Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRB5L04)

• DOT Name: Growth/differentiation factor 2 (GDF2)
• Synonyms: GDF-2; Bone morphogenetic protein 9; BMP-9
• Gene Name: GDF2
• Related Disease:
  Pulmonary arterial hypertension
  Telangiectasia, hereditary hemorrhagic, type 1
  Telangiectasia, hereditary hemorrhagic, type 5
  Hereditary hemorrhagic telangiectasia
• UniProt ID: GDF2_HUMAN
• PDB ID: 1ZKZ; 4FAO; 4MPL; 4YCG; 4YCI; 5HZW; 5I05
• Pfam ID: PF00019 ; PF00688
• Sequence:
  MCPGALWVALPLLSLLAGSLQGKPLQSWGRGSAGGNAHSPLGVPGGGLPEHTFNLKMFLE
  NVKVDFLRSLNLSGVPSQDKTRVEPPQYMIDLYNRYTSDKSTTPASNIVRSFSMEDAISI
  TATEDFPFQKHILLFNISIPRHEQITRAELRLYVSCQNHVDPSHDLKGSVVIYDVLDGTD
  AWDSATETKTFLVSQDIQDEGWETLEVSSAVKRWVRSDSTKSKNKLEVTVESHRKGCDTL
  DISVPPGSRNLPFFVVFSNDHSSGTKETRLELREMISHEQESVLKKLSKDGSTEAGESSH
  EEDTDGHVAAGSTLARRKRSAGAGSHCQKTSLRVNFEDIGWDSWIIAPKEYEAYECKGGC
  FFPLADDVTPTKHAIVQTLVHLKFPTKVGKACCVPTKLSPISVLYKDDMGVPTLKYHYEG
  MSVAECGCR
• Function: Potent circulating inhibitor of angiogenesis. Signals through the type I activin receptor ACVRL1 but not other Alks. Signaling through SMAD1 in endothelial cells requires TGF-beta coreceptor endoglin/ENG.
• Tissue Specificity: Detected in blood plasma (at protein level).
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[1]
Telangiectasia, hereditary hemorrhagic, type 1	DIS6IJC1	Strong	Autosomal dominant	[2]
Telangiectasia, hereditary hemorrhagic, type 5	DISMA992	Moderate	Autosomal dominant	[1]
Hereditary hemorrhagic telangiectasia	DISXTDNT	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Growth/differentiation factor 2 (GDF2).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Growth/differentiation factor 2 (GDF2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Growth/differentiation factor 2 (GDF2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Growth/differentiation factor 2 (GDF2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Growth/differentiation factor 2 (GDF2).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Growth/differentiation factor 2 (GDF2).	[4]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Growth/differentiation factor 2 (GDF2).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Growth/differentiation factor 2 (GDF2).	[8]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Growth/differentiation factor 2 (GDF2).	[4]

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] BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013 Sep 5;93(3):530-7. doi: 10.1016/j.ajhg.2013.07.004. Epub 2013 Aug 22.
• [3] 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.
• [4] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [5] 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.
• [6] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] 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.