Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6285L4)

• DOT Name: Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A)
• Synonyms: PPIase FKBP1A; EC 5.2.1.8; 12 kDa FK506-binding protein; 12 kDa FKBP; FKBP-12; Calstabin-1; FK506-binding protein 1A; FKBP-1A; Immunophilin FKBP12; Rotamase
• Gene Name: FKBP1A
• UniProt ID: FKB1A_HUMAN
• PDB ID: 1A7X ; 1B6C ; 1BKF ; 1BL4 ; 1D6O ; 1D7H ; 1D7I ; 1D7J ; 1EYM ; 1F40 ; 1FAP ; 1FKB ; 1FKD ; 1FKF ; 1FKG ; 1FKH ; 1FKI ; 1FKJ ; 1FKR ; 1FKS ; 1FKT ; 1J4H ; 1J4I ; 1J4R ; 1NSG ; 1QPF ; 1QPL ; 2DG3 ; 2DG4 ; 2DG9 ; 2FAP ; 2FKE ; 2ND5 ; 2PPN ; 2PPO ; 2PPP ; 2RSE ; 3FAP ; 3H9R ; 3MDY ; 4DH0 ; 4FAP ; 4IPX ; 4N19 ; 4ODP ; 4ODQ ; 4ODR ; 5I7P ; 5I7Q ; 6I1S ; 6M4U ; 6OQA ; 6VCU ; 6YF0 ; 6YF1 ; 6YF2 ; 6YF3 ; 7EPD ; 7U0T ; 7U8D ; 8CHI ; 8CHJ ; 8CHK ; 8CHL ; 8CHM ; 8ER6 ; 8ER7 ; 8ERA ; 8JCU ; 8JCV ; 8JCW ; 8JCX ; 8JCY ; 8JCZ ; 8JD0 ; 8JD1 ; 8JD2 ; 8JD4 ; 8PDF ; 8PPZ
• EC Number: 5.2.1.8
• Pfam ID: PF00254
• Sequence:
  MGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGW
  EEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLE
• Function: Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
• Reactome Pathway:
  Calcineurin activates NFAT (R-HSA-2025928)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  TGFBR1 LBD Mutants in Cancer (R-HSA-3656535)
  Potential therapeutics for SARS (R-HSA-9679191)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  mTORC1-mediated signalling (R-HSA-166208)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A) affects the response to substance of Vinblastine.	[18]

16 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 Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[11]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug affects the binding of Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A).	[17]

References

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• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [12] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [13] 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.
• [14] 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.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [17] Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol. 2007 Apr;49(4):228-35. doi: 10.1097/FJC.0b013e3180325b0a.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.