Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKMJXJ8)

• DOT Name: Serine/threonine-protein kinase PLK2 (PLK2)
• Synonyms: EC 2.7.11.21; Polo-like kinase 2; PLK-2; hPlk2; Serine/threonine-protein kinase SNK; hSNK; Serum-inducible kinase
• Gene Name: PLK2
• UniProt ID: PLK2_HUMAN
• PDB ID: 4I5M; 4I5P; 4I6B; 4I6F; 4I6H; 4RS6; 4XB0
• EC Number: 2.7.11.21
• Pfam ID: PF00069 ; PF00659
• Sequence:
  MELLRTITYQPAASTKMCEQALGKGCGADSKKKRPPQPPEESQPPQSQAQVPPAAPHHHH
  HHSHSGPEISRIIVDPTTGKRYCRGKVLGKGGFAKCYEMTDLTNNKVYAAKIIPHSRVAK
  PHQREKIDKEIELHRILHHKHVVQFYHYFEDKENIYILLEYCSRRSMAHILKARKVLTEP
  EVRYYLRQIVSGLKYLHEQEILHRDLKLGNFFINEAMELKVGDFGLAARLEPLEHRRRTI
  CGTPNYLSPEVLNKQGHGCESDIWALGCVMYTMLLGRPPFETTNLKETYRCIREARYTMP
  SSLLAPAKHLIASMLSKNPEDRPSLDDIIRHDFFLQGFTPDRLSSSCCHTVPDFHLSSPA
  KNFFKKAAAALFGGKKDKARYIDTHNRVSKEDEDIYKLRHDLKKTSITQQPSKHRTDEEL
  QPPTTTVARSGTPAVENKQQIGDAIRMIVRGTLGSCSSSSECLEDSTMGSVADTVARVLR
  GCLENMPEADCIPKEQLSTSFQWVTKWVDYSNKYGFGYQLSDHTVGVLFNNGAHMSLLPD
  KKTVHYYAELGQCSVFPATDAPEQFISQVTVLKYFSHYMEENLMDGGDLPSVTDIRRPRL
  YLLQWLKSDKALMMLFNDGTFQVNFYHDHTKIIICSQNEEYLLTYINEDRISTTFRLTTL
  LMSGCSSELKNRMEYALNMLLQRCN
• Function: Tumor suppressor serine/threonine-protein kinase involved in synaptic plasticity, centriole duplication and G1/S phase transition. Polo-like kinases act by binding and phosphorylating proteins that are already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates CENPJ, NPM1, RAPGEF2, RASGRF1, SNCA, SIPA1L1 and SYNGAP1. Plays a key role in synaptic plasticity and memory by regulating the Ras and Rap protein signaling: required for overactivity-dependent spine remodeling by phosphorylating the Ras activator RASGRF1 and the Rap inhibitor SIPA1L1 leading to their degradation by the proteasome. Conversely, phosphorylates the Rap activator RAPGEF2 and the Ras inhibitor SYNGAP1, promoting their activity. Also regulates synaptic plasticity independently of kinase activity, via its interaction with NSF that disrupts the interaction between NSF and the GRIA2 subunit of AMPARs, leading to a rapid rundown of AMPAR-mediated current that occludes long term depression. Required for procentriole formation and centriole duplication by phosphorylating CENPJ and NPM1, respectively. Its induction by p53/TP53 suggests that it may participate in the mitotic checkpoint following stress.
• Tissue Specificity: Expressed at higher level in the fetal lung, kidney, spleen and heart.
• KEGG Pathway: FoxO sig.ling pathway (hsa04068)
• Reactome Pathway:
  CD163 mediating an anti-inflammatory response (R-HSA-9662834)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)

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
Paclitaxel	DMLB81S	Approved	Serine/threonine-protein kinase PLK2 (PLK2) increases the Cytogenetic abnormality ADR of Paclitaxel.	[33]

33 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 Serine/threonine-protein kinase PLK2 (PLK2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[17]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[19]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[20]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[27]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[31]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Serine/threonine-protein kinase PLK2 (PLK2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein kinase PLK2 (PLK2).	[32]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol Cancer Ther. 2007 Apr;6(4):1300-9.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [7] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [8] 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.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol. 2007 Dec;31(6):1491-500.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [19] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [20] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [21] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [24] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [25] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [26] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [29] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [30] 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.
• [31] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [32] 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.
• [33] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.