Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEI1PJ1)

• DOT Name: Caspase recruitment domain-containing protein 6 (CARD6)
• Gene Name: CARD6
• Related Disease:
  Fatty liver disease
  Non-alcoholic fatty liver disease
• UniProt ID: CARD6_HUMAN
• Pfam ID: PF00619
• Sequence:
  MATESTPSEIIERERKKLLEILQHDPDSILDTLTSRRLISEEEYETLENVTDLLKKSRKL
  LILVQKKGEATCQHFLKCLFSTFPQSAAICGLRHEVLKHENTVPPQSMGASSNSEDAFSP
  GIKQPEAPEITVFFSEKEHLDLETSEFFRDKKTSYRETALSARKNEKEYDTPEVTLSYSV
  EKVGCEVPATITYIKDGQRYEELDDSLYLGKEEYLGSVDTPEDAEATVEEEVYDDPEHVG
  YDGEEDFENSETTEFSGEEPSYEGSETSLSLEEEQEKSIEERKKVFKDVLLCLNMDRSRK
  VLPDFVKQFSLDRGCKWTPESPGDLAWNFLMKVQARDVTARDSILSHKVLDEDSKEDLLA
  GVENLEIRDIQTINPLDVLCATMLCSDSSLQRQVMSNMYQCQFALPLLLPDAENNKSILM
  LGAMKDIVKKQSTQFSGGPTEDTEKFLTLMKMPVISFVRLGYCSFSKSRILNTLLSPAQL
  KLHKIFLHQDLPLLVLPRQISDGLVEITWCFPDSDDRKENPFFQKPVALANLRGNLESFW
  TQFGFLMEVSSAVFFFTDCLGEKEWDLLMFLGEAAIERCYFVLSSQARESEEAQIFQRIL
  NLKPAQLLFWERGDAGDRRKNMEGLQAALQEVMFSSCLRCVSVEDMAALARELGIQVDED
  FENTQRIQVSSGENMAGTAEGEGQQRHSQLKSSSKSQALMPIQEPGTQCELSQNLQNLYG
  TPVFRPVLENSWLFPTRIGGNFNHVSLKASWVMGRPFGSEQRPKWFHPLPFQNAGAQGRG
  KSFGIQSFHPQIFYSGERFMKFSRVARGCHSNGTFGRLPRPICQHVQACPERPQMMGTLE
  RSRAVASKIGHSYSLDSQPARAVGKPWPQQACTRVTELTEATGKLIRTSHIGKPHPQSFQ
  PAAATQKLRPASQQGVQMKTQGGASNPALQIGSHPMCKSSQFKSDQSNPSTVKHSQPKPF
  HSVPSQPKSSQTKSCQSQPSQTKPSPCKSTQPKPSQPWPPQSKPSQPRPPQPKSSSTNPS
  QAKAHHSKAGQKRGGKH
• Function: May be involved in apoptosis.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Caspase recruitment domain-containing protein 6 (CARD6).	[2]

18 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 Caspase recruitment domain-containing protein 6 (CARD6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[10]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[14]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[16]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol increases the expression of Caspase recruitment domain-containing protein 6 (CARD6).	[13]

References

• [1] Caspase Recruitment Domain Protein 6 Protects Against Hepatic Steatosis and Insulin Resistance by Suppressing Apoptosis Signal-Regulating Kinase 1.Hepatology. 2018 Dec;68(6):2212-2229. doi: 10.1002/hep.30075. Epub 2018 Nov 15.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [14] BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J. 2013 Jul 19;3(7):e126. doi: 10.1038/bcj.2013.24.
• [15] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [16] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.