Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT55W5WC)

• DOT Name: Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14)
• Synonyms: PPIase FKBP14; EC 5.2.1.8; 22 kDa FK506-binding protein; 22 kDa FKBP; FKBP-22; FK506-binding protein 14; FKBP-14; Rotamase
• Gene Name: FKBP14
• Related Disease:
  Ehlers-Danlos syndrome, kyphoscoliotic and deafness type
  Amyotrophic lateral sclerosis type 1
  B-cell neoplasm
  Bone osteosarcoma
  Cervical cancer
  Cervical carcinoma
  Colon carcinoma
  Ehlers-Danlos syndrome
  Ehlers-Danlos syndrome, kyphoscoliotic type 1
  Gastric cancer
  Morquio syndrome
  Osteosarcoma
  Stomach cancer
  Metastatic malignant neoplasm
  Neoplasm
  Sensorineural hearing loss disorder
  Amelocerebrohypohidrotic syndrome
  Connective tissue disorder
• UniProt ID: FKB14_HUMAN
• PDB ID: 4DIP; 4MSP
• EC Number: 5.2.1.8
• Pfam ID: PF00254
• Sequence:
  MRLFLWNAVLTLFVTSLIGALIPEPEVKIEVLQKPFICHRKTKGGDLMLVHYEGYLEKDG
  SLFHSTHKHNNGQPIWFTLGILEALKGWDQGLKGMCVGEKRKLIIPPALGYGKEGKGKIP
  PESTLIFNIDLLEIRNGPRSHESFQEMDLNDDWKLSKDEVKAYLKKEFEKHGAVVNESHH
  DALVEDIFDKEDEDKDGFISAREFTYKHDEL
• Function: PPIase which accelerates the folding of proteins during protein synthesis. Has a preference for substrates containing 4-hydroxylproline modifications, including type III collagen. May also target type VI and type X collagens.
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ehlers-Danlos syndrome, kyphoscoliotic and deafness type	DISA74TB	Definitive	Autosomal recessive	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Genetic Variation	[6]
Ehlers-Danlos syndrome, kyphoscoliotic type 1	DISVE04H	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Morquio syndrome	DIS2Y2P2	Strong	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[11]
Amelocerebrohypohidrotic syndrome	DIS0DATV	Limited	Genetic Variation	[12]
Connective tissue disorder	DISKXBS3	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[13]

12 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 FKBP14 (FKBP14).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Peptidyl-prolyl cis-trans isomerase FKBP14 (FKBP14).	[24]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] The role of immunophilins in mutant superoxide dismutase-1linked familial amyotrophic lateral sclerosis.Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3251-6. doi: 10.1073/pnas.96.6.3251.
• [3] Inhibitory effects of FKBP14 on human cervical cancer cells.Mol Med Rep. 2017 Oct;16(4):4265-4272. doi: 10.3892/mmr.2017.7043. Epub 2017 Jul 21.
• [4] MiR-361 inhibits osteosarcoma cell lines invasion and proliferation by targeting FKBP14.Eur Rev Med Pharmacol Sci. 2018 Jan;22(1):79-86. doi: 10.26355/eurrev_201801_14103.
• [5] FKBP14 Promotes The Proliferation And Migration Of Colon Carcinoma Cells Through Targeting IL-6/STAT3 Signaling Pathway.Onco Targets Ther. 2019 Nov 1;12:9069-9076. doi: 10.2147/OTT.S222555. eCollection 2019.
• [6] Primary muscle involvement in a 15-year-old girl with the recurrent homozygous c.362dupC variant in FKBP14.Am J Med Genet A. 2019 Feb;179(2):317-321. doi: 10.1002/ajmg.a.61006. Epub 2018 Dec 18.
• [7] Further delineation of FKBP14-related Ehlers-Danlos syndrome: A patient with early vascular complications and non-progressive kyphoscoliosis, and literature review.Am J Med Genet A. 2016 Aug;170(8):2031-8. doi: 10.1002/ajmg.a.37728. Epub 2016 May 5.
• [8] Downregulation of FKBP14 by RNA interference inhibits the proliferation, adhesion and invasion of gastric cancer cells.Oncol Lett. 2017 Apr;13(4):2811-2816. doi: 10.3892/ol.2017.5781. Epub 2017 Feb 28.
• [9] Excessively redundant umbilical skin as a potential early clinical feature of Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome.Clin Genet. 2014 Nov;86(5):469-72. doi: 10.1111/cge.12414. Epub 2014 May 22.
• [10] FKBP14 overexpression contributes to osteosarcoma carcinogenesis and indicates poor survival outcome.Oncotarget. 2016 Jun 28;7(26):39872-39884. doi: 10.18632/oncotarget.9524.
• [11] Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet. 2012 Feb 10;90(2):201-16. doi: 10.1016/j.ajhg.2011.12.004. Epub 2012 Jan 19.
• [12] Genotype-based databases for variants causing rare diseases.Gene. 2014 Oct 15;550(1):136-40. doi: 10.1016/j.gene.2014.08.016. Epub 2014 Aug 8.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.