Details of Drug Off-Target (DOT)

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

• DOT Name: Mothers against decapentaplegic homolog 4 (SMAD4)
• Synonyms: MAD homolog 4; Mothers against DPP homolog 4; Deletion target in pancreatic carcinoma 4; SMAD family member 4; SMAD 4; Smad4; hSMAD4
• Gene Name: SMAD4
• Related Disease:
  Cognitive impairment
  Juvenile polyposis syndrome
  Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
  Myhre syndrome
  Brachydactyly
  Breast neoplasm
  Carcinoma of esophagus
  Chronic obstructive pulmonary disease
  Colorectal neoplasm
  Familial pancreatic carcinoma
  Gastric adenocarcinoma
  Generalized juvenile polyposis/juvenile polyposis coli
  Head-neck squamous cell carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Intrahepatic cholangiocarcinoma
  Liver cancer
  Lung adenocarcinoma
  Melanoma
  Myocardial infarction
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Osteogenesis imperfecta
  Pancreatic adenocarcinoma
  Patent ductus arteriosus
  Precocious puberty
  Prostate cancer
  Prostate carcinoma
  Prostatitis
  Pulmonary fibrosis
  Pulmonary hypertension
  Telangiectasis
  Type-1/2 diabetes
  Gastric cancer
  Gastric neoplasm
  Heritable pulmonary arterial hypertension
  Myopathy
  Familial thoracic aortic aneurysm and aortic dissection
  Hereditary hemorrhagic telangiectasia
  Lung cancer
  Pulmonary arterial hypertension
  Anemia
  Cataract
  Epithelial ovarian cancer
  Invasive ductal breast carcinoma
  Ovarian cancer
  Pancreatic cancer
  Pancreatic tumour
• UniProt ID: SMAD4_HUMAN
• PDB ID: 1DD1; 1G88; 1MR1; 1U7F; 1U7V; 1YGS; 5C4V; 5MEY; 5MEZ; 5MF0; 5UWU; 6YIC
• Pfam ID: PF03165 ; PF03166
• Sequence:
  MDNMSITNTPTSNDACLSIVHSLMCHRQGGESETFAKRAIESLVKKLKEKKDELDSLITA
  ITTNGAHPSKCVTIQRTLDGRLQVAGRKGFPHVIYARLWRWPDLHKNELKHVKYCQYAFD
  LKCDSVCVNPYHYERVVSPGIDLSGLTLQSNAPSSMMVKDEYVHDFEGQPSLSTEGHSIQ
  TIQHPPSNRASTETYSTPALLAPSESNATSTANFPNIPVASTSQPASILGGSHSEGLLQI
  ASGPQPGQQQNGFTGQPATYHHNSTTTWTGSRTAPYTPNLPHHQNGHLQHHPPMPPHPGH
  YWPVHNELAFQPPISNHPAPEYWCSIAYFEMDVQVGETFKVPSSCPIVTVDGYVDPSGGD
  RFCLGQLSNVHRTEAIERARLHIGKGVQLECKGEGDVWVRCLSDHAVFVQSYYLDREAGR
  APGDAVHKIYPSAYIKVFDLRQCHRQMQQQAATAQAAAAAQAAAVAGNIPGPGSVGGIAP
  AISLSAAAGIGVDDLRRLCILRMSFVKGWGPDYPRQSIKETPCWIEIHLHRALQLLDEVL
  HTMPIADPQPLD
• Function: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Cell cycle (hsa04110)
  Wnt sig.ling pathway (hsa04310)
  TGF-beta sig.ling pathway (hsa04350)
  Apelin sig.ling pathway (hsa04371)
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Th17 cell differentiation (hsa04659)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Signaling by Activin (R-HSA-1502540)
  Signaling by BMP (R-HSA-201451)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Downregulation of SMAD2/3 (R-HSA-2173795)
  SMAD2/SMAD3 (R-HSA-2173796)
  SMAD4 MH2 Domain Mutants in Cancer (R-HSA-3311021)
  SMAD2/3 MH2 Domain Mutants in Cancer (R-HSA-3315487)
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  Ub-specific processing proteases (R-HSA-5689880)
  RUNX2 regulates bone development (R-HSA-8941326)
  RUNX3 regulates CDKN1A transcription (R-HSA-8941855)
  RUNX3 regulates BCL2L11 (BIM) transcription (R-HSA-8952158)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  FOXO-mediated transcription of cell cycle genes (R-HSA-9617828)
  Cardiogenesis (R-HSA-9733709)
  SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871)
  Germ layer formation at gastrulation (R-HSA-9754189)
  Formation of definitive endoderm (R-HSA-9823730)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[1]
Juvenile polyposis syndrome	DISBPSLH	Definitive	Autosomal dominant	[2]
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	DISHDB84	Definitive	Autosomal dominant	[3]
Myhre syndrome	DISE3L8A	Definitive	Autosomal dominant	[3]
Brachydactyly	DIS2533F	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Familial pancreatic carcinoma	DIS1XROR	Strong	SusceptibilityMutation	[6]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[7]
Generalized juvenile polyposis/juvenile polyposis coli	DISWA3FF	Strong	Autosomal dominant	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[9]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[12]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[13]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[14]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[17]
Osteogenesis imperfecta	DIS7XQSD	Strong	Biomarker	[18]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[4]
Patent ductus arteriosus	DIS9P8YS	Strong	Genetic Variation	[19]
Precocious puberty	DISYI2XZ	Strong	Genetic Variation	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Prostatitis	DISL8OGN	Strong	Biomarker	[22]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[23]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[24]
Telangiectasis	DIS8WCAO	Strong	Genetic Variation	[25]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[26]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[27]
Gastric neoplasm	DISOKN4Y	moderate	Biomarker	[10]
Heritable pulmonary arterial hypertension	DISD1Y94	moderate	Biomarker	[28]
Myopathy	DISOWG27	moderate	Biomarker	[29]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Supportive	Autosomal dominant	[30]
Hereditary hemorrhagic telangiectasia	DISXTDNT	Supportive	Autosomal dominant	[31]
Lung cancer	DISCM4YA	Disputed	Biomarker	[32]
Pulmonary arterial hypertension	DISP8ZX5	Disputed	Autosomal dominant	[3]
Anemia	DISTVL0C	Limited	Genetic Variation	[33]
Cataract	DISUD7SL	Limited	Altered Expression	[34]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[35]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[36]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[35]
Pancreatic cancer	DISJC981	Limited	Biomarker	[37]
Pancreatic tumour	DIS3U0LK	Limited	Genetic Variation	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[39]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[40]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[41]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[42]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[43]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[44]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[45]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[47]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[48]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[49]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[50]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[51]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[52]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[49]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[53]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[54]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[55]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[41]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[56]
Piperlongumine	DMIZCOE	Preclinical	Piperlongumine increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[58]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[59]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[60]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[61]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[62]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[63]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[64]
ROLIPRAM	DMJ03UM	Investigative	ROLIPRAM decreases the expression of Mothers against decapentaplegic homolog 4 (SMAD4).	[65]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mothers against decapentaplegic homolog 4 (SMAD4).	[46]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mothers against decapentaplegic homolog 4 (SMAD4).	[57]

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