Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTPFUU5)

• DOT Name: Cell division cycle 5-like protein (CDC5L)
• Synonyms: Cdc5-like protein; Pombe cdc5-related protein
• Gene Name: CDC5L
• Related Disease:
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Colorectal carcinoma
  Colorectal neoplasm
  Hepatocellular carcinoma
  Neoplasm
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Melanoma
  Multicystic dysplastic kidney
• UniProt ID: CDC5L_HUMAN
• PDB ID: 2DIM; 2DIN; 5MQF; 5XJC; 5YZG; 5Z56; 5Z57; 5Z58; 6FF4; 6FF7; 6ICZ; 6ID0; 6ID1; 6QDV; 6ZYM; 7A5P; 7AAV; 7ABG; 7ABH; 7ABI; 7DVQ; 7QTT; 7W59; 7W5A; 7W5B; 8C6J; 8CH6
• Pfam ID: PF11831 ; PF13921
• Sequence:
  MPRIMIKGGVWRNTEDEILKAAVMKYGKNQWSRIASLLHRKSAKQCKARWYEWLDPSIKK
  TEWSREEEEKLLHLAKLMPTQWRTIAPIIGRTAAQCLEHYEFLLDKAAQRDNEEETTDDP
  RKLKPGEIDPNPETKPARPDPIDMDEDELEMLSEARARLANTQGKKAKRKAREKQLEEAR
  RLAALQKRRELRAAGIEIQKKRKRKRGVDYNAEIPFEKKPALGFYDTSEENYQALDADFR
  KLRQQDLDGELRSEKEGRDRKKDKQHLKRKKESDLPSAILQTSGVSEFTKKRSKLVLPAP
  QISDAELQEVVKVGQASEIARQTAEESGITNSASSTLLSEYNVTNNSVALRTPRTPASQD
  RILQEAQNLMALTNVDTPLKGGLNTPLHESDFSGVTPQRQVVQTPNTVLSTPFRTPSNGA
  EGLTPRSGTTPKPVINSTPGRTPLRDKLNINPEDGMADYSDPSYVKQMERESREHLRLGL
  LGLPAPKNDFEIVLPENAEKELEEREIDDTYIEDAADVDARKQAIRDAERVKEMKRMHKA
  VQKDLPRPSEVNETILRPLNVEPPLTDLQKSEELIKKEMITMLHYDLLHHPYEPSGNKKG
  KTVGFGTNNSEHITYLEHNPYEKFSKEELKKAQDVLVQEMEVVKQGMSHGELSSEAYNQV
  WEECYSQVLYLPGQSRYTRANLASKKDRIESLEKRLEINRGHMTTEAKRAAKMEKKMKIL
  LGGYQSRAMGLMKQLNDLWDQIEQAHLELRTFEELKKHEDSAIPRRLECLKEDVQRQQER
  EKELQHRYADLLLEKETLKSKF
• Function: DNA-binding protein involved in cell cycle control. May act as a transcription activator. Plays a role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. The PRP19-CDC5L complex may also play a role in the response to DNA damage (DDR). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
• Tissue Specificity: Ubiquitously expressed in both fetal and adult tissues.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	moderate	Biomarker	[6]
Melanoma	DIS1RRCY	Limited	Altered Expression	[7]
Multicystic dysplastic kidney	DISJ9R1F	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Cell division cycle 5-like protein (CDC5L) affects the response to substance of Acetaminophen.	[21]

10 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 Cell division cycle 5-like protein (CDC5L).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cell division cycle 5-like protein (CDC5L).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cell division cycle 5-like protein (CDC5L).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cell division cycle 5-like protein (CDC5L).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Cell division cycle 5-like protein (CDC5L).	[13]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Cell division cycle 5-like protein (CDC5L).	[14]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Cell division cycle 5-like protein (CDC5L).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cell division cycle 5-like protein (CDC5L).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cell division cycle 5-like protein (CDC5L).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell division cycle 5-like protein (CDC5L).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Cell division cycle 5-like protein (CDC5L).	[15]

3 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 decreases the sumoylation of Cell division cycle 5-like protein (CDC5L).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cell division cycle 5-like protein (CDC5L).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Cell division cycle 5-like protein (CDC5L).	[17]

References

• [1] Oncogenic Properties of NEAT1 in Prostate Cancer Cells Depend on the CDC5L-AGRN Transcriptional Regulation Circuit.Cancer Res. 2018 Aug 1;78(15):4138-4149. doi: 10.1158/0008-5472.CAN-18-0688. Epub 2018 Jun 5.
• [2] Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma.Mol Cancer Res. 2008 Jun;6(6):937-46. doi: 10.1158/1541-7786.MCR-07-2115.
• [3] A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells.Genetics. 2016 Oct;204(2):807-819. doi: 10.1534/genetics.116.190231. Epub 2016 Aug 24.
• [4] CDC5L Promotes hTERT Expression and Colorectal Tumor Growth.Cell Physiol Biochem. 2017;41(6):2475-2488. doi: 10.1159/000475916. Epub 2017 May 4.
• [5] Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells.Int J Mol Sci. 2017 Apr 7;18(4):778. doi: 10.3390/ijms18040778.
• [6] CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target.Am J Surg Pathol. 2005 Mar;29(3):390-9. doi: 10.1097/00000478-200503000-00014.
• [7] CDC5L drives FAH expression to promote metabolic reprogramming in melanoma.Oncotarget. 2017 Dec 7;8(69):114328-114343. doi: 10.18632/oncotarget.23107. eCollection 2017 Dec 26.
• [8] Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia.Genomics. 1998 Apr 15;49(2):218-29. doi: 10.1006/geno.1998.5254.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [14] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] 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.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] 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.
• [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] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.