Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPV1D60)

• DOT Name: Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4)
• Synonyms: PPIase FKBP4; EC 5.2.1.8; 51 kDa FK506-binding protein; FKBP51; 52 kDa FK506-binding protein; 52 kDa FKBP; FKBP-52; 59 kDa immunophilin; p59; FK506-binding protein 4; FKBP-4; FKBP59; HSP-binding immunophilin; HBI; Immunophilin FKBP52; Rotamase
• Gene Name: FKBP4
• UniProt ID: FKBP4_HUMAN
• PDB ID: 1N1A; 1P5Q; 1Q1C; 1QZ2; 4DRJ; 4LAV; 4LAW; 4LAX; 4LAY; 4TW8; 6RCY; 8FFV
• EC Number: 5.2.1.8
• Pfam ID: PF00254 ; PF00515 ; PF07719
• Sequence:
  MTAEEMKATESGAQSAPLPMEGVDISPKQDEGVLKVIKREGTGTEMPMIGDRVFVHYTGW
  LLDGTKFDSSLDRKDKFSFDLGKGEVIKAWDIAIATMKVGEVCHITCKPEYAYGSAGSPP
  KIPPNATLVFEVELFEFKGEDLTEEEDGGIIRRIQTRGEGYAKPNEGAIVEVALEGYYKD
  KLFDQRELRFEIGEGENLDLPYGLERAIQRMEKGEHSIVYLKPSYAFGSVGKEKFQIPPN
  AELKYELHLKSFEKAKESWEMNSEEKLEQSTIVKERGTVYFKEGKYKQALLQYKKIVSWL
  EYESSFSNEEAQKAQALRLASHLNLAMCHLKLQAFSAAIESCNKALELDSNNEKGLFRRG
  EAHLAVNDFELARADFQKVLQLYPNNKAAKTQLAVCQQRIRRQLAREKKLYANMFERLAE
  EENKAKAEASSGDHPTDTEMKEEQKSNTAGSQSQVETEA
• Function: Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Estrogen sig.ling pathway (hsa04915)
• Reactome Pathway:
  Attenuation phase (R-HSA-3371568)
  ESR-mediated signaling (R-HSA-8939211)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Potential therapeutics for SARS (R-HSA-9679191)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

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 increases the methylation of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[1]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[13]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[21]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP4 (FKBP4).	[22]

References

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• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
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• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] 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.
• [14] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [15] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [16] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] 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.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] 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.
• [22] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.