Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5133XY)

• DOT Name: Cell division cycle 7-related protein kinase (CDC7)
• Synonyms: CDC7-related kinase; HsCdc7; huCdc7; EC 2.7.11.1
• Gene Name: CDC7
• UniProt ID: CDC7_HUMAN
• PDB ID: 4F99; 4F9A; 4F9B; 4F9C; 5UWQ; 5UWR; 6YA6; 6YA7; 6YA8
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MEASLGIQMDEPMAFSPQRDRFQAEGSLKKNEQNFKLAGVKKDIEKLYEAVPQLSNVFKI
  EDKIGEGTFSSVYLATAQLQVGPEEKIALKHLIPTSHPIRIAAELQCLTVAGGQDNVMGV
  KYCFRKNDHVVIAMPYLEHESFLDILNSLSFQEVREYMLNLFKALKRIHQFGIVHRDVKP
  SNFLYNRRLKKYALVDFGLAQGTHDTKIELLKFVQSEAQQERCSQNKSHIITGNKIPLSG
  PVPKELDQQSTTKASVKRPYTNAQIQIKQGKDGKEGSVGLSVQRSVFGERNFNIHSSISH
  ESPAVKLMKQSKTVDVLSRKLATKKKAISTKVMNSAVMRKTASSCPASLTCDCYATDKVC
  SICLSRRQQVAPRAGTPGFRAPEVLTKCPNQTTAIDMWSAGVIFLSLLSGRYPFYKASDD
  LTALAQIMTIRGSRETIQAAKTFGKSILCSKEVPAQDLRKLCERLRGMDSSTPKLTSDIQ
  GHASHQPAISEKTDHKASCLVQTPPGQYSGNSFKKGDSNSCEHCFDEYNTNLEGWNEVPD
  EAYDLLDKLLDLNPASRITAEEALLHPFFKDMSL
• Function: Kinase involved in initiation of DNA replication. Phosphorylates critical substrates that regulate the G1/S phase transition and initiation of DNA replication, such as MCM proteins and CLASPIN.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Activation of the pre-replicative complex (R-HSA-68962)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cell division cycle 7-related protein kinase (CDC7).	[1]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cell division cycle 7-related protein kinase (CDC7).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cell division cycle 7-related protein kinase (CDC7).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cell division cycle 7-related protein kinase (CDC7).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cell division cycle 7-related protein kinase (CDC7).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cell division cycle 7-related protein kinase (CDC7).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cell division cycle 7-related protein kinase (CDC7).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cell division cycle 7-related protein kinase (CDC7).	[2]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[16]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell division cycle 7-related protein kinase (CDC7).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[22]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[23]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[24]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Cell division cycle 7-related protein kinase (CDC7).	[25]

References

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• [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] 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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol. 2004 Jan;11(1):63-9. doi: 10.1128/cdli.11.1.63-69.2004.
• [7] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [18] 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.
• [19] 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.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Molecular signatures of cytotoxic effects in human embryonic kidney 293?cells treated with single and mixture of ochratoxin A and citrinin. Food Chem Toxicol. 2019 Jan;123:374-384. doi: 10.1016/j.fct.2018.11.015. Epub 2018 Nov 11.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [23] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [24] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [25] 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.