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
• GTEx eGene: eQTL in 45 tissues, sQTL in 9 (q < 0.05)
• Drug target: yes — 1 via a complex or family; 1 molecules with ChEMBL bioactivity
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.92 (unconstrained)
• MANE Select transcript: NM_002611
• Interaction hub: 1,820 STRING partners (top 9% of genes corpus-wide)

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: 39 — 27 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000503176

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 6, TSL 3: 1, TSL 4: 6, TSL 5: 2

ENST00000503176, ENST00000007708, ENST00000503076, ENST00000503614, ENST00000505440, ENST00000505897, ENST00000506242, ENST00000506647, ENST00000508030, ENST00000508960, ENST00000510219, ENST00000511026, ENST00000512204, ENST00000512238, ENST00000515040, ENST00000614357, ENST00000892665, ENST00000892666, ENST00000892667, ENST00000892668, ENST00000892669, ENST00000892670, ENST00000892671, ENST00000930435, ENST00000969548, ENST00000969549, ENST00000969550, ENST00000998854, ENST00000998855, ENST00001019850, ENST00001019851, ENST00001019852, ENST00001019853, ENST00001019855, ENST00001112389, ENST00001126843, ENST00001126844, ENST00001126845, ENST00001142211

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.

Highest expression (Bgee): hindlimb stylopod muscle, hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, apex of heart.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PDK2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 9 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 54 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	6.6e-69	+0.42	17:50106107:G:A
Artery Tibial	eqtl	2.6e-51	-0.34	17:50111615:C:T
Nerve Tibial	eqtl	1.2e-44	-0.33	17:50107013:A:G
Lung	eqtl	2.2e-39	-0.28	17:50106924:G:A
Cells Cultured fibroblasts	eqtl	3.9e-37	-0.36	17:50095212:C:CG
Artery Aorta	eqtl	1.1e-33	-0.38	17:50104396:G:A
Colon Transverse	eqtl	6.6e-28	+0.24	17:50106107:G:A
Esophagus Muscularis	eqtl	1.5e-27	-0.23	17:50104396:G:A
Spleen	eqtl	6.2e-27	-0.54	17:50107013:A:G
Whole Blood	eqtl	9.9e-25	+1.31	17:50094805:G:A
Colon Sigmoid	eqtl	1.0e-23	-0.23	17:50108767:T:TCTC
Skin Sun Exposed Lower leg	eqtl	9.5e-22	-0.20	17:50106372:T:C
Muscle Skeletal	sqtl	1.2e-21	+0.81	17:50095801:G:A
Esophagus Mucosa	eqtl	7.9e-21	-0.25	17:50106372:T:C
Esophagus Gastroesophageal Junction	eqtl	9.5e-20	-0.21	17:50106372:T:C
Testis	eqtl	2.2e-19	-0.30	17:50101957:T:C
Prostate	eqtl	1.9e-18	-0.38	17:50095415:A:C
Breast Mammary Tissue	eqtl	3.1e-17	-0.26	17:50106924:G:A
Stomach	eqtl	4.7e-17	-0.25	17:50107013:A:G
Pituitary	eqtl	2.9e-16	-0.42	17:50095415:A:C

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

showing 100 of 295 tissues 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
triceps brachii	UBERON:0001509	94.42	gold quality
body of pancreas	UBERON:0001150	94.36	gold quality
cingulate cortex	UBERON:0003027	94.36	gold quality
anterior cingulate cortex	UBERON:0009835	94.36	gold quality
caudate nucleus	UBERON:0001873	94.31	gold quality
vastus lateralis	UBERON:0001379	94.27	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.27	gold quality
left ovary	UBERON:0002119	94.11	gold quality
skeletal muscle tissue	UBERON:0001134	94.10	gold quality
putamen	UBERON:0001874	94.08	gold quality
quadriceps femoris	UBERON:0001377	94.07	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.98	gold quality
stromal cell of endometrium	CL:0002255	93.94	gold quality
left ventricle myocardium	UBERON:0006566	93.94	gold quality
transverse colon	UBERON:0001157	93.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.90	gold quality
aorta	UBERON:0000947	93.87	gold quality
muscle tissue	UBERON:0002385	93.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.86	gold quality
adult mammalian kidney	UBERON:0000082	93.76	gold quality
body of stomach	UBERON:0001161	93.69	gold quality
middle frontal gyrus	UBERON:0002702	93.61	gold quality
left coronary artery	UBERON:0001626	93.57	gold quality
frontal cortex	UBERON:0001870	93.45	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.38	gold quality
descending thoracic aorta	UBERON:0002345	93.32	gold quality
lower esophagus	UBERON:0013473	93.32	gold quality
mucosa of transverse colon	UBERON:0004991	93.29	gold quality
coronary artery	UBERON:0001621	93.27	gold quality
amygdala	UBERON:0001876	93.14	gold quality
neocortex	UBERON:0001950	93.09	gold quality
body of tongue	UBERON:0011876	93.05	gold quality
metanephros cortex	UBERON:0010533	92.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.78	gold quality
frontal pole	UBERON:0002795	92.76	gold quality
thoracic aorta	UBERON:0001515	92.71	gold quality
ascending aorta	UBERON:0001496	92.53	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.44	gold quality
right lobe of liver	UBERON:0001114	92.35	gold quality
right lobe of thyroid gland	UBERON:0001119	92.23	gold quality
gall bladder	UBERON:0002110	92.12	gold quality
stomach	UBERON:0000945	92.09	gold quality
small intestine	UBERON:0002108	92.02	gold quality
biceps brachii	UBERON:0001507	91.85	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.82	gold quality
telencephalon	UBERON:0001893	91.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.77	gold quality
body of uterus	UBERON:0009853	91.68	gold quality
left lobe of thyroid gland	UBERON:0001120	91.63	gold quality
nerve	UBERON:0001021	91.60	gold quality
tibial nerve	UBERON:0001323	91.60	gold quality
fundus of stomach	UBERON:0001160	91.54	gold quality
brain	UBERON:0000955	91.44	gold quality
gluteal muscle	UBERON:0002000	91.44	gold quality
central nervous system	UBERON:0001017	91.35	gold quality
endocervix	UBERON:0000458	91.29	gold quality
cerebral cortex	UBERON:0000956	91.27	gold quality
forebrain	UBERON:0001890	91.11	gold quality
right uterine tube	UBERON:0001302	91.10	gold quality
myocardium	UBERON:0002349	90.96	gold quality
omental fat pad	UBERON:0010414	90.89	gold quality
peritoneum	UBERON:0002358	90.86	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.85	gold quality
thyroid gland	UBERON:0002046	90.83	gold quality
ectocervix	UBERON:0012249	90.79	gold quality
corpus epididymis	UBERON:0004359	90.65	gold quality
colon	UBERON:0001155	90.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.43	gold quality
intestine	UBERON:0000160	90.41	gold quality
ganglionic eminence	UBERON:0004023	90.41	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	265.8
Skeletal muscle	tissue	202.5	medium
Epididymis	tissue	117.4	medium
Heart muscle	tissue	94.1	medium
Frontal cortex	tissue	81.9
Cerebellum	tissue	78.6	high
Caudate putamen	tissue	71.7
Thalamus	tissue	65.5
Midbrain	tissue	65.4
Spinal cord	tissue	64.2
Kidney	tissue	58.6	medium
Nucleus accumbens	tissue	58.1
Medulla oblongata	tissue	57.7
Substantia nigra	tissue	55.5
Superior colliculi	tissue	54.7
Pons	tissue	54.1
Hippocampal formation	tissue	53.6
Cerebral cortex	tissue	53.0	medium
Somatosensory cortex	tissue	53.0
Periaqueductal gray	tissue	52.8
Hippocampus	tissue	50.5	medium
Postcentral gyrus	tissue	50.3
Occipital cortex	tissue	49.9
Corpus callosum	tissue	47.8
Liver	tissue	47.5	low
Motor cortex	tissue	47.0
Prefrontal cortex	tissue	45.8
Ovary	tissue	45.5	medium
Temporal cortex	tissue	44.7
Hypothalamus	tissue	44.3
Ventral forebrain	tissue	44.3
Septum	tissue	44.2
Entorhinal cortex	tissue	43.8
Putamen	tissue	41.9
Retrosplenial and cingulate cortex	tissue	40.8
Insular cortex	tissue	40.4
Locus coeruleus	tissue	39.8
Retrosplenial cortex	tissue	39.0
Basal ganglia	tissue	38.6	medium
Adipose tissue	tissue	38.3	low
Parathyroid gland	tissue	38.3	medium
Amygdala	tissue	38.3
Adrenal gland	tissue	36.4	high
Pancreas	tissue	33.6	high
Choroid plexus	tissue	30.2
Small intestine	tissue	29.0	high
Olfactory bulb	tissue	28.3
Duodenum	tissue	26.4	medium
Seminal vesicle	tissue	25.8	medium
Thyroid gland	tissue	25.6	medium
Salivary gland	tissue	24.3	low
Smooth muscle	tissue	24.0	low
Fallopian tube	tissue	22.8	medium
Endometrium 1	tissue	21.5	high
Colon	tissue	21.4	medium
Esophagus	tissue	20.3	medium
Vagina	tissue	20.2	not detected
Rectum	tissue	20.2	high
Prostate	tissue	20.0	medium
Skin 1	tissue	17.5	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Cerebellar cortex (89.6), Flocculonodular lobe (86.1), Vermis (83.2), Ventral spinal cord (64.2), Caudate nucleus (59.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PPARG

miRNA regulators (miRDB)

Targeting PDK2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 47 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 1.98e-07, LOEUF 0.92, missense Z 2.58 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000503176 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
17:50,095,436–50,105,390	100 / 115.5	0.87	no
17:50,105,391–50,106,837	63 / 135.1	0.47	no
17:50,106,838–50,110,094	214 / 294.0	0.73	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1343087) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver morphology	1
abnormal spleen morphology	1
enlarged spleen	1
enlarged lymph nodes	1
abnormal uterus morphology	1
abnormal testis morphology	1
enlarged testis	1
microphthalmia	1
abnormal skin morphology	1
abnormal kidney morphology	1
abnormal brain morphology	1
abnormal lymph node morphology	1
impaired skeletal muscle contractility	1
enlarged kidney	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q2KJG8	96.6%	Diamond
Rhinolophus ferrumequinum	Q1KMR4	93.6%	Diamond
Ictidomys tridecemlineatus	O88345	92.2%	Diamond
Ascaris suum	O02623	78.8%	Diamond
Arabidopsis thaliana	Q9SBJ1	41.8%	Diamond
Schizosaccharomyces pombe 972h-	Q9P6P9	38.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
COL1A1	protein-coding	1277
SAMD14	protein-coding	201191
SGCA	protein-coding	6442
PPP1R9B	protein-coding	84687
PDK2-AS1	ncRNA	124904026
PICART1	ncRNA	284080
ITGA3	protein-coding	3675
DLX3	protein-coding	1747
TILAM	ncRNA	101927230

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 (4): NP_001186827, NP_001186828, NP_001186829, 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)

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

UniProt features (52 total): helix 19, strand 13, 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)

showing 30 of 38 structures by resolution:

PDB	Title	Method	Resolution (Å)
5J71	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor …	X-RAY DIFFRACTION	1.65
4MPC	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS2	X-RAY DIFFRACTION	1.7
4MP2	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1	X-RAY DIFFRACTION	1.75
4MPN	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor …	X-RAY DIFFRACTION	1.75
6LIO	Crystal structure of human PDK2 complexed with GM67520	X-RAY DIFFRACTION	1.76
6TN2	Rapid optimisation of fragments and hits to lead compounds from screening of crude …	X-RAY DIFFRACTION	1.77
4MP7	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA7	X-RAY DIFFRACTION	1.8
7VBU	Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 5	X-RAY DIFFRACTION	1.89
6TN0	Rapid optimisation of fragments and hits to lead compounds from screening of crude …	X-RAY DIFFRACTION	1.91
9M3U	Crystal structure of human pyruvate dehydrogenase kinase isoform 2 in complex with ATP …	X-RAY DIFFRACTION	1.92
6LIL	Crystal structure of human PDK2 complexed with an allosteric inhibitor compound 8c	X-RAY DIFFRACTION	1.93
4MPE	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS8	X-RAY DIFFRACTION	1.95
7EBH	Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 13	X-RAY DIFFRACTION	1.96
7EAS	Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 2	X-RAY DIFFRACTION	1.97
5J6A	Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor …	X-RAY DIFFRACTION	2.04
6TMP	Rapid optimisation of fragments and hits to lead compounds from screening of crude …	X-RAY DIFFRACTION	2.08
9M3T	Crystal structure of human pyruvate dehydrogenase kinase isoform 2 in complex with ATP …	X-RAY DIFFRACTION	2.08
6TMQ	Rapid optimisation of fragments and hits to lead compounds from screening of crude …	X-RAY DIFFRACTION	2.11
9M3R	Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP …	X-RAY DIFFRACTION	2.14
2BTZ	crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and …	X-RAY DIFFRACTION	2.2
7VBV	Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 7	X-RAY DIFFRACTION	2.21
5M4P	Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors …	X-RAY DIFFRACTION	2.3
7EA0	Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 1	X-RAY DIFFRACTION	2.34
8ZM2	Structure of human pyruvate dehydrogenase kinase 2 complexed with compound 16	X-RAY DIFFRACTION	2.34
2BU5	crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and …	X-RAY DIFFRACTION	2.35
8ZM1	Structure of human pyruvate dehydrogenase kinase 2 complexed with compound 6	X-RAY DIFFRACTION	2.35
2BU2	crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and …	X-RAY DIFFRACTION	2.4
2BU6	crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and …	X-RAY DIFFRACTION	2.4
2BU7	crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and …	X-RAY DIFFRACTION	2.4
5M4M	Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors …	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Atypical kinases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm

Antibody reliability (HPA): IH supported · IF approved

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)

Position	Role
251–258	ATP
290	ATP
309–310	ATP
325–330	ATP

Post-translational modifications (3)

Type	Positions
Phosphotyrosine	215, 216
N6-succinyllysine	376

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex	curated
R-HSA-5362517	Signaling by Retinoic Acid	curated
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-1430728	Metabolism	—
R-HSA-70268	Pyruvate metabolism	—
R-HSA-9861718	Regulation of pyruvate metabolism	—
R-HSA-162582	Signal Transduction	—
R-HSA-9006931	Signaling by Nuclear Receptors	—

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

Reactome top-level categories

6 top-level categories:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1
Signal Transduction	1
Pyruvate metabolism	1

GO top-level categories

46 GO namespaces:

Category	Terms
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
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
anion binding	1
identical protein binding	1
protein dimerization activity	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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to reactive oxygen species	BP	mutant phenotype
intrinsic apoptotic signaling pathway by p53 class mediator	BP	mutant phenotype
mitochondrion	CC	direct assay
ATP binding	MF	direct assay
protein homodimerization activity	MF	physical interaction
pyruvate dehydrogenase (acetyl-transferring) kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,820 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDK2	AKT1	P31749	753
PDK2	PDP2	Q9P2J9	698
PDK2	KIF3C	O14782	656
PDK2	KIF3B	O15066	626
PDK2	PDP1	Q9P0J1	593
PDK2	KIF3A	Q9Y496	591
PDK2	PRKD1	Q15139	574
PDK2	PPP1R15A	O75807	564
PDK2	PDHA1	P08559	563
PDK2	PDHB	P11177	551
PDK2	PDHX	O00330	548
PDK2	PDPR	Q8NCN5	546
PDK2	RICTOR	Q6R327	536
PDK2	ARRB1	P49407	520
PDK2	MTOR	P42345	507

IntAct

Human interaction partners of PDK2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
PDK1	association	0.710	1
HTT	physical association	0.670	10
PDK4	association	0.640	1
SYT12	association	0.530	1
SPG11	physical association	0.370	1
VSIG4	physical association	0.370	1
HLA-A	association	0.350	1
HIC2	physical association	0.000	1
ISOC2	physical association	0.000	1

BioGRID (58 interactions; top human partners by supporting records): PDK1 (Affinity Capture-MS; 7 records), ACAD9 (Affinity Capture-MS; 3 records), PDHB (Affinity Capture-MS; 3 records), PDK3 (Affinity Capture-MS; 3 records), DLAT (Reconstituted Complex; 2 records), FECH (Affinity Capture-MS; 2 records), FOXD4 (Affinity Capture-MS; 2 records), PDK4 (Affinity Capture-MS; 2 records), SIRT3 (Affinity Capture-MS; 2 records), STAT5A (Affinity Capture-MS; 2 records), SYT12 (Affinity Capture-MS; 2 records), AARS2 (Proximity Label-MS), ADCK2 (Affinity Capture-MS), CKM (Positive Genetic), CSK (Positive Genetic)

SIGNOR signaling

showing 5 of 9 signaling 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

Disease & clinical

Genetic variants

Variant evidence for PDK2: 42 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

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)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
425666	Single allele	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PDK2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 740):

Position(s)	Effect	Δscore	Sites
17:50095555	donor_loss	1.0000
17:50105369–50105370	acceptor_loss	1.0000	3
17:50105443–50105444	donor_loss	1.0000	5
17:50105883–50105884	acceptor_loss	1.0000	4
17:50106070	donor_loss	1.0000	2
17:50106785	acceptor_gain	1.0000
17:50106792–50106793	acceptor_loss	1.0000	4
17:50106884–50106885	donor_loss	1.0000	5
17:50107074	acceptor_loss	1.0000	3
17:50107154–50107155	donor_loss	1.0000	5

AlphaMissense

1,342 missense substitutions predicted likely pathogenic (of 2,702 scored), across 294 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M167	9	0.943	0.998
N255	8	0.997	0.999
H123	8	0.995	0.998
D290	8	0.995	0.998
F39	8	0.987	0.999
F340	8	0.985	0.998
H172	8	0.983	0.996
F52	8	0.979	1.000
F154	8	0.979	0.999
D390	8	0.979	0.994
H244	8	0.977	0.998
D156	8	0.971	0.999
F176	8	0.966	0.998
F304	8	0.965	0.999
D38	8	0.963	0.988
F112	8	0.959	0.999
D283	8	0.959	0.988
F36	8	0.954	0.998
F158	8	0.951	0.998
F250	8	0.939	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.42e-06
Kidney Renal Clear Cell Carcinoma (validation)	favorable	7.17e-05
Lung Adenocarcinoma (TCGA)	favorable	0.000532

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)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes PDK2 — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
SODIUM DICHLOROACETATE	Pyruvate dehydrogenase kinase	4	3

Molecules with ChEMBL bioactivity

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).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3673096	JTT-251	2	22

PharmGKB: 1 entry (CPIC guideline: no)

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)

1187 measured of 1295 human assays (1297 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1-methyl-3-phenylpyrazol-5-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	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[1-cyclopropyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazol-3-yl]benzonitrile	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[5-cyclopropyl-1-(2,2,2-trifluoroethyl)pyrazol-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	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl]-(3-pyridin-2-ylphenyl)methanone	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
6-[2-fluoro-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]pyridine-3-carbonitrile	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
5-fluoro-2-[1-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazol-3-yl]benzonitrile	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
3-fluoro-4-[4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-fluoro-3-(5-fluoro-2-pyridinyl)phenyl]-[(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	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[5-(4-fluorophenyl)-3-pyridinyl]-[(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	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[2-(2,4-difluorophenyl)-4-pyridinyl]-[(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	3 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
(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
2-methyl-3-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]indazole-6-carbonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[3-cyclopropyl-1-(2,2,2-trifluoroethyl)pyrazol-5-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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[5-(4-fluorophenyl)-2-pyridinyl]-[(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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
3-fluoro-4-[1-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazol-3-yl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-(1-hydroxycyclobutyl)phenyl]-[(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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-(1-hydroxycyclopentyl)phenyl]-[(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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[1-cyclopropyl-3-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazol-5-yl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
5-fluoro-2-[4-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[3-methyl-4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[3-(5-chloro-2-pyridinyl)-1-methylpyrazol-5-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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[5-fluoro-4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
3-fluoro-4-[5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-3-pyridinyl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[3-fluoro-4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
5,6-dihydro-4H-pyrrolo[2,1-e]pyrazol-2-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
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
(5-cyclopropyl-1-methylpyrazol-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
[1-methyl-3-(1-methylcyclopropyl)pyrazol-5-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
[1-methyl-5-(1-methylcyclopropyl)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	4 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
CHEMBL5079949	IC50	4.5 nM
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
3-cyclopropyl-1-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazole-4-carbonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[4-chloro-1-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]pyrazol-3-yl]benzonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[1-methyl-3-(4-methylsulfonylphenyl)pyrazol-5-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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[4-methyl-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-1,3-oxazol-2-yl]benzonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
3-methyl-4-[4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-fluoro-3-(2-methylpyrazol-3-yl)phenyl]-[(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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[4-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-2-pyridinyl]benzonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
5-fluoro-2-[2-fluoro-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]pyridine-3-carbonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
6-[3-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]pyridine-3-carbonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[3-(5-fluoro-2-pyridinyl)-1-methylpyrazol-5-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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-fluoro-3-(3-fluoro-4-pyridinyl)phenyl]-[(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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
[4-fluoro-3-(5-fluoro-3-pyridinyl)phenyl]-[(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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
4-[2-fluoro-5-[(5S)-5-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]pyridine-3-carbonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
1-[(1S)-1-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl]-3,4-dihydro-1H-isoquinolin-2-yl]ethanone	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
(3-cyclopropyl-1-methylpyrazol-5-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	5 nM	US-10800784: Nitrogen-containing heterocyclic amide compound and pharmaceutical use thereof
1-cyclopropyl-5-[(4R)-4-methyl-3-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl]pyrazole-3-carbonitrile	IC50	5 nM	US-10800784: Nitrogen-containing heterocyclic amide 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

276 with measured affinity, of 471 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
2-cyano-N-[(3R)-1-[3-ethyl-7-(ethylamino)-5-fluoro-2-oxo-1H-indol-3-yl]piperidin-3-yl]-2-azaspiro[3.3]heptane-6-carboxamide	2276871: Inhibition of PDHK2 (unknown origin)	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
3-[3-chloro-4-[4-(ethylamino)-6-fluoro-2-oxo-3H-benzimidazol-1-yl]-5-methylphenoxy]benzoic acid	2276871: Inhibition of PDHK2 (unknown origin)	ic50	0.0340	uM
sodium (2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-3-phenylpropanoate	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0340	uM
(2R)-N-[2-chloro-4-[2-(4-fluorophenyl)ethylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0350	uM
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

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	affects expression, decreases 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	decreases activity, affects binding	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	increases oxidation, increases abundance, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PDK2 across ~30M SureChEMBL compounds — explore on Sugi Predict.