Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV8KZDZ)

• DOT Name: Serine/threonine-protein kinase PLK4 (PLK4)
• Synonyms: EC 2.7.11.21; Polo-like kinase 4; PLK-4; Serine/threonine-protein kinase 18; Serine/threonine-protein kinase Sak
• Gene Name: PLK4
• Related Disease:
  Microcephaly and chorioretinopathy 2
  Microcephaly and chorioretinopathy 1
  Seckel syndrome
• UniProt ID: PLK4_HUMAN
• PDB ID: 2N19; 3COK; 4JXF; 4N7V; 4N7Z; 4N9J; 4YUR; 4YYP; 5LHY; 5LHZ; 6N45; 6N46; 6W38; 6W3I; 6W3J
• EC Number: 2.7.11.21
• Pfam ID: PF00069 ; PF18190 ; PF18409
• Sequence:
  MATCIGEKIEDFKVGNLLGKGSFAGVYRAESIHTGLEVAIKMIDKKAMYKAGMVQRVQNE
  VKIHCQLKHPSILELYNYFEDSNYVYLVLEMCHNGEMNRYLKNRVKPFSENEARHFMHQI
  ITGMLYLHSHGILHRDLTLSNLLLTRNMNIKIADFGLATQLKMPHEKHYTLCGTPNYISP
  EIATRSAHGLESDVWSLGCMFYTLLIGRPPFDTDTVKNTLNKVVLADYEMPSFLSIEAKD
  LIHQLLRRNPADRLSLSSVLDHPFMSRNSSTKSKDLGTVEDSIDSGHATISTAITASSST
  SISGSLFDKRRLLIGQPLPNKMTVFPKNKSSTDFSSSGDGNSFYTQWGNQETSNSGRGRV
  IQDAEERPHSRYLRRAYSSDRSGTSNSQSQAKTYTMERCHSAEMLSVSKRSGGGENEERY
  SPTDNNANIFNFFKEKTSSSSGSFERPDNNQALSNHLCPGKTPFPFADPTPQTETVQQWF
  GNLQINAHLRKTTEYDSISPNRDFQGHPDLQKDTSKNAWTDTKVKKNSDASDNAHSVKQQ
  NTMKYMTALHSKPEIIQQECVFGSDPLSEQSKTRGMEPPWGYQNRTLRSITSPLVAHRLK
  PIRQKTKKAVVSILDSEEVCVELVKEYASQEYVKEVLQISSDGNTITIYYPNGGRGFPLA
  DRPPSPTDNISRYSFDNLPEKYWRKYQYASRFVQLVRSKSPKITYFTRYAKCILMENSPG
  ADFEVWFYDGVKIHKTEDFIQVIEKTGKSYTLKSESEVNSLKEEIKMYMDHANEGHRICL
  ALESIISEEERKTRSAPFFPIIIGRKPGSTSSPKALSPPPSVDSNYPTRERASFNRMVMH
  SAASPTQAPILNPSMVTNEGLGLTTTASGTDISSNSLKDCLPKSAQLLKSVFVKNVGWAT
  QLTSGAVWVQFNDGSQLVVQAGVSSISYTSPNGQTTRYGENEKLPDYIKQKLQCLSSILL
  MFSNPTPNFH
• Function: Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. Required for the recruitment of STIL to the centriole and for STIL-mediated centriole amplification. Phosphorylates CEP131 at 'Ser-78' and PCM1 at 'Ser-372' which is essential for proper organization and integrity of centriolar satellites.
• KEGG Pathway: FoxO sig.ling pathway (hsa04068)
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly and chorioretinopathy 2	DISH9D3D	Definitive	Autosomal recessive	[1]
Microcephaly and chorioretinopathy 1	DISGSTH2	Supportive	Autosomal recessive	[2]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[1]

27 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 PLK4 (PLK4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[15]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[5]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[18]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine/threonine-protein kinase PLK4 (PLK4).	[26]

References

• [1] Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-1292. doi: 10.1038/ng.3122. Epub 2014 Oct 26.
• [2] Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy. Eur J Hum Genet. 2016 Dec;24(12):1702-1706. doi: 10.1038/ejhg.2016.119. Epub 2016 Sep 21.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [8] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] 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.
• [12] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [13] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [17] 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.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] 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.
• [22] 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.
• [23] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.