Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLHHMC2)

• DOT Name: Pyruvate kinase PKM (PKM)
• Synonyms: EC 2.7.1.40; Cytosolic thyroid hormone-binding protein; CTHBP; Opa-interacting protein 3; OIP-3; Pyruvate kinase 2/3; Pyruvate kinase muscle isozyme; Threonine-protein kinase PKM2; EC 2.7.11.1; Thyroid hormone-binding protein 1; THBP1; Tumor M2-PK; Tyrosine-protein kinase PKM2; EC 2.7.10.2; p58
• Gene Name: PKM
• UniProt ID: KPYM_HUMAN
• PDB ID: 1T5A ; 1ZJH ; 3BJF ; 3BJT ; 3G2G ; 3GQY ; 3GR4 ; 3H6O ; 3ME3 ; 3SRD ; 3SRF ; 3SRH ; 3U2Z ; 4B2D ; 4FXF ; 4FXJ ; 4G1N ; 4JPG ; 4QG6 ; 4QG8 ; 4QG9 ; 4QGC ; 4RPP ; 4WJ8 ; 4YJ5 ; 5X0I ; 5X1V ; 5X1W ; 6B6U ; 6GG3 ; 6GG4 ; 6GG5 ; 6GG6 ; 6JFB ; 6NU1 ; 6NU5 ; 6NUB ; 6TTF ; 6TTH ; 6TTI ; 6TTQ ; 6V74 ; 6V75 ; 6V76 ; 6WP3 ; 6WP4 ; 6WP5 ; 6WP6 ; 7L21 ; 8G2E ; 8HGF ; 8HMQ ; 8HMR ; 8HMS ; 8HMU
• EC Number: 2.7.1.40; 2.7.10.2; 2.7.11.1
• Pfam ID: PF00224 ; PF02887
• Sequence:
  MSKPHSEAGTAFIQTQQLHAAMADTFLEHMCRLDIDSPPITARNTGIICTIGPASRSVET
  LKEMIKSGMNVARLNFSHGTHEYHAETIKNVRTATESFASDPILYRPVAVALDTKGPEIR
  TGLIKGSGTAEVELKKGATLKITLDNAYMEKCDENILWLDYKNICKVVEVGSKIYVDDGL
  ISLQVKQKGADFLVTEVENGGSLGSKKGVNLPGAAVDLPAVSEKDIQDLKFGVEQDVDMV
  FASFIRKASDVHEVRKVLGEKGKNIKIISKIENHEGVRRFDEILEASDGIMVARGDLGIE
  IPAEKVFLAQKMMIGRCNRAGKPVICATQMLESMIKKPRPTRAEGSDVANAVLDGADCIM
  LSGETAKGDYPLEAVRMQHLIAREAEAAIYHLQLFEELRRLAPITSDPTEATAVGAVEAS
  FKCCSGAIIVLTKSGRSAHQVARYRPRAPIIAVTRNPQTARQAHLYRGIFPVLCKDPVQE
  AWAEDVDLRVNFAMNVGKARGFFKKGDVVIVLTGWRPGSGFTNTMRVVPVP
• Function: Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival ; [Isoform M2]: Isoform specifically expressed during embryogenesis that has low pyruvate kinase activity by itself and requires allosteric activation by D-fructose 1,6-bisphosphate (FBP) for pyruvate kinase activity. In addition to its pyruvate kinase activity in the cytoplasm, also acts as a regulator of transcription in the nucleus by acting as a protein kinase. Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase. Catalyzes phosphorylation of STAT3 at 'Tyr-705' and histone H3 at 'Thr-11' (H3T11ph), leading to activate transcription. Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis. Promotes the expression of the immune checkpoint protein CD274 in BMAL1-deficient macrophages. May also act as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs. Plays a role in caspase independent cell death of tumor cells ; [Isoform M1]: Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth. In contrast to isoform M2, has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.
• Tissue Specificity: .Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells.; [Isoform M1]: Expressed in adult tissues . Not expressed in tumor cells .
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
  Glucagon sig.ling pathway (hsa04922)
  Type II diabetes mellitus (hsa04930)
  Human papillomavirus infection (hsa05165)
  Viral carcinogenesis (hsa05203)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Glycolysis (R-HSA-70171)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS00906-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Pyruvate kinase PKM (PKM) affects the response to substance of Paclitaxel.	[39]
Gemcitabine	DMSE3I7	Approved	Pyruvate kinase PKM (PKM) affects the response to substance of Gemcitabine.	[40]
Resveratrol	DM3RWXL	Phase 3	Pyruvate kinase PKM (PKM) decreases the response to substance of Resveratrol.	[41]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	Pyruvate kinase PKM (PKM) increases the uptake of D-glucose.	[41]
Phosphoenolpyruvate	DM2D947	Investigative	Pyruvate kinase PKM (PKM) increases the metabolism of Phosphoenolpyruvate.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Pyruvate kinase PKM (PKM).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pyruvate kinase PKM (PKM).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pyruvate kinase PKM (PKM).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pyruvate kinase PKM (PKM).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin affects the expression of Pyruvate kinase PKM (PKM).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pyruvate kinase PKM (PKM).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pyruvate kinase PKM (PKM).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pyruvate kinase PKM (PKM).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Pyruvate kinase PKM (PKM).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Pyruvate kinase PKM (PKM).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Pyruvate kinase PKM (PKM).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pyruvate kinase PKM (PKM).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Pyruvate kinase PKM (PKM).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Pyruvate kinase PKM (PKM).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Pyruvate kinase PKM (PKM).	[16]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Pyruvate kinase PKM (PKM).	[17]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Pyruvate kinase PKM (PKM).	[18]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Pyruvate kinase PKM (PKM).	[20]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Pyruvate kinase PKM (PKM).	[7]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the expression of Pyruvate kinase PKM (PKM).	[21]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Pyruvate kinase PKM (PKM).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Pyruvate kinase PKM (PKM).	[15]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Pyruvate kinase PKM (PKM).	[24]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the activity of Pyruvate kinase PKM (PKM).	[25]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Pyruvate kinase PKM (PKM).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Pyruvate kinase PKM (PKM).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pyruvate kinase PKM (PKM).	[28]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 increases the activity of Pyruvate kinase PKM (PKM).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Pyruvate kinase PKM (PKM).	[30]
Scutellarin	DMJT1E5	Preclinical	Scutellarin increases the activity of Pyruvate kinase PKM (PKM).	[25]
Baicalin	DMY1TLZ	Terminated	Baicalin increases the activity of Pyruvate kinase PKM (PKM).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pyruvate kinase PKM (PKM).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pyruvate kinase PKM (PKM).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Pyruvate kinase PKM (PKM).	[33]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of Pyruvate kinase PKM (PKM).	[35]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Pyruvate kinase PKM (PKM).	[36]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the expression of Pyruvate kinase PKM (PKM).	[37]
DIOSMETIN	DM4KXIM	Investigative	DIOSMETIN increases the activity of Pyruvate kinase PKM (PKM).	[25]
CID16020046	DMLWZRT	Investigative	CID16020046 decreases the expression of Pyruvate kinase PKM (PKM).	[38]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the binding of Pyruvate kinase PKM (PKM).	[6]
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Pyruvate kinase PKM (PKM).	[19]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal affects the binding of Pyruvate kinase PKM (PKM).	[34]
4-oxo-nonenal	DMPX1J9	Investigative	4-oxo-nonenal affects the binding of Pyruvate kinase PKM (PKM).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Pyruvate kinase PKM (PKM).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Pyruvate kinase PKM (PKM).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Pyruvate kinase PKM (PKM).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pyruvate kinase PKM (PKM).	[29]

2 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB increases the metabolism of Pyruvate kinase PKM (PKM).	[23]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the metabolism of Pyruvate kinase PKM (PKM).	[23]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci. 2011 Mar;120(1):109-22.
• [3] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [4] 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.
• [5] 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.
• [6] Identification of arsenic-binding proteins in human breast cancer cells. Cancer Lett. 2007 Sep 18;255(1):95-106. doi: 10.1016/j.canlet.2007.03.025. Epub 2007 May 17.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Arsenic trioxide inhibits EMT in hepatocellular carcinoma by promoting lncRNA MEG3 via PKM2. Biochem Biophys Res Commun. 2019 Jun 11;513(4):834-840. doi: 10.1016/j.bbrc.2019.04.081. Epub 2019 Apr 16.
• [10] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [14] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [17] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [18] Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. Toxicol Lett. 2017 Nov 5;281:26-34. doi: 10.1016/j.toxlet.2017.09.001. Epub 2017 Sep 5.
• [19] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [20] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [21] Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism. Chem Biol Interact. 2023 Jan 5;369:110278. doi: 10.1016/j.cbi.2022.110278. Epub 2022 Nov 22.
• [22] Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5. J Biochem Mol Toxicol. 2022 Nov;36(11):e23192. doi: 10.1002/jbt.23192. Epub 2022 Aug 5.
• [23] Determination of Protein Haptenation by Chemical Sensitizers Within the Complexity of the Human Skin Proteome. Toxicol Sci. 2018 Apr 1;162(2):429-438. doi: 10.1093/toxsci/kfx265.
• [24] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [25] In vitro effects of some flavones on human pyruvate kinase isoenzyme M2. J Biochem Mol Toxicol. 2015 Mar;29(3):109-13. doi: 10.1002/jbt.21673. Epub 2014 Nov 11.
• [26] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [27] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [28] 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.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [31] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [32] 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.
• [33] Autophagy induces mTOR-dependent glucose uptake and mTOR-independent lactate utilization in cadmium-treated A549 cells. Toxicol In Vitro. 2023 Feb;86:105513. doi: 10.1016/j.tiv.2022.105513. Epub 2022 Nov 4.
• [34] Electrophilic Modification of PKM2 by 4-Hydroxynonenal and 4-Oxononenal Results in Protein Cross-Linking and Kinase Inhibition. Chem Res Toxicol. 2017 Feb 20;30(2):635-641. doi: 10.1021/acs.chemrestox.6b00374. Epub 2017 Jan 3.
• [35] Inhibition of ATF4-mediated elevation of both autophagy and AKT/mTOR was involved in antitumorigenic activity of curcumin. Food Chem Toxicol. 2023 Mar;173:113609. doi: 10.1016/j.fct.2023.113609. Epub 2023 Jan 12.
• [36] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [37] Overexpression of HIF-1a could partially protect K562 cells from 1,4-benzoquinone induced toxicity by inhibiting ROS, apoptosis and enhancing glycolysis. Toxicol In Vitro. 2019 Mar;55:18-23. doi: 10.1016/j.tiv.2018.11.005. Epub 2018 Nov 15.
• [38] Selective GPR55 antagonism reduces chemoresistance in cancer cells. Pharmacol Res. 2016 Sep;111:757-766. doi: 10.1016/j.phrs.2016.07.013. Epub 2016 Jul 14.
• [39] 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.
• [40] Targeting PKM2 improves the gemcitabine sensitivity of intrahepatic cholangiocarcinoma cells via inhibiting -catenin signaling pathway. Chem Biol Interact. 2024 Jan 5;387:110816. doi: 10.1016/j.cbi.2023.110816. Epub 2023 Nov 22.
• [41] Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS One. 2012;7(5):e36764. doi: 10.1371/journal.pone.0036764. Epub 2012 May 4.