Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHQZV7)

• DTT Name: Mothers against decapentaplegic homolog 3 (SMAD3)
• Synonyms: TGF-beta response effector Smad3; Smad3; SMAD family member 3; SMAD 3; Mothers against DPP homolog 3; Mad3; MMad3; MADH3; MAD homolog 3; JV15-2; HSMAD3; HMAD-3
• Gene Name: SMAD3
• DTT Type: Successful target; [1]
• UniProt ID: SMAD3_HUMAN
• TTD ID: T35445
• Sequence:
  MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKKLKKTGQLDELEKAITTQNV
  NTKCITIPRSLDGRLQVSHRKGLPHVIYCRLWRWPDLHSHHELRAMELCEFAFNMKKDEV
  CVNPYHYQRVETPVLPPVLVPRHTEIPAEFPPLDDYSHSIPENTNFPAGIEPQSNIPETP
  PPGYLSEDGETSDHQMNHSMDAGSPNLSPNPMSPAHNNLDLQPVTYCEPAFWCSISYYEL
  NQRVGETFHASQPSMTVDGFTDPSNSERFCLGLLSNVNRNAAVELTRRHIGRGVRLYYIG
  GEVFAECLSDSAIFVQSPNCNQRYGWHPATVCKIPPGCNLKIFNNQEFAALLAQSVNQGF
  EAVYQLTRMCTIRMSFVKGWGAEYRRQTVTSTPCWIELHLNGPLQWLDKVLTQMGSPSIR
  CSSVS
• Function: Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Cell cycle (hsa04110)
  Endocytosis (hsa04144)
  Cellular senescence (hsa04218)
  Wnt signaling pathway (hsa04310)
  TGF-beta signaling pathway (hsa04350)
  Apelin signaling pathway (hsa04371)
  Hippo signaling pathway (hsa04390)
  Adherens junction (hsa04520)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Th17 cell differentiation (hsa04659)
  AGE-RAGE signaling 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)
  Inflammatory bowel disease (hsa05321)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Signaling by Activin (R-HSA-1502540)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Downregulation of SMAD2/3 (R-HSA-2173795)
  SMAD2/SMAD3 (R-HSA-2173796)
  SMAD2/3 Phosphorylation Motif Mutants in Cancer (R-HSA-3304356)
  SMAD4 MH2 Domain Mutants in Cancer (R-HSA-3311021)
  SMAD2/3 MH2 Domain Mutants in Cancer (R-HSA-3315487)
  TGFBR1 KD Mutants in Cancer (R-HSA-3656532)
  Ub-specific processing proteases (R-HSA-5689880)
  RUNX3 regulates CDKN1A transcription (R-HSA-8941855)
  RUNX3 regulates BCL2L11 (BIM) transcription (R-HSA-8952158)
  Interleukin-37 signaling (R-HSA-9008059)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  FOXO-mediated transcription of cell cycle genes (R-HSA-9617828)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FLUORESCEIN	DMQTFAO	Ocular disease	1F00.1Z	Approved	[1]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SIS-3	DMWBCTA	Renal fibrosis	GC01	Preclinical	[2]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[1]
GNF-PF-2272	DMONK0F	Discovery agent	N.A.	Investigative	[1]

References

• [1] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [2] Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol. 2006 Feb;69(2):597-607.