Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMABK9Z)

• DOT Name: kinase isozyme 1, mitochondrial (PDK1)
• Synonyms: EC 2.7.11.2; Pyruvate dehydrogenase kinase isoform 1; PDH kinase 1
• Gene Name: PDK1
• UniProt ID: PDK1_HUMAN
• PDB ID: 2Q8F; 2Q8G; 2Q8H
• EC Number: 2.7.11.2
• Pfam ID: PF10436 ; PF02518
• Sequence:
  MRLARLLRGAALAGPGPGLRAAGFSRSFSSDSGSSPASERGVPGQVDFYARFSPSPLSMK
  QFLDFGSVNACEKTSFMFLRQELPVRLANIMKEISLLPDNLLRTPSVQLVQSWYIQSLQE
  LLDFKDKSAEDAKAIYDFTDTVIRIRNRHNDVIPTMAQGVIEYKESFGVDPVTSQNVQYF
  LDRFYMSRISIRMLLNQHSLLFGGKGKGSPSHRKHIGSINPNCNVLEVIKDGYENARRLC
  DLYYINSPELELEELNAKSPGQPIQVVYVPSHLYHMVFELFKNAMRATMEHHANRGVYPP
  IQVHVTLGNEDLTVKMSDRGGGVPLRKIDRLFNYMYSTAPRPRVETSRAVPLAGFGYGLP
  ISRLYAQYFQGDLKLYSLEGYGTDAVIYIKALSTDSIERLPVYNKAAWKHYNTNHEADDW
  CVPSREPKDMTTFRSA
• Function: Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.
• Tissue Specificity: Expressed predominantly in the heart. Detected at lower levels in liver, skeletal muscle and pancreas.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Central carbon metabolism in cancer (hsa05230)
• 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

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	kinase isozyme 1, mitochondrial (PDK1) affects the response to substance of Methotrexate.	[30]

31 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 1, mitochondrial (PDK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of kinase isozyme 1, mitochondrial (PDK1).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[12]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[14]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[15]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[19]
EHT-1864	DMYAMP5	Terminated	EHT-1864 decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[23]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A affects the expression of kinase isozyme 1, mitochondrial (PDK1).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[25]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[2]
Manganese	DMKT129	Investigative	Manganese increases the expression of kinase isozyme 1, mitochondrial (PDK1).	[26]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[27]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of kinase isozyme 1, mitochondrial (PDK1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Curcumin	DMQPH29	Phase 3	Curcumin increases the phosphorylation of kinase isozyme 1, mitochondrial (PDK1).	[17]
USNIC ACID	DMGOURX	Investigative	USNIC ACID decreases the phosphorylation of kinase isozyme 1, mitochondrial (PDK1).	[29]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [14] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [15] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Curcumin-induced GADD153 upregulation: modulation by glutathione. J Cell Biochem. 2007 May 15;101(2):307-20. doi: 10.1002/jcb.21179.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Rac GTPases in acute myeloid leukemia cells: Expression profile and biological effects of pharmacological inhibition. Toxicol Appl Pharmacol. 2022 May 1;442:115990. doi: 10.1016/j.taap.2022.115990. Epub 2022 Mar 22.
• [21] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. Cancer Prev Res (Phila). 2008 Dec;1(7):577-87. doi: 10.1158/1940-6207.CAPR-08-0184.
• [24] Ochratoxin A upregulates biomarkers associated with hypoxia and transformation in human kidney cells. Toxicol In Vitro. 2019 Jun;57:211-216. doi: 10.1016/j.tiv.2019.03.016. Epub 2019 Mar 12.
• [25] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.
• [26] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [27] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [28] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [29] The role of autophagy in usnic acid-induced toxicity in hepatic cells. Toxicol Sci. 2014 Nov;142(1):33-44. doi: 10.1093/toxsci/kfu154. Epub 2014 Jul 30.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.