Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC73XJK)

• DOT Name: FERM domain-containing protein 5 (FRMD5)
• Gene Name: FRMD5
• Related Disease:
  Acute coronary syndrome
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neurodevelopmental disorder with eye movement abnormalities and ataxia
• UniProt ID: FRMD5_HUMAN
• Pfam ID: PF08736 ; PF09380 ; PF00373 ; PF09379
• Sequence:
  MLSRLMSGSSRSLEREYSCTVRLLDDSEYTCTIQRDAKGQYLFDLLCHHLNLLEKDYFGI
  RFVDPDKQRHWLEFTKSVVKQLRSQPPFTMCFRVKFYPADPAALKEEITRYLVFLQIKRD
  LYHGRLLCKTSDAALLAAYILQAEIGDYDSGKHPEGYSSKFQFFPKHSEKLERKIAEIHK
  TELSGQTPATSELNFLRKAQTLETYGVDPHPCKDVSGNAAFLAFTPFGFVVLQGNKRVHF
  IKWNEVTKLKFEGKTFYLYVSQKEEKKIILTYFAPTPEACKHLWKCGIENQAFYKLEKSS
  QVRTVSSSNLFFKGSRFRYSGRVAKEVMESSAKIKREPPEIHRAGMVPSRSCPSITHGPR
  LSSVPRTRRRAVHISIMEGLESLRDSAHSTPVRSTSHGDTFLPHVRSSRTDSNERVAVIA
  DEAYSPADSVLPTPVAEHSLELMLLSRQINGATCSIEEEKESEASTPTATEVEALGGELR
  ALCQGHSGPEEEQVNKFVLSVLRLLLVTMGLLFVLLLLLIILTESDLDIAFFRDIRQTPE
  FEQFHYQYFCPLRRWFACKIRSVVSLLIDT
• Function: May be involved in regulation of cell migration. May regulate cell-matrix interactions via its interaction with ITGB5 and modifying ITGB5 cytoplasmic tail interactions such as with FERMT2 and TLN1. May regulate ROCK1 kinase activity possibly involved in regulation of actin stress fiber formation.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neurodevelopmental disorder with eye movement abnormalities and ataxia	DISB2GTU	Strong	Autosomal dominant	[4]

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 FERM domain-containing protein 5 (FRMD5).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of FERM domain-containing protein 5 (FRMD5).	[10]

14 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 FERM domain-containing protein 5 (FRMD5).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FERM domain-containing protein 5 (FRMD5).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FERM domain-containing protein 5 (FRMD5).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of FERM domain-containing protein 5 (FRMD5).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of FERM domain-containing protein 5 (FRMD5).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of FERM domain-containing protein 5 (FRMD5).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of FERM domain-containing protein 5 (FRMD5).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of FERM domain-containing protein 5 (FRMD5).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of FERM domain-containing protein 5 (FRMD5).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of FERM domain-containing protein 5 (FRMD5).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FERM domain-containing protein 5 (FRMD5).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FERM domain-containing protein 5 (FRMD5).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of FERM domain-containing protein 5 (FRMD5).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of FERM domain-containing protein 5 (FRMD5).	[20]

References

• [1] Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.PLoS One. 2017 Jul 28;12(7):e0182115. doi: 10.1371/journal.pone.0182115. eCollection 2017.
• [2] C-terminal truncated HBx protein activates caveolin-1/LRP6/-catenin/FRMD5 axis in promoting hepatocarcinogenesis.Cancer Lett. 2019 Mar 1;444:60-69. doi: 10.1016/j.canlet.2018.12.003. Epub 2018 Dec 21.
• [3] FERM-containing protein FRMD5 is a p120-catenin interacting protein that regulates tumor progression.FEBS Lett. 2012 Sep 21;586(19):3044-50. doi: 10.1016/j.febslet.2012.07.019. Epub 2012 Jul 27.
• [4] Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. doi: 10.1016/j.ajhg.2019.11.003. Epub 2019 Nov 27.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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] 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.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.