Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS9LJW4)

• DOT Name: Calpain-10 (CAPN10)
• Synonyms: EC 3.4.22.-; Calcium-activated neutral proteinase 10; CANP 10
• Gene Name: CAPN10
• Related Disease:
  Metabolic disorder
  Arteriosclerosis
  Atherosclerosis
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Cystic fibrosis
  Diabetic kidney disease
  Diabetic retinopathy
  Esophageal squamous cell carcinoma
  Essential hypertension
  High blood pressure
  Laryngeal carcinoma
  Obstructive sleep apnea
  Snowflake vitreoretinal degeneration
  Cardiovascular disease
  Coronary atherosclerosis
  Coronary heart disease
  Intellectual disability
  Schizoaffective disorder
  Schizophrenia
  Hyperglycemia
• UniProt ID: CAN10_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF01067 ; PF00648
• Sequence:
  MRAGRGATPARELFRDAAFPAADSSLFCDLSTPLAQFREDITWRRPQEICATPRLFPDDP
  REGQVKQGLLGDCWFLCACAALQKSRHLLDQVIPPGQPSWADQEYRGSFTCRIWQFGRWV
  EVTTDDRLPCLAGRLCFSRCQREDVFWLPLLEKVYAKVHGSYEHLWAGQVADALVDLTGG
  LAERWNLKGVAGSGGQQDRPGRWEHRTCRQLLHLKDQCLISCCVLSPRAGARELGEFHAF
  IVSDLRELQGQAGQCILLLRIQNPWGRRCWQGLWREGGEGWSQVDAAVASELLSQLQEGE
  FWVEEEEFLREFDELTVGYPVTEAGHLQSLYTERLLCHTRALPGAWVKGQSAGGCRNNSG
  FPSNPKFWLRVSEPSEVYIAVLQRSRLHAADWAGRARALVGDSHTSWSPASIPGKHYQAV
  GLHLWKVEKRRVNLPRVLSMPPVAGTACHAYDREVHLRCELSPGYYLAVPSTFLKDAPGE
  FLLRVFSTGRVSLSAIRAVAKNTTPGAALPAGEWGTVQLRGSWRVGQTAGGSRNFASYPT
  NPCFPFSVPEGPGPRCVRITLHQHCRPSDTEFHPIGFHIFQVPEGGRSQDAPPLLLQEPL
  LSCVPHRYAQEVSRLCLLPAGTYKVVPSTYLPDTEGAFTVTIATRIDRPSIHSQEMLGQF
  LQEVSIMAVMKT
• Function: Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. May play a role in insulin-stimulated glucose uptake.
• Tissue Specificity: Detected in primary skeletal muscle cells (at protein level). Ubiquitous.
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	DISMTRY0	Strong	Genetic Variation	[3]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Essential hypertension	DIS7WI98	Strong	Biomarker	[10]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[2]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[11]
Obstructive sleep apnea	DIS0SVD1	Strong	Genetic Variation	[12]
Snowflake vitreoretinal degeneration	DISXFPWC	Strong	Genetic Variation	[13]
Cardiovascular disease	DIS2IQDX	moderate	Genetic Variation	[14]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[15]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[15]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[16]
Schizoaffective disorder	DISLBW6B	Disputed	Genetic Variation	[17]
Schizophrenia	DISSRV2N	Disputed	Genetic Variation	[17]
Hyperglycemia	DIS0BZB5	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Calpain-10 (CAPN10) affects the response to substance of Arsenic.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calpain-10 (CAPN10).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calpain-10 (CAPN10).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Calpain-10 (CAPN10).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calpain-10 (CAPN10).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Calpain-10 (CAPN10).	[22]
Glimepiride	DM5FSJA	Approved	Glimepiride increases the expression of Calpain-10 (CAPN10).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calpain-10 (CAPN10).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calpain-10 (CAPN10).	[25]

References

• [1] The CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population.PLoS One. 2008 Aug 13;3(8):e2953. doi: 10.1371/journal.pone.0002953.
• [2] Replication of calpain-10 genetic association with carotid intima-media thickness.Atherosclerosis. 2009 Aug;205(2):503-5. doi: 10.1016/j.atherosclerosis.2008.12.038. Epub 2009 Jan 9.
• [3] Monogenic and polygenic models detected in steroid 21-hydroxylase deficiency-related paediatric hyperandrogenism.Horm Res. 2009 Jan;71(1):28-37. doi: 10.1159/000173739. Epub 2008 Nov 27.
• [4] Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility.J Gastroenterol Hepatol. 2007 Dec;22(12):2298-302. doi: 10.1111/j.1440-1746.2007.04843.x. Epub 2007 Jun 7.
• [5] Gene polymorphisms related to insulin resistance and gene-environment interaction in colorectal cancer risk.Ann Hum Biol. 2015;42(6):560-8. doi: 10.3109/03014460.2014.1002532. Epub 2015 Jul 23.
• [6] Calpain 10 and development of diabetes mellitus in cystic fibrosis.J Cyst Fibros. 2006 Jan;5(1):47-51. doi: 10.1016/j.jcf.2005.09.011. Epub 2005 Dec 27.
• [7] Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injury.Kidney Int. 2012 Feb;81(4):391-400. doi: 10.1038/ki.2011.356. Epub 2011 Oct 19.
• [8] Alanine variant of the Pro12Ala polymorphism of the PPARgamma gene might be associated with decreased risk of diabetic retinopathy in type 2 diabetes.Diabetes Res Clin Pract. 2008 Apr;80(1):139-45. doi: 10.1016/j.diabres.2007.11.001. Epub 2008 Feb 20.
• [9] Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma.World J Gastroenterol. 2013 May 14;19(18):2772-80. doi: 10.3748/wjg.v19.i18.2772.
• [10] Association of CAPN10 gene with insulin sensitivity, glucose tolerance and renal function in essential hypertensive patients.Clin Chim Acta. 2010 Aug 5;411(15-16):1126-31. doi: 10.1016/j.cca.2010.04.012. Epub 2010 Apr 18.
• [11] Calpain 10 gene and laryngeal cancer: a survival analysis.Head Neck. 2011 Jan;33(1):72-6. doi: 10.1002/hed.21404.
• [12] Correlation between Calpain-10 single-nucleotide polymorphisms and obstructive sleep apnea/hypopnoea syndrome with ischemic stroke in a Chinese population: A population-based study.Medicine (Baltimore). 2017 Apr;96(16):e6570. doi: 10.1097/MD.0000000000006570.
• [13] The SNP43 (G/A) polymorphism in CAPN10 gene confers an increased risk of cognitive impairment in cerebral small vessel disease.J Clin Lab Anal. 2018 Nov;32(9):e22615. doi: 10.1002/jcla.22615. Epub 2018 Jul 16.
• [14] Association of Calpain (CAPN) 10 (UCSNP-43, rs3792267) gene polymorphism with elevated serum androgens in young women with the most severe phenotype of polycystic ovary syndrome (PCOS).Gynecol Endocrinol. 2015;31(8):630-4. doi: 10.3109/09513590.2015.1032932. Epub 2015 Sep 17.
• [15] Association of the diabetes gene calpain-10 with subclinical atherosclerosis: the Mexican-American Coronary Artery Disease Study.Diabetes. 2005 Apr;54(4):1228-32. doi: 10.2337/diabetes.54.4.1228.
• [16] New evidence for the role of calpain 10 in autosomal recessive intellectual disability: identification of two novel nonsense variants by exome sequencing in Iranian families.Arch Iran Med. 2015 Mar;18(3):179-84.
• [17] Genetic risk factors for type 2 diabetes with pharmacologic intervention in African-American patients with schizophrenia or schizoaffective disorder.Schizophr Res. 2009 Oct;114(1-3):50-6. doi: 10.1016/j.schres.2009.07.008. Epub 2009 Jul 29.
• [18] [Relationship between calpain-10 gene polymorphism, hypertension and plasma glucose].Zhonghua Nei Ke Za Zhi. 2002 Jun;41(6):370-3.
• [19] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [20] 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.
• [21] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [22] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [23] A potential role of calpains in sulfonylureas (SUs) -mediated death of human pancreatic cancer cells (1.2B4). Toxicol In Vitro. 2021 Jun;73:105128. doi: 10.1016/j.tiv.2021.105128. Epub 2021 Feb 27.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] Arsenic exposure and calpain-10 polymorphisms impair the function of pancreatic beta-cells in humans: a pilot study of risk factors for T2DM. PLoS One. 2013;8(1):e51642. doi: 10.1371/journal.pone.0051642. Epub 2013 Jan 22.