Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCMHMBZ)

• DOT Name: kinase isozyme 4, mitochondrial (PDK4)
• Synonyms: EC 2.7.11.2; Pyruvate dehydrogenase kinase isoform 4
• Gene Name: PDK4
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Primary biliary cholangitis
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Chronic kidney disease
  Colon carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Dilated cardiomyopathy
  Epithelial ovarian cancer
  Fatty liver disease
  Glioma
  Hyperglycemia
  Hyperinsulinemia
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Myocardial infarction
  Myocardial ischemia
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Pulmonary arterial hypertension
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Pancreatic cancer
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Bone osteosarcoma
  Cardiomyopathy
  Hepatocellular carcinoma
  Neoplasm
  Nervous system inflammation
  Osteosarcoma
• UniProt ID: PDK4_HUMAN
• PDB ID: 2E0A; 2ZDX; 2ZDY; 2ZKJ; 3D2R; 7EAT; 7EBB; 7EBG
• EC Number: 2.7.11.2
• Pfam ID: PF10436 ; PF02518
• Sequence:
  MKAARFVLRSAGSLNGAGLVPREVEHFSRYSPSPLSMKQLLDFGSENACERTSFAFLRQE
  LPVRLANILKEIDILPTQLVNTSSVQLVKSWYIQSLMDLVEFHEKSPDDQKALSDFVDTL
  IKVRNRHHNVVPTMAQGIIEYKDACTVDPVTNQNLQYFLDRFYMNRISTRMLMNQHILIF
  SDSQTGNPSHIGSIDPNCDVVAVVQDAFECSRMLCDQYYLSSPELKLTQVNGKFPDQPIH
  IVYVPSHLHHMLFELFKNAMRATVEHQENQPSLTPIEVIVVLGKEDLTIKISDRGGGVPL
  RIIDRLFSYTYSTAPTPVMDNSRNAPLAGFGYGLPISRLYAKYFQGDLNLYSLSGYGTDA
  IIYLKALSSESIEKLPVFNKSAFKHYQMSSEADDWCIPSREPKNLAKEVAM
• Function: Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.
• Tissue Specificity: Ubiquitous; highest levels of expression in heart and skeletal muscle.
• KEGG Pathway: Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Signaling by Retinoic Acid (R-HSA-5362517)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[4]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[16]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[17]
Liver cancer	DISDE4BI	Strong	Biomarker	[18]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[19]
Lung cancer	DISCM4YA	Strong	Altered Expression	[19]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[19]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[20]
Myocardial infarction	DIS655KI	Strong	Biomarker	[21]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[22]
Obesity	DIS47Y1K	Strong	Biomarker	[23]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[25]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[16]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[26]
Non-alcoholic fatty liver disease	DISDG1NL	Disputed	Biomarker	[27]
Non-alcoholic steatohepatitis	DIST4788	Disputed	Biomarker	[27]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[28]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[29]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[30]
Neoplasm	DISZKGEW	Limited	Biomarker	[28]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[31]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[28]

41 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[36]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[33]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[37]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[38]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[39]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[40]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[41]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[42]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of kinase isozyme 4, mitochondrial (PDK4).	[43]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[45]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[46]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[45]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[45]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[47]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[48]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[49]
Chlorambucil	DMRKE63	Approved	Chlorambucil affects the expression of kinase isozyme 4, mitochondrial (PDK4).	[50]
Hexachlorophene	DMLKSE0	Approved	Hexachlorophene affects the expression of kinase isozyme 4, mitochondrial (PDK4).	[50]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[50]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[48]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[52]
Terfenadine	DM4KLPT	Withdrawn from market	Terfenadine affects the expression of kinase isozyme 4, mitochondrial (PDK4).	[50]
GW-501516	DMPL2KM	Discontinued in Phase 4	GW-501516 increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[53]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[54]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[55]
AZD-7545	DMU6L4I	Terminated	AZD-7545 increases the activity of kinase isozyme 4, mitochondrial (PDK4).	[56]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[57]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[34]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[58]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[59]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[60]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[61]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[62]
CITCO	DM0N634	Investigative	CITCO decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[63]
EPI-001	DMYWV81	Investigative	EPI-001 increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[64]
GSK-3787	DMKDLB7	Investigative	GSK-3787 decreases the expression of kinase isozyme 4, mitochondrial (PDK4).	[65]
chaetocin	DMBK86L	Investigative	chaetocin increases the expression of kinase isozyme 4, mitochondrial (PDK4).	[66]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the methylation of kinase isozyme 4, mitochondrial (PDK4).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of kinase isozyme 4, mitochondrial (PDK4).	[51]

References

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