Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH3CSXA)

• DOT Name: Calponin-2 (CNN2)
• Synonyms: Calponin H2, smooth muscle; Neutral calponin
• Gene Name: CNN2
• Related Disease:
  Arthritis
  Rheumatoid arthritis
  Abdominal aortic aneurysm
  Age-related macular degeneration
  Aortic valve disorder
  Arteriosclerosis
  Atherosclerosis
  Clear cell renal carcinoma
  Gastric cancer
  Neovascular age-related macular degeneration
  Papillary renal cell carcinoma
  Renal cell carcinoma
  Stomach cancer
  Hepatocellular carcinoma
  Neoplasm
  Advanced cancer
  High blood pressure
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: CNN2_HUMAN
• PDB ID: 1WYN
• Pfam ID: PF00402 ; PF00307
• Sequence:
  MSSTQFNKGPSYGLSAEVKNRLLSKYDPQKEAELRTWIEGLTGLSIGPDFQKGLKDGTIL
  CTLMNKLQPGSVPKINRSMQNWHQLENLSNFIKAMVSYGMNPVDLFEANDLFESGNMTQV
  QVSLLALAGKAKTKGLQSGVDIGVKYSEKQERNFDDATMKAGQCVIGLQMGTNKCASQSG
  MTAYGTRRHLYDPKNHILPPMDHSTISLQMGTNKCASQVGMTAPGTRRHIYDTKLGTDKC
  DNSSMSLQMGYTQGANQSGQVFGLGRQIYDPKYCPQGTVADGAPSGTGDCPDPGEVPEYP
  PYYQEEAGY
• Function: Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction. It is capable of binding to actin, calmodulin and tropomyosin. The interaction of calponin with actin inhibits the actomyosin Mg-ATPase activity.
• Tissue Specificity: Heart and smooth muscle.
• Reactome Pathway:
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Genetic Variation	[2]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[3]
Aortic valve disorder	DISKLYD7	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[5]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[3]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[10]
High blood pressure	DISY2OHH	Limited	Biomarker	[11]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[10]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[10]
Prostate cancer	DISF190Y	Limited	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[10]

1 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 Calponin-2 (CNN2).	[12]

15 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 Calponin-2 (CNN2).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calponin-2 (CNN2).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Calponin-2 (CNN2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calponin-2 (CNN2).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calponin-2 (CNN2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calponin-2 (CNN2).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Calponin-2 (CNN2).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of Calponin-2 (CNN2).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Calponin-2 (CNN2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Calponin-2 (CNN2).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Calponin-2 (CNN2).	[22]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Calponin-2 (CNN2).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Calponin-2 (CNN2).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Calponin-2 (CNN2).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Calponin-2 (CNN2).	[26]

References

• [1] Deletion of calponin 2 in macrophages attenuates the severity of inflammatory arthritis in mice.Am J Physiol Cell Physiol. 2016 Oct 1;311(4):C673-C685. doi: 10.1152/ajpcell.00331.2015. Epub 2016 Aug 3.
• [2] The potential role of DNA methylation in abdominal aortic aneurysms.Int J Mol Sci. 2015 May 18;16(5):11259-75. doi: 10.3390/ijms160511259.
• [3] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [4] Deletion of calponin 2 attenuates the development of calcific aortic valve disease in ApoE(-/-) mice.J Mol Cell Cardiol. 2018 Aug;121:233-241. doi: 10.1016/j.yjmcc.2018.07.249. Epub 2018 Jul 24.
• [5] Downregulation of calponin 2 contributes to the quiescence of lung macrophages.Am J Physiol Cell Physiol. 2019 Oct 1;317(4):C749-C761. doi: 10.1152/ajpcell.00036.2019. Epub 2019 Jul 31.
• [6] Differential protein profiling in renal-cell carcinoma.Mol Carcinog. 2004 May;40(1):47-61. doi: 10.1002/mc.20015.
• [7] Knockdown of calponin 2 suppressed cell growth in gastric cancer cells.Tumour Biol. 2017 Jul;39(7):1010428317706455. doi: 10.1177/1010428317706455.
• [8] LncRNA NEAT1 Promotes Proliferation, Migration And Invasion Via Regulating miR-296-5p/CNN2 Axis In Hepatocellular Carcinoma Cells.Onco Targets Ther. 2019 Nov 18;12:9887-9897. doi: 10.2147/OTT.S228917. eCollection 2019.
• [9] Lentivirus-mediated shRNA Targeting CNN2 Inhibits Hepatocarcinoma in Vitro and in Vivo.Int J Med Sci. 2018 Jan 1;15(1):69-76. doi: 10.7150/ijms.21113. eCollection 2018.
• [10] Increased expression of calponin 2 is a positive prognostic factor in pancreatic ductal adenocarcinoma.Oncotarget. 2017 May 9;8(34):56428-56442. doi: 10.18632/oncotarget.17701. eCollection 2017 Aug 22.
• [11] Double deletion of calponin 1 and calponin 2 in mice decreases systemic blood pressure with blunted length-tension response of aortic smooth muscle.J Mol Cell Cardiol. 2019 Apr;129:49-57. doi: 10.1016/j.yjmcc.2019.01.026. Epub 2019 Jan 29.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] The retinoid anticancer signal: mechanisms of target gene regulation. Br J Cancer. 2005 Aug 8;93(3):310-8. doi: 10.1038/sj.bjc.6602700.
• [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] 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.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] 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.
• [20] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [21] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
• [22] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [23] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.