
17:50105443:GTGA:G	donor_loss	1.0000
17:50105444:T:A	donor_loss	1.0000
17:50105879:CCACA:C	acceptor_loss	1.0000
17:50105880:CACAG:C	acceptor_loss	1.0000
17:50105882:CAGG:C	acceptor_loss	1.0000
17:50105883:A:AG	acceptor_gain	1.0000
17:50105883:A:C	acceptor_loss	1.0000
17:50105883:AG:A	acceptor_gain	1.0000
17:50105884:G:A	acceptor_loss	1.0000
17:50105884:G:GA	acceptor_gain	1.0000
17:50105884:GG:G	acceptor_gain	1.0000
17:50105884:GGT:G	acceptor_gain	1.0000
17:50105884:GGTT:G	acceptor_gain	1.0000
17:50105884:GGTTC:G	acceptor_gain	1.0000
17:50106008:G:GG	donor_gain	1.0000
17:50106065:GCACA:G	donor_gain	1.0000
17:50106066:CACA:C	donor_gain	1.0000
17:50106068:CA:C	donor_gain	1.0000
17:50106069:AG:A	donor_loss	1.0000
17:50106070:G:GG	donor_gain	1.0000

AlphaMissense

2702 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:50097458:T:C	F52L	1.000
17:50097460:C:A	F52L	1.000
17:50097460:C:G	F52L	1.000
17:50105381:A:C	S91R	1.000
17:50105383:C:A	S91R	1.000
17:50105383:C:G	S91R	1.000
17:50105917:G:C	R122P	1.000
17:50106016:T:C	L155P	1.000
17:50106022:G:C	R157P	1.000
17:50106037:G:C	R162P	1.000
17:50106043:C:T	S164F	1.000
17:50108232:G:C	K254N	1.000
17:50108232:G:T	K254N	1.000
17:50109297:G:A	G327D	1.000
17:50109302:G:T	G329W	1.000
17:50109303:G:A	G329E	1.000
17:50109341:G:A	G342R	1.000
17:50109341:G:C	G342R	1.000
17:50095527:T:C	L31P	0.999
17:50095530:C:T	S32F	0.999
17:50095550:T:C	F39L	0.999
17:50095552:C:A	F39L	0.999
17:50095552:C:G	F39L	0.999
17:50097423:G:A	G40E	0.999
17:50097459:T:C	F52S	0.999
17:50097462:T:A	L53H	0.999
17:50097462:T:C	L53P	0.999
17:50097470:G:A	E56K	0.999
17:50097474:T:C	L57P	0.999
17:50097482:C:A	R60S	0.999

dbSNP variants (sampled 300 via entrez): RS1000183546 (17:50098680 C>T), RS1000192711 (17:50094503 CG>C), RS1000296936 (17:50102677 G>A), RS1000297765 (17:50098938 G>A), RS1000459142 (17:50104695 C>A,T), RS1001185835 (17:50095980 G>A), RS1001238360 (17:50096241 G>A,C,T), RS1001288873 (17:50096453 G>A,C), RS1001354963 (17:50109047 T>C), RS1001569686 (17:50103728 A>G), RS1001603322 (17:50108058 C>A,T), RS1001791087 (17:50110080 A>G), RS1001823076 (17:50102089 G>A), RS1001884719 (17:50106367 A>G), RS1002081420 (17:50109710 T>A)

Disease associations

OMIM: gene MIM:602525 | disease phenotypes: MIM:166200

GenCC curated gene-disease

Mondo (1): osteogenesis imperfecta type 1 (MONDO:0008146)

Orphanet (2): Osteogenesis imperfecta type 1 (Orphanet:216796), Osteogenesis imperfecta (Orphanet:666)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096665 (PROTEIN FAMILY), CHEMBL3861 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 22 (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
CHEMBL3673096	JTT-251	2	22

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
AZD7545	Inhibition	8.19	pIC50
VER-246608	Inhibition	7.08	pIC50

Binding affinities (BindingDB)

609 measured of 667 human assays (667 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
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
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-[4-[(9R)-9-hydroxy-2-[2-(3-hydroxy-1-adamantyl)ethoxy]-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]acetamide	IC50	5.1 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
2-[4-[(9R)-2-fluoro-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-2-methylpropanamide	IC50	5.1 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
PA1	KD	6 nM
(9R)-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-(2-hydroxy-2-methylpropoxy)-9-(trifluoromethyl)fluoren-9-ol	IC50	6.7 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
(9R)-2-(2-hydroxy-2-methylpropoxy)-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-9-ol	IC50	7.4 nM	US-9040717: Pyrazole-amide compounds and pharmaceutical use thereof
2-(4-hydroxybutoxy)-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	IC50	14 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[9-hydroxy-2-methyl-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-N-methylacetamide	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[9-hydroxy-2-[2-(3-hydroxy-1-adamantyl)ethoxy]-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]acetamide	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[2-(3-hydroxy-1-adamantyl)ethoxy]-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[1-[1-(hydroxymethyl)cyclopentyl]pyrazol-4-yl]-2-methyl-9-(trifluoromethyl)fluoren-9-ol	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[1-(cyclohexylmethyl)pyrazol-4-yl]-9-hydroxy-9-(trifluoromethyl)fluorene-4-carboxamide	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[9-hydroxy-2-(2-methylprop-1-enyl)-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propane-1,3-diol	IC50	15 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[9-hydroxy-2-methyl-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]acetamide	IC50	16 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[2-fluoro-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-N-methylacetamide	IC50	16 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[2-(3-hydroxy-1-adamantyl)ethoxy]-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-9-ol	IC50	16 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-fluoro-4-[1-[1-(hydroxymethyl)cyclopentyl]pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	IC50	16 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[1-(2,2-dimethylpropyl)pyrazol-4-yl]-9-hydroxy-9-(trifluoromethyl)fluorene-4-carboxamide	IC50	16 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-chloro-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-9-ol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-9-(trifluoromethyl)fluoren-9-ol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-fluoro-4-[1-[1-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
5-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxypentanoic acid	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[1-(2,2-dimethylpropyl)pyrazol-4-yl]-4-(hydroxymethyl)-9-(trifluoromethyl)fluoren-9-ol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[2-(3,3-dimethylbutyl)-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propane-1,3-diol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[1-(cyclohexylmethyl)pyrazol-4-yl]-4-(hydroxymethyl)-9-(trifluoromethyl)fluoren-9-ol	IC50	17 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyacetamide	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[9-hydroxy-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-2-yl]oxyacetamide	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[9-hydroxy-4-(1-propan-2-ylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxybutanoic acid	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
(2S)-3-[4-[2-fluoro-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propane-1,2-diol	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-(1-methylpyrazol-4-yl)-2-[3-(2H-tetrazol-5-yl)propoxy]-9-(trifluoromethyl)fluoren-9-ol	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[[4-[9-hydroxy-2-methyl-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]methyl]propane-1,3-diol	IC50	18 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[9-hydroxy-4-pyrimidin-5-yl-9-(trifluoromethyl)fluoren-2-yl]oxy-N,N-dimethylbutanamide	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
1-[3-(hydroxymethyl)azetidin-1-yl]-2-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyethanone	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxybutanoic acid	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2,4-bis(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-9-ol	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
3-[4-[2-ethoxy-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propanoic acid	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[9-hydroxy-2-methyl-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propane-1,3-diol	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-(hydroxymethyl)-2-[4-[9-hydroxy-2-methyl-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]propane-1,3-diol	IC50	19 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
1-[4-[9-hydroxy-4-pyridin-3-yl-9-(trifluoromethyl)fluoren-2-yl]piperazin-1-yl]-2,2-dimethylpropan-1-one	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxy-N,N-dimethylbutanamide	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
1-(3-hydroxyazetidin-1-yl)-2-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyethanone	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
[9-hydroxy-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-2-yl]-pyrrolidin-1-ylmethanone	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
1-[2-[9-hydroxy-4-(1H-pyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyethyl]pyrrolidin-2-one	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-fluoro-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-(1-ethylpyrazol-4-yl)-9-hydroxy-9-(trifluoromethyl)fluorene-4-carboxamide	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
4-[4-(1-ethylpyrazol-4-yl)-9-hydroxy-9-(trifluoromethyl)fluoren-2-yl]oxybutanoic acid	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-[4-[2-fluoro-9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-2-(hydroxymethyl)propane-1,3-diol	IC50	20 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
N-[2-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyethyl]-N-methylacetamide	IC50	21 nM	US-8871934: Fluorene compound and pharmaceutical use thereof
2-hydroxy-N-[2-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxyethyl]-N-methylacetamide	IC50	21 nM	US-8871934: Fluorene compound and pharmaceutical use thereof

ChEMBL bioactivities

1541 potent at pChembl≥5 of 1634 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	Kd	2.4	nM	CHEMBL5896437
8.60	Kd	2.5	nM	CHEMBL6011956
8.59	Kd	2.6	nM	CHEMBL5777543
8.55	Kd	2.8	nM	CHEMBL5835287
8.52	IC50	3	nM	CHEMBL5768930
8.52	IC50	3	nM	CHEMBL5938067
8.44	Kd	3.6	nM	CHEMBL6056190
8.42	Kd	3.8	nM	CHEMBL5801470
8.40	IC50	4	nM	CHEMBL5820129
8.40	IC50	4	nM	CHEMBL5748573
8.40	IC50	4	nM	CHEMBL5841031
8.40	IC50	4	nM	CHEMBL5835731
8.40	IC50	4	nM	CHEMBL5863265
8.40	IC50	4	nM	CHEMBL5746971
8.40	IC50	4	nM	CHEMBL5770074
8.40	IC50	4	nM	CHEMBL5751502
8.40	IC50	4	nM	CHEMBL5853304
8.40	IC50	4	nM	CHEMBL5932414
8.40	IC50	4	nM	CHEMBL6000011
8.40	IC50	4	nM	CHEMBL6008639
8.39	Kd	4.1	nM	CHEMBL5833317
8.38	IC50	4.2	nM	CHEMBL3673097
8.38	IC50	4.2	nM	CHEMBL5079107
8.38	Kd	4.2	nM	CHEMBL5856417
8.35	IC50	4.5	nM	CHEMBL5079949
8.34	IC50	4.6	nM	JTT-251
8.31	IC50	4.9	nM	JTT-251
8.31	Kd	4.9	nM	CHEMBL5815931
8.30	IC50	5	nM	CHEMBL5993765
8.30	IC50	5	nM	CHEMBL5915744
8.30	IC50	5	nM	CHEMBL5857688
8.30	IC50	5	nM	CHEMBL5782152
8.30	IC50	5	nM	CHEMBL5966862
8.30	IC50	5	nM	CHEMBL5741827
8.30	IC50	5	nM	CHEMBL5760395
8.30	IC50	5	nM	CHEMBL5844120
8.30	IC50	5	nM	CHEMBL5963093
8.30	IC50	5	nM	CHEMBL6040894
8.30	IC50	5	nM	CHEMBL5880436
8.30	IC50	5	nM	CHEMBL6024658
8.30	IC50	5	nM	CHEMBL5897540
8.30	IC50	5	nM	CHEMBL5988965
8.30	IC50	5	nM	CHEMBL5750845
8.30	IC50	5	nM	CHEMBL5871755
8.30	IC50	5	nM	CHEMBL6058366
8.30	IC50	5	nM	CHEMBL5971779
8.29	IC50	5.1	nM	CHEMBL3673092
8.29	IC50	5.1	nM	CHEMBL3673095
8.29	IC50	5.1	nM	CHEMBL5087040
8.26	IC50	5.5	nM	CHEMBL5072731

PubChem BioAssay actives

272 with measured affinity, of 454 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-[1-[5-(8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indol-3-yl)-1,3,4-oxadiazol-2-yl]-2-methylpropyl]-3-phenylpropanamide	1833814: Inhibition of human recombinant PDHK2 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	0.0042	uM
(3S,5S)-3-benzyl-1-(8-cyclopropyl-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-(hydroxymethyl)pyrrolidine-3-carboxamide	1833814: Inhibition of human recombinant PDHK2 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	0.0045	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	1833814: Inhibition of human recombinant PDHK2 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	0.0051	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	1833814: Inhibition of human recombinant PDHK2 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	0.0055	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	1833814: Inhibition of human recombinant PDHK2 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	0.0060	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
4-[(2R,5S)-2,5-dimethyl-4-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carbonyl]benzonitrile	1613835: Inhibition of E2-activated human PDHK2	ic50	0.0078	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-[(4-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604072: Inhibition of PDHK2 (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
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	1833814: Inhibition of human recombinant PDHK2 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	0.0092	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-[(5-bromofuran-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604072: Inhibition of PDHK2 (unknown origin) by radiometric biochemical kinase assay	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
[(2S,4S)-4-benzyl-1-(8-cyclopropyl-2-methyl-9H-pyrimido[4,5-b]indol-4-yl)-4-(hydroxymethyl)pyrrolidin-2-yl]methanol	1833814: Inhibition of human recombinant PDHK2 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	0.0146	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
4-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-9-(trifluoromethyl)fluoren-9-ol	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	ic50	0.0170	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	1833814: Inhibition of human recombinant PDHK2 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	0.0171	uM
N-[(5-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604072: Inhibition of PDHK2 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0180	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
4-[9-hydroxy-4-(1-methylpyrazol-4-yl)-9-(trifluoromethyl)fluoren-2-yl]oxybutanoic acid	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	ic50	0.0200	uM
2-fluoro-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	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
(3S)-3-amino-4-[4-[[2-(2,4-dihydroxyphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]amino]piperidin-1-yl]-4-oxobutanamide	1431615: Binding affinity to N-terminal His6-SUMO tagged recombinant human PDK2 by isothermal titration calorimetry	kd	0.0220	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
(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
azetidin-1-yl-[9-hydroxy-4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-2-yl]methanone	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	ic50	0.0300	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
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
N-benzyl-N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-dihydroxybenzamide	1833814: Inhibition of human recombinant PDHK2 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	0.0350	uM
2-[4-[9-hydroxy-9-(trifluoromethyl)fluoren-4-yl]pyrazol-1-yl]-N-methylacetamide	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	ic50	0.0440	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
(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
2-(8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indol-3-yl)-5-(2-methylpropyl)-1,3,4-oxadiazole	1833814: Inhibition of human recombinant PDHK2 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	0.0560	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
N-[(5-bromo-1,3-thiazol-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604072: Inhibition of PDHK2 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0640	uM
(3S)-3-amino-4-[3-[[2-(2,4-dihydroxyphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]amino]azetidin-1-yl]-4-oxobutanamide	1431607: Inhibition of N-terminal His6-SUMO tagged recombinant human PDK2 using [32P]-gamma-ATP assessed as decrease in incorporation of radioactivity into E1 protein incubated for 2 mins	ic50	0.0650	uM
N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-[[4-[[(2,2-difluoroacetyl)amino]methyl]phenyl]methyl]-2,4-dihydroxybenzamide	1604072: Inhibition of PDHK2 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0650	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
4-[1-(2-hydroxyethyl)pyrazol-4-yl]-9-(trifluoromethyl)fluoren-9-ol	2112526: Inhibition of human recombinant PDHK2 assessed as residual PDH activity in presence of ATP using sodium pyruvate/Coenzyme A/thiamine pyrophosphate as substrates incubated for 90 mins by UV-transparent microplate analysis	ic50	0.0660	uM
(2S)-2-amino-N-[3-[[2-(2,4-dihydroxyphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]amino]propyl]butanediamide	1431607: Inhibition of N-terminal His6-SUMO tagged recombinant human PDK2 using [32P]-gamma-ATP assessed as decrease in incorporation of radioactivity into E1 protein incubated for 2 mins	ic50	0.0670	uM
(2S)-2-amino-1-[4-[[2-(2,4-dihydroxyphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]amino]piperidin-1-yl]-3-hydroxypropan-1-one	1431607: Inhibition of N-terminal His6-SUMO tagged recombinant human PDK2 using [32P]-gamma-ATP assessed as decrease in incorporation of radioactivity into E1 protein incubated for 2 mins	ic50	0.0680	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
(4S)-4-amino-5-[4-[[2-(2,4-dihydroxyphenyl)sulfonyl-1,3-dihydroisoindol-5-yl]amino]piperidin-1-yl]-5-oxopentanamide	1431607: Inhibition of N-terminal His6-SUMO tagged recombinant human PDK2 using [32P]-gamma-ATP assessed as decrease in incorporation of radioactivity into E1 protein incubated for 2 mins	ic50	0.0720	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression, decreases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Estradiol	decreases expression, affects expression	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Quercetin	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
afuresertib	increases expression	1
VER-246608	affects binding, decreases activity	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
cupric chloride	decreases expression	1
vanadyl sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentabromodiphenyl ether	decreases expression	1
abrine	decreases expression	1
Bortezomib	decreases expression	1
Decitabine	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1

ChEMBL screening assays

98 unique, capped per target: 97 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

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TC80	HAP1 PDK2 (-) 1	Cancer cell line	Male
CVCL_TC81	HAP1 PDK2 (-) 2	Cancer cell line	Male
CVCL_TC82	HAP1 PDK2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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