Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBL7JHQ)

• DOT Name: Protein DBF4 homolog A (DBF4)
• Synonyms: Activator of S phase kinase; Chiffon homolog A; DBF4-type zinc finger-containing protein 1
• Gene Name: DBF4
• Related Disease:
  Advanced cancer
  Candidemia
  Candidiasis, invasive
  Invasive candidiasis
  Cutaneous melanoma
  Melanoma
  Neoplasm
• UniProt ID: DBF4A_HUMAN
• PDB ID: 4F99; 4F9A; 4F9B; 4F9C; 6YA6; 6YA7; 6YA8
• Pfam ID: PF07535
• Sequence:
  MNSGAMRIHSKGHFQGGIQVKNEKNRPSLKSLKTDNRPEKSKCKPLWGKVFYLDLPSVTI
  SEKLQKDIKDLGGRVEEFLSKDISYLISNKKEAKFAQTLGRISPVPSPESAYTAETTSPH
  PSHDGSSFKSPDTVCLSRGKLLVEKAIKDHDFIPSNSILSNALSWGVKILHIDDIRYYIE
  QKKKELYLLKKSSTSVRDGGKRVGSGAQKTRTGRLKKPFVKVEDMSQLYRPFYLQLTNMP
  FINYSIQKPCSPFDVDKPSSMQKQTQVKLRIQTDGDKYGGTSIQLQLKEKKKKGYCECCL
  QKYEDLETHLLSEQHRNFAQSNQYQVVDDIVSKLVFDFVEYEKDTPKKKRIKYSVGSLSP
  VSASVLKKTEQKEKVELQHISQKDCQEDDTTVKEQNFLYKETQETEKKLLFISEPIPHPS
  NELRGLNEKMSNKCSMLSTAEDDIRQNFTQLPLHKNKQECILDISEHTLSENDLEELRVD
  HYKCNIQASVHVSDFSTDNSGSQPKQKSDTVLFPAKDLKEKDLHSIFTHDSGLITINSSQ
  EHLTVQAKAPFHTPPEEPNECDFKNMDSLPSGKIHRKVKIILGRNRKENLEPNAEFDKRT
  EFITQEENRICSSPVQSLLDLFQTSEEKSEFLGFTSYTEKSGICNVLDIWEEENSDNLLT
  AFFSSPSTSTFTGF
• Function: Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.
• Tissue Specificity: Highly expressed in testis and thymus. Expressed also in most cancer cells lines.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Activation of the pre-replicative complex (R-HSA-68962)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Candidemia	DISVKFN7	Strong	Biomarker	[2]
Candidiasis, invasive	DIS5VDG3	Strong	Biomarker	[3]
Invasive candidiasis	DIS5EI0L	Strong	Biomarker	[3]
Cutaneous melanoma	DIS3MMH9	moderate	Altered Expression	[4]
Melanoma	DIS1RRCY	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Protein DBF4 homolog A (DBF4) increases the response to substance of Irinotecan.	[28]

22 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 Protein DBF4 homolog A (DBF4).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein DBF4 homolog A (DBF4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein DBF4 homolog A (DBF4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein DBF4 homolog A (DBF4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein DBF4 homolog A (DBF4).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein DBF4 homolog A (DBF4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Protein DBF4 homolog A (DBF4).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein DBF4 homolog A (DBF4).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein DBF4 homolog A (DBF4).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Protein DBF4 homolog A (DBF4).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Protein DBF4 homolog A (DBF4).	[15]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Protein DBF4 homolog A (DBF4).	[16]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Protein DBF4 homolog A (DBF4).	[17]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Protein DBF4 homolog A (DBF4).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein DBF4 homolog A (DBF4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein DBF4 homolog A (DBF4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein DBF4 homolog A (DBF4).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein DBF4 homolog A (DBF4).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein DBF4 homolog A (DBF4).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein DBF4 homolog A (DBF4).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Protein DBF4 homolog A (DBF4).	[26]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Protein DBF4 homolog A (DBF4).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein DBF4 homolog A (DBF4).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein DBF4 homolog A (DBF4).	[21]

References

• [1] Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach.EBioMedicine. 2018 Oct;36:241-251. doi: 10.1016/j.ebiom.2018.09.030. Epub 2018 Oct 5.
• [2] Development of fluconazole resistance in a series of Candida parapsilosis isolates from a persistent candidemia patient with prolonged antifungal therapy.BMC Infect Dis. 2015 Aug 18;15:340. doi: 10.1186/s12879-015-1086-6.
• [3] Five-Year National Surveillance of Invasive Candidiasis: Species Distribution and Azole Susceptibility from the China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study.J Clin Microbiol. 2018 Jun 25;56(7):e00577-18. doi: 10.1128/JCM.00577-18. Print 2018 Jul.
• [4] Transcriptional regulation of ASK/Dbf4 in cutaneous melanoma is dependent on E2F1.Exp Dermatol. 2008 Dec;17(12):986-91. doi: 10.1111/j.1600-0625.2008.00730.x. Epub 2008 May 21.
• [5] Functional interaction between tumor suppressor menin and activator of S-phase kinase.Cancer Res. 2004 Sep 15;64(18):6791-6. doi: 10.1158/0008-5472.CAN-04-0724.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [15] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [18] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [28] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.