Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4UYZ71)

• DOT Name: Ankyrin repeat domain-containing protein 2 (ANKRD2)
• Synonyms: Skeletal muscle ankyrin repeat protein; hArpp
• Gene Name: ANKRD2
• Related Disease:
  Emery-Dreifuss muscular dystrophy
  Emery-Dreifuss muscular dystrophy 2, autosomal dominant
  Qualitative or quantitative defects of dysferlin
  Renal cell carcinoma
  Amyotrophic lateral sclerosis
  Rhabdomyosarcoma
  Type-1/2 diabetes
• UniProt ID: ANKR2_HUMAN
• Pfam ID: PF12796
• Sequence:
  MAKAPSWAGVGALAYKAPEALWPAEAVMDGTMEDSEAVQRATALIEQRLAQEEENEKLRG
  DARQKLPMDLLVLEDEKHHGAQSAALQKVKGQERVRKTSLDLRREIIDVGGIQNLIELRK
  KRKQKKRDALAASHEPPPEPEEITGPVDEETFLKAAVEGKMKVIEKFLADGGSADTCDQF
  RRTALHRASLEGHMEILEKLLDNGATVDFQDRLDCTAMHWACRGGHLEVVKLLQSHGADT
  NVRDKLLSTPLHVAVRTGQVEIVEHFLSLGLEINARDREGDTALHDAVRLNRYKIIKLLL
  LHGADMMTKNLAGKTPTDLVQLWQADTRHALEHPEPGAEHNGLEGPNDSGRETPQPVPAQ
• Function: Functions as a negative regulator of myocyte differentiation. May interact with both sarcoplasmic structural proteins and nuclear proteins to regulate gene expression during muscle development and in response to muscle stress.
• Tissue Specificity: Mostly expressed in skeletal and cardiac muscles. Found in slow fibers. Also expressed in kidney, but to a lower extent (at protein level).
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Emery-Dreifuss muscular dystrophy	DISYTPR5	Strong	Biomarker	[1]
Emery-Dreifuss muscular dystrophy 2, autosomal dominant	DIS4FT32	Strong	Biomarker	[1]
Qualitative or quantitative defects of dysferlin	DIS59VEJ	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[4]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Ankyrin repeat domain-containing protein 2 (ANKRD2) decreases the response to substance of Arsenic trioxide.	[22]

3 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 Ankyrin repeat domain-containing protein 2 (ANKRD2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ankyrin repeat domain-containing protein 2 (ANKRD2).	[21]

References

• [1] Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies.Oxid Med Cell Longev. 2019 Jul 24;2019:7318796. doi: 10.1155/2019/7318796. eCollection 2019.
• [2] Proteomic analysis of the skeletal muscles from dysferlinopathy patients.J Clin Neurosci. 2020 Jan;71:186-190. doi: 10.1016/j.jocn.2019.08.068. Epub 2019 Aug 19.
• [3] ARPP protein is selectively expressed in renal oncocytoma, but rarely in renal cell carcinomas.Mod Pathol. 2007 Feb;20(2):199-207. doi: 10.1038/modpathol.3800730. Epub 2007 Jan 5.
• [4] Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis.Pathobiology. 2002-2003;70(4):197-203. doi: 10.1159/000069329.
• [5] Immunohistochemical analysis of a muscle ankyrin-repeat protein, Arpp, in paraffin-embedded tumors: evaluation of Arpp as a tumor marker for rhabdomyosarcoma.Hum Pathol. 2005 Jun;36(6):620-5. doi: 10.1016/j.humpath.2005.04.014.
• [6] Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy.Circulation. 2004 Jul 13;110(2):155-62. doi: 10.1161/01.CIR.0000135591.37759.AF. Epub 2004 Jul 6.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] 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.
• [14] Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle. 2011 Mar;2(1):45-56. doi: 10.1007/s13539-011-0021-y. Epub 2011 Feb 26.
• [15] 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.
• [16] 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.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] 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.
• [22] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.