Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE2W0DH)

• DOT Name: Cofilin-2 (CFL2)
• Synonyms: Cofilin, muscle isoform
• Gene Name: CFL2
• Related Disease:
  Nemaline myopathy 7
  Breast cancer
  Cardiomyopathy
  Congenital myopathy
  Dilated cardiomyopathy 1A
  Myofibrillar myopathy
  Nemaline myopathy
  Prostate cancer
  Prostate carcinoma
  Vascular dementia
  Atrial fibrillation
  Familial atrial fibrillation
  Typical nemaline myopathy
  Bladder cancer
  Breast carcinoma
  Lateral meningocele syndrome
  Limb-mammary syndrome
  Myopathy
  Nasopharyngeal carcinoma
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: COF2_HUMAN
• PDB ID: 7M0G; 7U8K
• Pfam ID: PF00241
• Sequence:
  MASGVTVNDEVIKVFNDMKVRKSSTQEEIKKRKKAVLFCLSDDKRQIIVEEAKQILVGDI
  GDTVEDPYTSFVKLLPLNDCRYALYDATYETKESKKEDLVFIFWAPESAPLKSKMIYASS
  KDAIKKKFTGIKHEWQVNGLDDIKDRSTLGEKLGGNVVVSLEGKPL
• Function: Controls reversibly actin polymerization and depolymerization in a pH-sensitive manner. Its F-actin depolymerization activity is regulated by association with CSPR3. It has the ability to bind G- and F-actin in a 1:1 ratio of cofilin to actin. It is the major component of intranuclear and cytoplasmic actin rods. Required for muscle maintenance. May play a role during the exchange of alpha-actin forms during the early postnatal remodeling of the sarcomere.
• Tissue Specificity: Isoform CFL2b is expressed predominantly in skeletal muscle and heart. Isoform CFL2a is expressed in various tissues.
• KEGG Pathway:
  Axon guidance (hsa04360)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Pertussis (hsa05133)
  Human immunodeficiency virus 1 infection (hsa05170)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nemaline myopathy 7	DISIWD5A	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Posttranslational Modification	[3]
Myofibrillar myopathy	DISF24LW	Strong	Genetic Variation	[5]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Vascular dementia	DISVO82H	Strong	Biomarker	[7]
Atrial fibrillation	DIS15W6U	moderate	Biomarker	[8]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[8]
Typical nemaline myopathy	DISY1645	Supportive	Autosomal dominant	[9]
Bladder cancer	DISUHNM0	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[2]
Lateral meningocele syndrome	DISG74RP	Limited	Altered Expression	[11]
Limb-mammary syndrome	DIS7H4FP	Limited	Altered Expression	[11]
Myopathy	DISOWG27	Limited	Biomarker	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[10]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[10]

4 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 Cofilin-2 (CFL2).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Cofilin-2 (CFL2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cofilin-2 (CFL2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Cofilin-2 (CFL2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cofilin-2 (CFL2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cofilin-2 (CFL2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cofilin-2 (CFL2).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cofilin-2 (CFL2).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cofilin-2 (CFL2).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cofilin-2 (CFL2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cofilin-2 (CFL2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cofilin-2 (CFL2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cofilin-2 (CFL2).	[23]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells.J Transl Med. 2013 Mar 5;11:57. doi: 10.1186/1479-5876-11-57.
• [3] Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy.J Am Coll Cardiol. 2015 Mar 31;65(12):1199-1214. doi: 10.1016/j.jacc.2015.01.031.
• [4] Expanding the histopathological spectrum of CFL2-related myopathies.Clin Genet. 2018 Jun;93(6):1234-1239. doi: 10.1111/cge.13240. Epub 2018 Mar 25.
• [5] Congenital myopathy caused by a novel missense mutation in the CFL2 gene.Neuromuscul Disord. 2012 Jul;22(7):632-9. doi: 10.1016/j.nmd.2012.03.008. Epub 2012 May 4.
• [6] Long noncoding RNA SOX2-OT facilitates prostate cancer cell proliferation and migration via miR-369-3p/CFL2 axis.Biochem Biophys Res Commun. 2019 Dec 10;520(3):586-593. doi: 10.1016/j.bbrc.2019.09.108. Epub 2019 Oct 14.
• [7] Cofilin 2 in Serum as a Novel Biomarker for Alzheimer's Disease in Han Chinese.Front Aging Neurosci. 2019 Aug 9;11:214. doi: 10.3389/fnagi.2019.00214. eCollection 2019.
• [8] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [9] Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. Am J Hum Genet. 2007 Jan;80(1):162-7. doi: 10.1086/510402. Epub 2006 Nov 14.
• [10] Characterization of mRNA Expression and Endogenous RNA Profiles in Bladder Cancer Based on The Cancer Genome Atlas (TCGA) Database.Med Sci Monit. 2019 Apr 25;25:3041-3060. doi: 10.12659/MSM.915487.
• [11] Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling.Oncogene. 2010 Feb 11;29(6):845-54. doi: 10.1038/onc.2009.381. Epub 2009 Nov 9.
• [12] Cofilin-2 Acts as a Marker for Predicting Radiotherapy Response and Is a Potential Therapeutic Target in Nasopharyngeal Carcinoma.Med Sci Monit. 2018 Apr 17;24:2317-2329. doi: 10.12659/msm.909832.
• [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] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [21] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.