Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR9ND6K)

• DOT Name: FK506-binding protein-like (FKBPL)
• Synonyms: WAF-1/CIP1 stabilizing protein 39; WISp39
• Gene Name: FKBPL
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Breast neoplasm
  Estrogen-receptor positive breast cancer
  Neoplasm
  Glycogen storage disease type II
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Breast cancer
  Breast carcinoma
• UniProt ID: FKBPL_HUMAN
• Pfam ID: PF00515
• Sequence:
  METPPVNTIGEKDTSQPQQEWEKNLRENLDSVIQIRQQPRDPPTETLELEVSPDPASQIL
  EHTQGAEKLVAELEGDSHKSHGSTSQMPEALQASDLWYCPDGSFVKKIVIRGHGLDKPKL
  GSCCRVLALGFPFGSGPPEGWTELTMGVGPWREETWGELIEKCLESMCQGEEAELQLPGH
  SGPPVRLTLASFTQGRDSWELETSEKEALAREERARGTELFRAGNPEGAARCYGRALRLL
  LTLPPPGPPERTVLHANLAACQLLLGQPQLAAQSCDRVLEREPGHLKALYRRGVAQAALG
  NLEKATADLKKVLAIDPKNRAAQEELGKVVIQGKNQDAGLAQGLRKMFG
• Function: May be involved in response to X-ray. Regulates p21 protein stability by binding to Hsp90 and p21.
• Tissue Specificity: Ubiquitously expressed with higher levels in testis.
• Reactome Pathway: The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Therapeutic	[3]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Glycogen storage disease type II	DISXZPBC	moderate	Genetic Variation	[5]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[6]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[6]
Lung neoplasm	DISVARNB	moderate	Biomarker	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	FK506-binding protein-like (FKBPL) increases the response to substance of Fulvestrant.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of FK506-binding protein-like (FKBPL).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of FK506-binding protein-like (FKBPL).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of FK506-binding protein-like (FKBPL).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of FK506-binding protein-like (FKBPL).	[10]
Epirubicin	DMPDW6T	Approved	Epirubicin increases the expression of FK506-binding protein-like (FKBPL).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of FK506-binding protein-like (FKBPL).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of FK506-binding protein-like (FKBPL).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of FK506-binding protein-like (FKBPL).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of FK506-binding protein-like (FKBPL).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of FK506-binding protein-like (FKBPL).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of FK506-binding protein-like (FKBPL).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of FK506-binding protein-like (FKBPL).	[12]

References

• [1] FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4.BMC Cancer. 2019 Apr 11;19(1):351. doi: 10.1186/s12885-019-5500-0.
• [2] Pin1 facilitates isoproterenolinduced cardiac fibrosis and collagen deposition by promoting oxidative stress and activating the MEK1/2ERK1/2 signal transduction pathway in rats.Int J Mol Med. 2018 Mar;41(3):1573-1583. doi: 10.3892/ijmm.2017.3354. Epub 2017 Dec 29.
• [3] FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res. 2010 Feb 1;70(3):1090-100. doi: 10.1158/0008-5472.CAN-09-2515. Epub 2010 Jan 26.
• [4] FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis.Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):845-54. doi: 10.1161/ATVBAHA.114.304539. Epub 2015 Mar 12.
• [5] Associations of 6p21.3 Region with Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy.Sci Rep. 2016 Feb 10;6:20914. doi: 10.1038/srep20914.
• [6] Low-frequency coding variants at 6p21.33 and 20q11.21 are associated with lung cancer risk in Chinese populations.Am J Hum Genet. 2015 May 7;96(5):832-40. doi: 10.1016/j.ajhg.2015.03.009. Epub 2015 Apr 30.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] The differential effects of cyclophosphamide, epirubicin and 5-fluorouracil on apoptotic marker (CPP-32), pro-apoptotic protein (p21(WAF-1)) and anti-apoptotic protein (bcl-2) in breast cancer cells. Breast Cancer Res Treat. 2003 Aug;80(3):239-44. doi: 10.1023/A:1024995202135.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res. 2010 Feb 1;70(3):1090-100. doi: 10.1158/0008-5472.CAN-09-2515. Epub 2010 Jan 26.