PDK3

Summary

PDK3 (pyruvate dehydrogenase kinase 3, HGNC:8811) is a protein-coding gene on chromosome Xp22.11, encoding [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial (Q15120). Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration.

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5165 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease X-linked dominant 6 (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 309 total
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_005391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8811
Approved symbol	PDK3
Name	pyruvate dehydrogenase kinase 3
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000067992
Ensembl biotype	protein_coding
OMIM	300906
Entrez	5165

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000379162, ENST00000493226, ENST00000568479, ENST00000648777, ENST00000688031, ENST00000688551, ENST00000862654, ENST00000930024

RefSeq mRNA: 2 — MANE Select: NM_005391 NM_001142386, NM_005391

CCDS: CCDS14212, CCDS48088

Canonical transcript exons

ENST00000379162 — 11 exons

Exon	Start	End
ENSE00000370908	24527574	24527675
ENSE00000370910	24531657	24531770
ENSE00000667142	24498829	24498900
ENSE00000667143	24503327	24503511
ENSE00000667144	24505209	24505298
ENSE00000667146	24526198	24526274
ENSE00000667176	24528076	24528186
ENSE00000863221	24494742	24494883
ENSE00001259254	24518933	24519010
ENSE00001857428	24533929	24534422
ENSE00003844616	24465286	24465561

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.5172 / max 504.7009, expressed in 1717 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195798	22.5172	1717

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	98.76	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.69	gold quality
corpus epididymis	UBERON:0004359	98.07	gold quality
saphenous vein	UBERON:0007318	97.33	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.11	gold quality
upper leg skin	UBERON:0004262	97.04	gold quality
caput epididymis	UBERON:0004358	96.88	gold quality
jejunal mucosa	UBERON:0000399	96.73	gold quality
endothelial cell	CL:0000115	96.59	gold quality
parotid gland	UBERON:0001831	96.33	gold quality
tibia	UBERON:0000979	95.66	gold quality
skin of hip	UBERON:0001554	95.59	gold quality
parietal lobe	UBERON:0001872	95.41	gold quality
postcentral gyrus	UBERON:0002581	95.33	gold quality
pons	UBERON:0000988	95.07	gold quality
visceral pleura	UBERON:0002401	95.01	gold quality
superficial temporal artery	UBERON:0001614	94.37	gold quality
entorhinal cortex	UBERON:0002728	94.36	gold quality
renal medulla	UBERON:0000362	94.25	gold quality
dorsal root ganglion	UBERON:0000044	94.07	gold quality
gingival epithelium	UBERON:0001949	93.85	gold quality
mammary duct	UBERON:0001765	93.81	gold quality
trigeminal ganglion	UBERON:0001675	93.77	gold quality
germinal epithelium of ovary	UBERON:0001304	93.67	gold quality
vena cava	UBERON:0004087	93.47	gold quality
pleura	UBERON:0000977	93.41	gold quality
parietal pleura	UBERON:0002400	93.38	gold quality
trabecular bone tissue	UBERON:0002483	93.35	gold quality
gingiva	UBERON:0001828	93.23	gold quality
cauda epididymis	UBERON:0004360	93.03	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	27.06
E-MTAB-5061	yes	26.61
E-GEOD-83139	yes	9.07
E-MTAB-6379	no	750.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, PPARA

miRNA regulators (miRDB)

23 targeting PDK3, 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-432-3P	100.00	67.86	705
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-2355-3P	96.84	68.54	909
HSA-MIR-4714-3P	96.53	67.44	452

Literature-anchored findings (GeneRIF, showing 18)

• mRNA levels not changed in skeletal muscle during fasting (PMID:14966024)
• analysis of residues in L2 and residues in the C-terminal region and the lipoyl-binding pocket of PDK3 which are critical determinants for the cross-talk between L2 and PDK3, which up-regulates PDK3 activity (PMID:16849321)
• crystal structure of the asymmetric PDHK3/lipoyl domain 2 complex; data suggest that the asymmetric complex represents a physiological state in which binding of a single L2-domain activates one of the PDHK protomers while inactivating another (PMID:17532006)
• 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)
• Distinct structural mechanisms for inhibition of PDK3 by AZD7545, dichloroacetate, and radicol. (PMID:17683942)
• increased PDK3 expression due to elevated HIF-1alpha in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy (PMID:18718909)
• Findings suggest the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma. (PMID:22865452)
• Reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the pyruvate dehydrogenase complex is the underlying pathogenic cause of peripheral neuropathy in X-linked dominant Charcot-Marie-Tooth disease. (PMID:23297365)
• Accordingly, elevated levels of PDK1, PDK3, and PKM2 and reduced PK activity could be observed in iPSCs and human embryonic stem cells in the undifferentiated state (PMID:24123565)
• We have identified a p.R158H PDK3 mutation in a Korean X-linked dominant Charcot-Marie-Tooth type 6 family (PMID:26801680)
• The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. (PMID:27626669)
• Overexpression of PDK2 and PDK3 reflects poor prognosis in acute myeloid leukemia. (PMID:30578412)
• PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance. (PMID:31244938)
• miR-497-5p inhibits gastric cancer cell proliferation and growth through targeting PDK3. (PMID:31409724)
• Effect of pH on the structure and function of pyruvate dehydrogenase kinase 3: Combined spectroscopic and MD simulation studies. (PMID:31982536)
• Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation. (PMID:32504000)
• Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model. (PMID:34387338)
• Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families. (PMID:37849068)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdk3a	ENSDARG00000014527
danio_rerio	pdk3b	ENSDARG00000099791
mus_musculus	Pdk3	ENSMUSG00000035232
rattus_norvegicus	Pdk3	ENSRNOG00000012513
drosophila_melanogaster	Pdk	FBGN0017558
caenorhabditis_elegans		WBGENE00022719

Paralogs (4): PDK4 (ENSG00000004799), PDK2 (ENSG00000005882), BCKDK (ENSG00000103507), PDK1 (ENSG00000152256)

Protein

Protein identifiers

[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial — Q15120 (reviewed: Q15120)

Alternative names: Pyruvate dehydrogenase kinase isoform 3

All UniProt accessions (1): Q15120

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.

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

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed in heart, skeletal muscle, spinal cord, as well as fetal and adult brain.

Disease relevance. Charcot-Marie-Tooth disease, X-linked dominant, 6 (CMTX6) [MIM:300905] A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by interaction with DLAT. Inhibited by AZD7545, dichloroacetate and radicicol.

Induction. Up-regulated in response to hypoxia. Up-regulated in response to fatty acids. Up-regulated by PPARD.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q15120-1	1	yes
Q15120-2	2

RefSeq proteins (2): NP_001135858, NP_005382* (*=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 (47 total): helix 17, strand 11, sequence variant 4, binding site 4, mutagenesis site 2, turn 2, transit peptide 1, chain 1, splice variant 1, domain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
1Y8O	X-RAY DIFFRACTION	2.48
2PNR	X-RAY DIFFRACTION	2.5
1Y8N	X-RAY DIFFRACTION	2.6
2Q8I	X-RAY DIFFRACTION	2.6
1Y8P	X-RAY DIFFRACTION	2.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15120-F1	91.32	0.81

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): 247–254; 287; 306–307; 323–328

Post-translational modifications (1): 278

Mutagenesis-validated functional residues (2):

Position	Phenotype
120	no effect on kinase activity; when associated with n-121.
121	no effect on kinase activity; when associated with h-120.

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: 359 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_CELLULAR_RESPONSE_TO_LIPID, CHUNG_BLISTER_CYTOTOXICITY_DN, MORF_BRCA1, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOZGIT_ESR1_TARGETS_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (9): regulation of pyruvate decarboxylation to acetyl-CoA (GO:0010510), regulation of glucose metabolic process (GO:0010906), peptidyl-serine phosphorylation (GO:0018105), peroxisome proliferator activated receptor signaling pathway (GO:0035357), cellular response to glucose stimulus (GO:0071333), cellular response to fatty acid (GO:0071398), hypoxia-inducible factor-1alpha signaling pathway (GO:0097411), regulation of reactive oxygen species metabolic process (GO:2000377), cellular response to stress (GO:0033554)

GO Molecular Function (8): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), pyruvate dehydrogenase (acetyl-transferring) kinase activity (GO:0004740), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
pyruvate decarboxylation to acetyl-CoA	1
regulation of acyl-CoA biosynthetic process	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
protein phosphorylation	1
peptidyl-serine modification	1
nuclear receptor-mediated signaling pathway	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
response to fatty acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
intracellular signal transduction	1
cellular response to hypoxia	1
regulation of metabolic process	1
reactive oxygen species metabolic process	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 kinase activity	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDK3	SMPX	Q9UHP9	893
PDK3	PDHA1	P08559	881
PDK3	ITGB1BP2	Q9UKP3	829
PDK3	PDP2	Q9P2J9	712
PDK3	DLAT	P10515	654
PDK3	PDHB	P11177	622
PDK3	FOXO4	P98177	616
PDK3	PDHX	O00330	588
PDK3	PDPR	Q8NCN5	572
PDK3	LDHA	P00338	550
PDK3	PDP1	Q9P0J1	547
PDK3	DLD	P09622	505
PDK3	HIF1A	Q16665	480
PDK3	DHTKD1	Q96HY7	474
PDK3	PKM	P14618	467
PDK3	SLC2A1	P11166	467

IntAct

73 interactions, top by confidence:

A	B	Type	Score
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PDK1	PDK2	psi-mi:“MI:0914”(association)	0.710
DLAT	PDK3	psi-mi:“MI:0407”(direct interaction)	0.690
STAT5A	PDHA1	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
PDK4	PDK2	psi-mi:“MI:0914”(association)	0.640
EGFR	PDK3	psi-mi:“MI:0915”(physical association)	0.550
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
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
STAT5A	PDHX	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
PDK3	iglC2	psi-mi:“MI:0915”(physical association)	0.370
PDK3	ECD	psi-mi:“MI:0914”(association)	0.350
PDK1	VWA8	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (180): PDK3 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), PDK3 (Affinity Capture-MS), HLTF (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), UTRN (Affinity Capture-MS), VCP (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT8 (Affinity Capture-MS), ECD (Affinity Capture-MS)

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

Diamond homologs: 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

5 interactions.

A	Effect	B	Mechanism
PDK3	down-regulates	PDHA2	phosphorylation
PDK3	“down-regulates activity”	PDHA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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	8	121.5×	3e-13
Signaling by Retinoic Acid	8	69.4×	3e-11
Complex I biogenesis	5	17.6×	9e-04
Mitochondrial protein degradation	7	17.0×	2e-05
Respiratory electron transport	5	10.1×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
glucose metabolic process	6	27.4×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	80
Benign	39

Top pathogenic / likely-pathogenic (0)

SpliceAI

1707 predictions. Top by Δscore:

Variant	Effect	Δscore
X:24465562:G:GG	donor_gain	1.0000
X:24465562:GTG:G	donor_loss	1.0000
X:24465563:TGAG:T	donor_loss	1.0000
X:24490480:GACCA:G	donor_gain	1.0000
X:24498824:TTTA:T	acceptor_loss	1.0000
X:24498825:TTA:T	acceptor_loss	1.0000
X:24498827:A:AG	acceptor_gain	1.0000
X:24498827:AG:A	acceptor_gain	1.0000
X:24498828:G:C	acceptor_loss	1.0000
X:24498828:G:GC	acceptor_gain	1.0000
X:24498828:GG:G	acceptor_gain	1.0000
X:24498828:GGT:G	acceptor_gain	1.0000
X:24498828:GGTA:G	acceptor_gain	1.0000
X:24498828:GGTAT:G	acceptor_gain	1.0000
X:24498896:GA:G	donor_gain	1.0000
X:24498896:GATAA:G	donor_gain	1.0000
X:24498897:A:G	donor_gain	1.0000
X:24498898:TAA:T	donor_gain	1.0000
X:24498900:AG:A	donor_loss	1.0000
X:24498901:GTAA:G	donor_gain	1.0000
X:24498904:AG:A	donor_loss	1.0000
X:24498905:G:C	donor_loss	1.0000
X:24503507:GCACA:G	donor_gain	1.0000
X:24518927:TTGCA:T	acceptor_loss	1.0000
X:24518930:CAGAT:C	acceptor_loss	1.0000
X:24518931:A:AG	acceptor_gain	1.0000
X:24518931:A:C	acceptor_loss	1.0000
X:24518932:G:GA	acceptor_gain	1.0000
X:24518932:GAT:G	acceptor_gain	1.0000
X:24518932:GATGC:G	acceptor_gain	1.0000

AlphaMissense

2661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:24494808:C:A	A58D	1.000
X:24503458:T:C	L151P	1.000
X:24503464:G:C	R153P	1.000
X:24531667:G:A	G325D	1.000
X:24531676:T:C	L328S	1.000
X:24531711:G:A	G340R	1.000
X:24531711:G:C	G340R	1.000
X:24465558:T:C	F35L	0.999
X:24465560:C:A	F35L	0.999
X:24465560:C:G	F35L	0.999
X:24494777:T:C	F48L	0.999
X:24494778:T:C	F48S	0.999
X:24494779:T:A	F48L	0.999
X:24494779:T:G	F48L	0.999
X:24494781:T:C	L49P	0.999
X:24494807:G:C	A58P	0.999
X:24494874:T:A	V80D	0.999
X:24498839:A:C	S87R	0.999
X:24498841:T:A	S87R	0.999
X:24498841:T:G	S87R	0.999
X:24503391:G:A	G129R	0.999
X:24503391:G:C	G129R	0.999
X:24503479:G:C	R158P	0.999
X:24505257:G:A	G185E	0.999
X:24518948:C:A	A204D	0.999
X:24526246:T:C	L241P	0.999
X:24526263:G:A	E247K	0.999
X:24526264:A:T	E247V	0.999
X:24526274:G:C	K250N	0.999
X:24526274:G:T	K250N	0.999

dbSNP variants (sampled 300 via entrez): RS1000008914 (X:24506708 T>C), RS1000054428 (X:24507694 A>G), RS1000106602 (X:24508290 A>C), RS1000126824 (X:24496987 A>G), RS1000196239 (X:24498949 G>C), RS1000216789 (X:24515673 A>G), RS1000259358 (X:24542916 G>A), RS1000310366 (X:24497341 G>T), RS1000354364 (X:24463749 G>C), RS1000367067 (X:24524945 T>C), RS1000533288 (X:24513169 G>A), RS1000588796 (X:24515307 A>G), RS1000598340 (X:24470737 C>G,T), RS1000626876 (X:24518059 T>C), RS1000686181 (X:24521983 T>C)

Disease associations

OMIM: gene MIM:300906 | disease phenotypes: MIM:300905, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease X-linked dominant 6	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease X-linked dominant 6	Definitive	XL

Mondo (2): Charcot-Marie-Tooth disease X-linked dominant 6 (MONDO:0010479), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (2): X-linked Charcot-Marie-Tooth disease type 6 (Orphanet:352675), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000762	Decreased nerve conduction velocity
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001423	X-linked dominant inheritance
HP:0001761	Pes cavus
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002378	Hand tremor
HP:0002936	Distal sensory impairment
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003376	Steppage gait
HP:0003393	Thenar muscle atrophy
HP:0003438	Absent Achilles reflex
HP:0003482	EMG: axonal abnormality
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0006886	Impaired distal vibration sensation
HP:0007141	Sensorimotor neuropathy
HP:0007328	Impaired pain sensation
HP:0007340	Lower limb muscle weakness
HP:0008944	Distal lower limb amyotrophy
HP:0008954	Intrinsic hand muscle atrophy
HP:0009072	Decreased Achilles reflex
HP:0009830	Peripheral neuropathy
HP:0011463	Childhood onset
HP:0030237	Hand muscle weakness

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_25	Malaria	7.000000e-06
GCST010725_41	Malaria	8.000000e-06
GCST010725_82	Malaria	8.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096665 (PROTEIN FAMILY), CHEMBL3893 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — PDHK family

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

Ligand	Action	Affinity	Parameter
VER-246608	Inhibition	7.4	pIC50

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
PS10	KD	47000 nM
PS8	KD	60100 nM

ChEMBL bioactivities

471 potent at pChembl≥5 of 496 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL4519504
8.15	IC50	7.1	nM	CHEMBL73068
8.10	IC50	8	nM	CHEMBL74582
8.08	IC50	8.4	nM	CHEMBL73204
8.00	IC50	10	nM	CHEMBL3718383
8.00	IC50	10	nM	CHEMBL3719344
8.00	IC50	10	nM	CHEMBL3717579
8.00	IC50	10	nM	CHEMBL3716924
8.00	IC50	10	nM	CHEMBL3716176
8.00	IC50	10	nM	CHEMBL3719004
8.00	IC50	10	nM	CHEMBL3715313
8.00	IC50	10	nM	CHEMBL3716404
8.00	IC50	10	nM	CHEMBL3719305
8.00	IC50	10	nM	CHEMBL3717052
8.00	IC50	10	nM	CHEMBL3715598
8.00	IC50	10	nM	CHEMBL3714928
8.00	IC50	10	nM	CHEMBL3717436
8.00	IC50	10	nM	CHEMBL3717459
8.00	IC50	10	nM	CHEMBL3717764
8.00	IC50	10	nM	CHEMBL3718319
8.00	IC50	10	nM	CHEMBL3717613
8.00	IC50	10	nM	CHEMBL3715330
8.00	IC50	10	nM	CHEMBL3715072
8.00	IC50	10	nM	CHEMBL3717025
8.00	IC50	10	nM	CHEMBL3715512
8.00	IC50	10	nM	CHEMBL3716740
8.00	IC50	10	nM	CHEMBL3715842
8.00	IC50	10	nM	CHEMBL3715757
8.00	IC50	10	nM	CHEMBL3717836
8.00	IC50	10	nM	CHEMBL3715049
8.00	IC50	10	nM	CHEMBL3715972
8.00	IC50	10	nM	CHEMBL3715771
8.00	IC50	10	nM	CHEMBL3716746
8.00	IC50	10	nM	CHEMBL3717827
8.00	IC50	10	nM	CHEMBL3717940
8.00	IC50	10	nM	CHEMBL3714889
8.00	IC50	10	nM	CHEMBL3717799
8.00	IC50	10	nM	CHEMBL3719348
8.00	IC50	10	nM	CHEMBL3715964
8.00	IC50	10	nM	CHEMBL3719035
8.00	IC50	10	nM	CHEMBL3719333
8.00	IC50	10	nM	CHEMBL3715044
8.00	IC50	10	nM	CHEMBL3719351
8.00	IC50	10	nM	CHEMBL3714823
8.00	IC50	10	nM	CHEMBL3716865
8.00	IC50	10	nM	CHEMBL3715674
8.00	IC50	10	nM	CHEMBL3717530
8.00	IC50	10	nM	CHEMBL75821
7.89	IC50	13	nM	CHEMBL73099
7.82	IC50	15	nM	CHEMBL307687

PubChem BioAssay actives

137 with measured affinity, of 255 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-[(5-iodofuran-2-yl)methyl]benzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0050	uM
(2R)-N-[2-chloro-4-(cyclopropylmethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0071	uM
(2R)-N-[2-chloro-4-(prop-2-enylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0080	uM
(2R)-N-[4-[(3-aminocyclohexyl)sulfamoyl]-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0084	uM
(2R)-N-[2-chloro-4-(2-morpholin-4-ylethylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0100	uM
(2R)-N-[2-chloro-4-(2-methylpropylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0130	uM
(2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-4-phenylbutanoic acid	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0150	uM
(2R)-N-[2-chloro-4-[3-(2-oxopyrrolidin-1-yl)propylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0160	uM
(2R)-N-[4-[[4-(2-aminoethyl)phenyl]sulfonylsulfamoyl]-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0160	uM
4-[(2R,5S)-2,5-dimethyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carbonyl]benzonitrile	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0165	uM
(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
benzyl (2R)-2-methyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carboxylate	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0210	uM
(2R)-N-[4-(3-aminopyrrolidin-1-yl)sulfonyl-2-chlorophenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0230	uM
N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-[[4-[[(2,2-difluoroacetyl)amino]methyl]phenyl]methyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0260	uM
(2R)-N-[2-chloro-4-(3-hydroxypropylsulfamoyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0290	uM
(2R)-N-[2-chloro-4-[2-(dimethylamino)ethylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0320	uM
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
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
N-[(5-bromofuran-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0590	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	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0640	uM
(2R)-N-[2-chloro-4-[3-(diethylamino)propylsulfamoyl]phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0660	uM
N-[4-(dimethylcarbamoyl)phenyl]-N-(furan-2-ylmethyl)-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0670	uM
(2R)-N-(2-chloro-4-methylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0700	uM
(2R)-N-[2-chloro-4-(4-pyridin-2-ylpiperazin-1-yl)sulfonylphenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0730	uM
3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzenesulfonyl fluoride	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0770	uM
(2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]amino]-3-(4-phenylphenyl)propanoic acid	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0770	uM
3-chloro-4-[(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)amino]benzenesulfonyl fluoride	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0770	uM
4-[(2R)-2-methyl-4-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperazine-1-carbonyl]benzonitrile	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0790	uM
N-[(4-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0800	uM
(2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methylpropan-1-one	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0820	uM
3-chloro-N-(3-hydroxypropyl)-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0870	uM
N-[(5-bromothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0900	uM
N-[(2-bromo-1,3-thiazol-5-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0900	uM
3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoic acid	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.0900	uM
N-[2-chloro-4-(2-methylpropylsulfamoyl)phenyl]-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.0980	uM
N-[(5-cyanothiophen-2-yl)methyl]-N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxybenzamide	1604075: Inhibition of PDHK3 (unknown origin) by radiometric biochemical kinase assay	ic50	0.0980	uM
methyl (2S)-2-[[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoyl]-methylamino]-3-(1H-indol-3-yl)propanoate	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.1100	uM
(2R)-N-(4-benzoyl-2-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.1100	uM
(2R)-N-[2-chloro-4-(4-pyridin-2-ylpiperazine-1-carbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.1100	uM
N-(4-benzoyl-2-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.1130	uM
methyl 3-chloro-4-[(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)amino]benzoate	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.1150	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148967: Binding affinity to human PDK3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1192	uM
methyl 3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]benzoate	162832: In vitro inhibitory activity against Pyruvate dehydrogenase kinase by primary enzymatic assay	ic50	0.1200	uM
4-[3-chloro-4-[[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]amino]phenyl]sulfonyl-N,N-dimethylbenzamide	2096660: Inhibition of N-terminal GST-tagged recombinant human full length PDK3 (1 to 406 residues) expressed in baculovirus infected Sf9 cells using PDHA1 as substrate incubated for 1 hrs in presence of ATP by ADP-Glo luminescence assay	ic50	0.1205	uM
3-chloro-N-hexyl-4-[(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)amino]benzamide	162971: Inhibition of porcine pyruvate dehydrogenase kinase (PDHK)in a primary enzymatic assay	ic50	0.1260	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	4
sodium arsenite	decreases expression, increases expression	3
Acetaminophen	decreases expression, increases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases expression	2
Nickel	decreases expression	2
Oxygen	decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
VER-246608	decreases activity	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
1,10-phenanthroline	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	decreases expression	1
gypenoside	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1

ChEMBL screening assays

53 unique, capped per target: 52 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TC83	HAP1 PDK3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT