Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9PZHXV)

• DOT Name: TIMELESS-interacting protein (TIPIN)
• Gene Name: TIPIN
• Related Disease:
  Breast cancer
  Breast carcinoma
  Triple negative breast cancer
  Testicular germ cell tumor
  Neoplasm
  Patent ductus arteriosus
  Colorectal carcinoma
• UniProt ID: TIPIN_HUMAN
• PDB ID: 7PFO; 7PLO; 8B9D
• Pfam ID: PF07962
• Sequence:
  MLEPQENGVIDLPDYEHVEDETFPPFPPPASPERQDGEGTEPDEESGNGAPVRVPPKRTV
  KRNIPKLDAQRLISERGLPALRHVFDKAKFKGKGHEAEDLKMLIRHMEHWAHRLFPKLQF
  EDFIDRVEYLGSKKEVQTCLKRIRLDLPILHEDFVSNNDEVAENNEHDVTSTELDPFLTN
  LSESEMFASELSRSLTEEQQQRIERNKQLALERRQAKLLSNSQTLGNDMLMNTPRAHTVE
  EVNTDEDQKEESNGLNEDILDNPCNDAIANTLNEEETLLDQSFKNVQQQLDATSRNITEA
  R
• Function: Plays an important role in the control of DNA replication and the maintenance of replication fork stability. Important for cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. Forms a complex with TIMELESS and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress.
• Reactome Pathway: Processing of DNA double-strand break ends (R-HSA-5693607)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Triple negative breast cancer	DISAMG6N	Definitive	Biomarker	[1]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Patent ductus arteriosus	DIS9P8YS	moderate	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Disputed	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of TIMELESS-interacting protein (TIPIN).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TIMELESS-interacting protein (TIPIN).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TIMELESS-interacting protein (TIPIN).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TIMELESS-interacting protein (TIPIN).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of TIMELESS-interacting protein (TIPIN).	[10]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of TIMELESS-interacting protein (TIPIN).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of TIMELESS-interacting protein (TIPIN).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of TIMELESS-interacting protein (TIPIN).	[13]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of TIMELESS-interacting protein (TIPIN).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TIMELESS-interacting protein (TIPIN).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of TIMELESS-interacting protein (TIPIN).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of TIMELESS-interacting protein (TIPIN).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of TIMELESS-interacting protein (TIPIN).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of TIMELESS-interacting protein (TIPIN).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TIMELESS-interacting protein (TIPIN).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of TIMELESS-interacting protein (TIPIN).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of TIMELESS-interacting protein (TIPIN).	[21]

References

• [1] TIPIN depletion leads to apoptosis in breast cancer cells.Mol Oncol. 2015 Oct;9(8):1580-98. doi: 10.1016/j.molonc.2015.04.010. Epub 2015 May 9.
• [2] Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1141-1147. doi: 10.1038/ng.3879. Epub 2017 Jun 12.
• [3] Circadian gene expression and clinicopathologic correlates in pancreatic cancer.J Gastrointest Surg. 2013 Mar;17(3):443-50. doi: 10.1007/s11605-012-2112-2. Epub 2012 Dec 20.
• [4] Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients.Chronobiol Int. 2011 Dec;28(10):841-51. doi: 10.3109/07420528.2011.615182.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] 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.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.