Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-actinin-1 (ACTN1)
• Synonyms: Alpha-actinin cytoskeletal isoform; F-actin cross-linking protein; Non-muscle alpha-actinin-1
• Gene Name: ACTN1
• Related Disease:
  Myopathy
  Nemaline myopathy
  Neoplasm
  Platelet-type bleeding disorder 15
  Astrocytoma
  Bladder cancer
  Coagulation defect
  Endometriosis
  Idiopathic thrombocytopenic purpura
  Osteoarthritis
  Rheumatoid arthritis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Thrombocytopenia
  Autosomal dominant macrothrombocytopenia
  Breast cancer
  Breast carcinoma
• UniProt ID: ACTN1_HUMAN
• PDB ID: 2EYI; 2EYN; 2N8Y; 2N8Z
• Pfam ID: PF00307 ; PF13405 ; PF08726 ; PF00435
• Sequence:
  MDHYDSQQTNDYMQPEEDWDRDLLLDPAWEKQQRKTFTAWCNSHLRKAGTQIENIEEDFR
  DGLKLMLLLEVISGERLAKPERGKMRVHKISNVNKALDFIASKGVKLVSIGAEEIVDGNV
  KMTLGMIWTIILRFAIQDISVEETSAKEGLLLWCQRKTAPYKNVNIQNFHISWKDGLGFC
  ALIHRHRPELIDYGKLRKDDPLTNLNTAFDVAEKYLDIPKMLDAEDIVGTARPDEKAIMT
  YVSSFYHAFSGAQKAETAANRICKVLAVNQENEQLMEDYEKLASDLLEWIRRTIPWLENR
  VPENTMHAMQQKLEDFRDYRRLHKPPKVQEKCQLEINFNTLQTKLRLSNRPAFMPSEGRM
  VSDINNAWGCLEQVEKGYEEWLLNEIRRLERLDHLAEKFRQKASIHEAWTDGKEAMLRQK
  DYETATLSEIKALLKKHEAFESDLAAHQDRVEQIAAIAQELNELDYYDSPSVNARCQKIC
  DQWDNLGALTQKRREALERTEKLLETIDQLYLEYAKRAAPFNNWMEGAMEDLQDTFIVHT
  IEEIQGLTTAHEQFKATLPDADKERLAILGIHNEVSKIVQTYHVNMAGTNPYTTITPQEI
  NGKWDHVRQLVPRRDQALTEEHARQQHNERLRKQFGAQANVIGPWIQTKMEEIGRISIEM
  HGTLEDQLSHLRQYEKSIVNYKPKIDQLEGDHQLIQEALIFDNKHTNYTMEHIRVGWEQL
  LTTIARTINEVENQILTRDAKGISQEQMNEFRASFNHFDRDHSGTLGPEEFKACLISLGY
  DIGNDPQGEAEFARIMSIVDPNRLGVVTFQAFIDFMSRETADTDTADQVMASFKILAGDK
  NYITMDELRRELPPDQAEYCIARMAPYTGPDSVPGALDYMSFSTALYGESDL
• Function: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.
• KEGG Pathway:
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Shigellosis (hsa05131)
  Amoebiasis (hsa05146)
  Viral carcinogenesis (hsa05203)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Syndecan interactions (R-HSA-3000170)
  Nephrin family interactions (R-HSA-373753)
  Regulation of cytoskeletal remodeling and cell spreading by IPP complex components (R-HSA-446388)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOBTB2 GTPase cycle (R-HSA-9013418)
  RHOF GTPase cycle (R-HSA-9035034)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy	DISOWG27	Definitive	Biomarker	[1]
Nemaline myopathy	DIS5IYLY	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Platelet-type bleeding disorder 15	DISZV2E4	Definitive	Autosomal dominant	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[6]
Endometriosis	DISX1AG8	Strong	Altered Expression	[7]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Genetic Variation	[8]
Osteoarthritis	DIS05URM	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Thrombocytopenia	DISU61YW	moderate	Genetic Variation	[10]
Autosomal dominant macrothrombocytopenia	DISUTMSW	Supportive	Autosomal dominant	[6]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	Alpha-actinin-1 (ACTN1) affects the binding of 4-hydroxy-2-nonenal.	[34]

4 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 Alpha-actinin-1 (ACTN1).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-actinin-1 (ACTN1).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Alpha-actinin-1 (ACTN1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Alpha-actinin-1 (ACTN1).	[29]

21 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 Alpha-actinin-1 (ACTN1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-actinin-1 (ACTN1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alpha-actinin-1 (ACTN1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Alpha-actinin-1 (ACTN1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alpha-actinin-1 (ACTN1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-actinin-1 (ACTN1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Alpha-actinin-1 (ACTN1).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Alpha-actinin-1 (ACTN1).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Alpha-actinin-1 (ACTN1).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Alpha-actinin-1 (ACTN1).	[24]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Alpha-actinin-1 (ACTN1).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-actinin-1 (ACTN1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Alpha-actinin-1 (ACTN1).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Alpha-actinin-1 (ACTN1).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Alpha-actinin-1 (ACTN1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alpha-actinin-1 (ACTN1).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Alpha-actinin-1 (ACTN1).	[32]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Alpha-actinin-1 (ACTN1).	[27]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Alpha-actinin-1 (ACTN1).	[33]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Alpha-actinin-1 (ACTN1).	[27]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Alpha-actinin-1 (ACTN1).	[27]

References

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• [3] 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.
• [4] Alpha-actinin 1 and alpha-actinin 4: contrasting roles in the survival, motility, and RhoA signaling of astrocytoma cells.Exp Cell Res. 2010 Apr 15;316(7):1137-47. doi: 10.1016/j.yexcr.2010.02.011. Epub 2010 Feb 12.
• [5] Mass spectrometric detection combined with bioinformatic analysis identified possible protein markers and key pathways associated with bladder cancer.Gene. 2017 Aug 30;626:407-413. doi: 10.1016/j.gene.2017.05.054. Epub 2017 May 25.
• [6] ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet. 2013 Mar 7;92(3):431-8. doi: 10.1016/j.ajhg.2013.01.015. Epub 2013 Feb 21.
• [7] The cytoskeletal proteins alpha-actinin, Ezrin, and talin are De-expressed in endometriosis and endometrioid carcinoma compared with normal uterine epithelium.Appl Immunohistochem Mol Morphol. 2007 Jun;15(2):170-4. doi: 10.1097/01.pai.0000194762.78889.26.
• [8] Familial macrothrombocytopenia due to a double mutation in cis in the alpha-actinin 1 gene (ACTN1), previously considered to be chronic immune thrombocytopenic purpura.Pediatr Blood Cancer. 2018 Dec;65(12):e27418. doi: 10.1002/pbc.27418. Epub 2018 Aug 19.
• [9] Novel insight into the role of -actinin-1 in rheumatoid arthritis.Discov Med. 2014 Feb;17(92):75-80.
• [10] Novel ACTN1 variants in cases of thrombocytopenia.Hum Mutat. 2019 Dec;40(12):2258-2269. doi: 10.1002/humu.23840. Epub 2019 Nov 6.
• [11] Increased -actinin-1 destabilizes E-cadherin-based adhesions and associates with poor prognosis in basal-like breast cancer.PLoS One. 2018 May 9;13(5):e0196986. doi: 10.1371/journal.pone.0196986. eCollection 2018.
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• [18] 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.
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• [22] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [23] 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.
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• [31] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
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• [33] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [34] Site-specific protein adducts of 4-hydroxy-2(E)-nonenal in human THP-1 monocytic cells: protein carbonylation is diminished by ascorbic acid. Chem Res Toxicol. 2010 Jan;23(1):37-47. doi: 10.1021/tx9002462.