Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCHG3YK)

• DOT Name: Calpain-3 (CAPN3)
• Synonyms: EC 3.4.22.54; Calcium-activated neutral proteinase 3; CANP 3; Calpain L3; Calpain p94; Muscle-specific calcium-activated neutral protease 3; New calpain 1; nCL-1
• Gene Name: CAPN3
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy
  Autosomal recessive limb-girdle muscular dystrophy type 2A
  Congenital muscular dystrophy
  Coronary heart disease
  Advanced cancer
  Autosomal recessive limb-girdle muscular dystrophy type 2C
  Autosomal recessive limb-girdle muscular dystrophy type 2D
  Becker muscular dystrophy
  Bethlem myopathy
  Campomelic dysplasia
  Castration-resistant prostate carcinoma
  Craniometaphyseal dysplasia, autosomal dominant
  Diabetic cataract
  Epilepsy, idiopathic generalized
  Esophageal squamous cell carcinoma
  facioscapulohumeral muscular dystrophy
  Hepatocellular carcinoma
  Liposarcoma
  Liver cancer
  Matthew-Wood syndrome
  Muscular dystrophy, limb-girdle, autosomal dominant 4
  Myofibrillar myopathy
  Myopathy
  Neuromuscular disease
  Neuronal ceroid lipofuscinosis
  Non-insulin dependent diabetes
  Obesity
  Pelizeaus-Merzbacher spectrum disorder
  Prostate cancer
  Prostate carcinoma
  Respiratory failure
  Tibial muscular dystrophy
  Autosomal recessive limb-girdle muscular dystrophy type 2B
  Emery-Dreifuss muscular dystrophy
  Inclusion body myositis
  Melanoma
  Metastatic malignant neoplasm
  Type-1/2 diabetes
  CLN2 Batten disease
  Duchenne muscular dystrophy
  Lysosomal storage disease
  Muscular dystrophy
  Muscular dystrophy, limb-girdle, autosomal dominant
  Neoplasm
• UniProt ID: CAN3_HUMAN
• PDB ID: 4OKH; 6BDT; 6BGP; 6BJD; 6BKJ
• EC Number: 3.4.22.54
• Pfam ID: PF01067 ; PF16648 ; PF13405 ; PF13833 ; PF00648
• Sequence:
  MPTVISASVAPRTAAEPRSPGPVPHPAQSKATEAGGGNPSGIYSAIISRNFPIIGVKEKT
  FEQLHKKCLEKKVLYVDPEFPPDETSLFYSQKFPIQFVWKRPPEICENPRFIIDGANRTD
  ICQGELGDCWFLAAIACLTLNQHLLFRVIPHDQSFIENYAGIFHFQFWRYGEWVDVVIDD
  CLPTYNNQLVFTKSNHRNEFWSALLEKAYAKLHGSYEALKGGNTTEAMEDFTGGVAEFFE
  IRDAPSDMYKIMKKAIERGSLMGCSIDDGTNMTYGTSPSGLNMGELIARMVRNMDNSLLQ
  DSDLDPRGSDERPTRTIIPVQYETRMACGLVRGHAYSVTGLDEVPFKGEKVKLVRLRNPW
  GQVEWNGSWSDRWKDWSFVDKDEKARLQHQVTEDGEFWMSYEDFIYHFTKLEICNLTADA
  LQSDKLQTWTVSVNEGRWVRGCSAGGCRNFPDTFWTNPQYRLKLLEEDDDPDDSEVICSF
  LVALMQKNRRKDRKLGASLFTIGFAIYEVPKEMHGNKQHLQKDFFLYNASKARSKTYINM
  REVSQRFRLPPSEYVIVPSTYEPHQEGEFILRVFSEKRNLSEEVENTISVDRPVKKKKTK
  PIIFVSDRANSNKELGVDQESEEGKGKTSPDKQKQSPQPQPGSSDQESEEQQQFRNIFKQ
  IAGDDMEICADELKKVLNTVVNKHKDLKTHGFTLESCRSMIALMDTDGSGKLNLQEFHHL
  WNKIKAWQKIFKHYDTDQSGTINSYEMRNAVNDAGFHLNNQLYDIITMRYADKHMNIDFD
  SFICCFVRLEGMFRAFHAFDKDGDGIIKLNVLEWLQLTMYA
• Function: Calcium-regulated non-lysosomal thiol-protease. Proteolytically cleaves CTBP1 at 'His-409'. Mediates, with UTP25, the proteasome-independent degradation of p53/TP53.
• Tissue Specificity: Isoform I is skeletal muscle specific.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy	DISWPGLM	Definitive	Autosomal recessive	[1]
Autosomal recessive limb-girdle muscular dystrophy type 2A	DISIHX4S	Definitive	Autosomal recessive	[1]
Congenital muscular dystrophy	DISKY7OY	Definitive	Genetic Variation	[2]
Coronary heart disease	DIS5OIP1	Definitive	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Autosomal recessive limb-girdle muscular dystrophy type 2C	DISE0ICN	Strong	Biomarker	[5]
Autosomal recessive limb-girdle muscular dystrophy type 2D	DISRD6EW	Strong	Biomarker	[6]
Becker muscular dystrophy	DIS5IYHL	Strong	Biomarker	[7]
Bethlem myopathy	DISVF5K2	Strong	Biomarker	[8]
Campomelic dysplasia	DISVTW53	Strong	Biomarker	[9]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[10]
Craniometaphyseal dysplasia, autosomal dominant	DISU12OO	Strong	Biomarker	[9]
Diabetic cataract	DISKRB4V	Strong	Biomarker	[11]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[13]
facioscapulohumeral muscular dystrophy	DISSE0H0	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[4]
Liver cancer	DISDE4BI	Strong	Biomarker	[15]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[16]
Muscular dystrophy, limb-girdle, autosomal dominant 4	DISS9M30	Strong	Autosomal dominant	[17]
Myofibrillar myopathy	DISF24LW	Strong	Genetic Variation	[18]
Myopathy	DISOWG27	Strong	Genetic Variation	[19]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[20]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Biomarker	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[22]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Pelizeaus-Merzbacher spectrum disorder	DIS1ODJO	Strong	Altered Expression	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[23]
Tibial muscular dystrophy	DIS8YQKI	Strong	Genetic Variation	[24]
Autosomal recessive limb-girdle muscular dystrophy type 2B	DISWWCL7	moderate	Biomarker	[25]
Emery-Dreifuss muscular dystrophy	DISYTPR5	moderate	Genetic Variation	[26]
Inclusion body myositis	DISZXXG5	moderate	Altered Expression	[27]
Melanoma	DIS1RRCY	moderate	Altered Expression	[28]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[29]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[22]
CLN2 Batten disease	DISZC5YB	Limited	Biomarker	[30]
Duchenne muscular dystrophy	DISRQ3NV	Limited	Biomarker	[18]
Lysosomal storage disease	DIS6QM6U	Limited	Genetic Variation	[30]
Muscular dystrophy	DISJD6P7	Limited	Biomarker	[31]
Muscular dystrophy, limb-girdle, autosomal dominant	DISMMHPT	Limited	Autosomal dominant	[1]
Neoplasm	DISZKGEW	Limited	Biomarker	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Calpain-3 (CAPN3).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calpain-3 (CAPN3).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calpain-3 (CAPN3).	[36]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Calpain-3 (CAPN3).	[37]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Calpain-3 (CAPN3).	[38]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Calpain-3 (CAPN3).	[39]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Calpain-3 (CAPN3).	[40]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Calpain-3 (CAPN3).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Calpain-3 (CAPN3).	[42]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Calpain-3 (CAPN3).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Calpain-3 (CAPN3).	[44]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Calpain-3 (CAPN3).	[34]

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] Mutations in LAMA2 and CAPN3 genes associated with genetic and phenotypic heterogeneities within a single consanguineous family involving both congenital and progressive muscular dystrophies.Biosci Rep. 2011 Apr;31(2):125-35. doi: 10.1042/BSR20100026.
• [3] Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.Int J Epidemiol. 2017 Aug 1;46(4):1211-1222. doi: 10.1093/ije/dyw245.
• [4] DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies.PLoS Genet. 2011 Apr;7(4):e1002042. doi: 10.1371/journal.pgen.1002042. Epub 2011 Apr 14.
• [5] Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G.Am J Med Genet. 1999 Feb 19;82(5):392-8. doi: 10.1002/(sici)1096-8628(19990219)82:5<392::aid-ajmg7>3.0.co;2-0.
• [6] Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs.J Neurol. 2005 May;252(5):538-47. doi: 10.1007/s00415-005-0684-4. Epub 2005 Feb 23.
• [7] Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.BMC Musculoskelet Disord. 2012 Mar 23;13:43. doi: 10.1186/1471-2474-13-43.
• [8] Reliability and accuracy of skeletal muscle imaging in limb-girdle muscular dystrophies.Neurology. 2012 Oct 16;79(16):1716-23. doi: 10.1212/WNL.0b013e31826e9b73. Epub 2012 Oct 3.
• [9] LAMA2-related myopathy: Frequency among congenital and limb-girdle muscular dystrophies.Muscle Nerve. 2015 Oct;52(4):547-53. doi: 10.1002/mus.24588. Epub 2015 Aug 13.
• [10] NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy.J Clin Med. 2019 Mar 31;8(4):442. doi: 10.3390/jcm8040442.
• [11] Calpains and their multiple roles in diabetes mellitus.Ann N Y Acad Sci. 2006 Nov;1084:452-80. doi: 10.1196/annals.1372.011.
• [12] Epilepsy and limb girdle muscular dystrophy type 2A: double trouble, serendipitous finding or new phenotype?.Neurol Sci. 2006 Jun;27(2):134-6. doi: 10.1007/s10072-006-0615-x.
• [13] Genome-wide ChIP-seq data with a transcriptome analysis reveals the groups of genes regulated by histone demethylase LSD1 inhibition in esophageal squamous cell carcinoma cells.Oncol Lett. 2019 Jul;18(1):872-881. doi: 10.3892/ol.2019.10350. Epub 2019 May 13.
• [14] Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).PLoS Genet. 2013;9(1):e1003186. doi: 10.1371/journal.pgen.1003186. Epub 2013 Jan 3.
• [15] Calpain-3 gene expression is decreased during experimental cancer cachexia.Biochim Biophys Acta. 2000 Jun 1;1475(1):5-9. doi: 10.1016/s0304-4165(00)00050-7.
• [16] Expression of three calpain isoform genes in human skeletal muscles.J Neurol Sci. 1998 Mar 5;155(2):163-9. doi: 10.1016/s0022-510x(97)00309-2.
• [17] Mutations in Czech LGMD2A patients revealed by analysis of calpain3 mRNA and their phenotypic outcome. Neuromuscul Disord. 2004 Oct;14(10):659-65. doi: 10.1016/j.nmd.2004.05.005.
• [18] Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function.Acta Neuropathol Commun. 2017 Sep 15;5(1):72. doi: 10.1186/s40478-017-0474-0.
• [19] A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.Brain. 2016 Aug;139(Pt 8):2154-63. doi: 10.1093/brain/aww133. Epub 2016 Jun 3.
• [20] Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A.Sci Transl Med. 2019 Nov 27;11(520):eaat6072. doi: 10.1126/scitranslmed.aat6072.
• [21] Characteristics of PPT1 and TPP1 enzymes in neuronal ceroid lipofuscinosis (NCL) 1 and 2 by dried blood spots (DBS) and leukocytes and their application to newborn screening.Mol Genet Metab. 2018 May;124(1):64-70. doi: 10.1016/j.ymgme.2018.03.007. Epub 2018 Mar 19.
• [22] Characterization of GLUT4 and calpain expression in healthy human skeletal muscle during fasting and refeeding.Acta Physiol (Oxf). 2007 Mar;189(3):233-40. doi: 10.1111/j.1748-1716.2006.01639.x.
• [23] A novel CAPN3 mutation in late-onset limb-girdle muscular dystrophy with early respiratory insufficiency.J Clin Neurosci. 2018 Jul;53:229-231. doi: 10.1016/j.jocn.2018.04.025. Epub 2018 Apr 21.
• [24] CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy.Hum Mol Genet. 2015 Jul 1;24(13):3718-31. doi: 10.1093/hmg/ddv116. Epub 2015 Apr 15.
• [25] MicroRNA signatures predict dysregulated vitamin D receptor and calcium pathways status in limb girdle muscle dystrophies (LGMD) 2A/2B.Cell Biochem Funct. 2016 Aug;34(6):414-22. doi: 10.1002/cbf.3202.
• [26] Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine.Ann Neurol. 2010 Feb;67(2):201-8. doi: 10.1002/ana.21846.
• [27] Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis.Acta Neuropathol Commun. 2017 Mar 22;5(1):24. doi: 10.1186/s40478-017-0427-7.
• [28] Platelet-derived growth factor C and calpain-3 are modulators of human melanoma cell invasiveness.Oncol Rep. 2013 Dec;30(6):2887-96. doi: 10.3892/or.2013.2791. Epub 2013 Oct 10.
• [29] Calpain-3 impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells.PLoS One. 2015 Feb 6;10(2):e0117258. doi: 10.1371/journal.pone.0117258. eCollection 2015.
• [30] Batten disease: biochemical and molecular characterization revealing novel PPT1 and TPP1 gene mutations in Indian patients.BMC Neurol. 2018 Dec 12;18(1):203. doi: 10.1186/s12883-018-1206-1.
• [31] Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations.Int J Mol Sci. 2019 Sep 13;20(18):4548. doi: 10.3390/ijms20184548.
• [32] Intravenous and intratumoral injection of Pluronic P94: The effect of administration route on biodistribution and tumor retention.Nanomedicine. 2017 Oct;13(7):2179-2188. doi: 10.1016/j.nano.2017.04.015. Epub 2017 May 20.
• [33] 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.
• [34] 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.
• [35] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [36] 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.
• [37] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [38] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [39] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [40] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [41] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [42] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [43] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [44] 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.