Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYY0P69)

• DOT Name: Apelin receptor early endogenous ligand (APELA)
• Synonyms: Protein Elabela; ELA; Protein Toddler
• Gene Name: APELA
• Related Disease:
  Acinar cell carcinoma
  Epithelial ovarian cancer
  Gaucher disease
  Myocardial infarction
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Stroke
• UniProt ID: ELA_HUMAN
• PDB ID: 7W0N; 7W0O; 7W0P
• Sequence: MRFQQFLFAFFIFIMSLLLISGQRPVNLTMRRKLRKHNCLQRRCMPLHSRVPFP
• Function: Endogenous ligand for the apelin receptor (APLNR). Hormone required for mesendodermal differentiation, blood vessels formation and heart morphogenesis during early development and for adult cardiovascular homeostasis. Drives internalization of APLNR. Acts as a motogen by promoting mesendodermal cell migration during gastrulation by binding and activating APLNR. Acts as an early embryonic regulator of cellular movement with a role in migration and development of cardiac progenitor cells. May act as a chemoattractant for the activation of angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Positively regulates sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel sprouting. Plays a role in placental vascular development; promotes placental trophoblast invasion and spiral artery remodeling in the uterus. Involved in the regulation of maternal cardiovascular homeostasis to prevent gestational hypertension and for potent cardioprotective functions during heart failure. Mediates myocardial contractility in an ERK1/2-dependent manner.
• Tissue Specificity: Expressed in the intima of blood vessels . Expressed in endothelial cells in blood vessels in the heart and lung . Expressed in cytotrophoblasts and syncytiotrophoblasts of first-trimester placental tissue and term placentas (at protein level) . Not detected in smooth muscle cells or cardiomyocytes (at protein level) . Expressed in kidney . Expressed in blood vessels . Expressed in embryonic (ESCs) and induced (iPSCs) pluripotent stem cells . Most highly expressed in undifferentiated embryonic stem cell and is rapidly down-regulated during differentiation .
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Apelin sig.ling pathway (hsa04371)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acinar cell carcinoma	DIS37Y0J	Strong	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Gaucher disease	DISTW5JG	Strong	Biomarker	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Stroke	DISX6UHX	Limited	Biomarker	[5]

10 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 Apelin receptor early endogenous ligand (APELA).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Apelin receptor early endogenous ligand (APELA).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Apelin receptor early endogenous ligand (APELA).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Apelin receptor early endogenous ligand (APELA).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Apelin receptor early endogenous ligand (APELA).	[6]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Apelin receptor early endogenous ligand (APELA).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Apelin receptor early endogenous ligand (APELA).	[6]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Apelin receptor early endogenous ligand (APELA).	[6]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Apelin receptor early endogenous ligand (APELA).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Apelin receptor early endogenous ligand (APELA).	[6]

References

• [1] Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.Int J Cancer. 2012 Sep 1;131(5):1243-8. doi: 10.1002/ijc.27322. Epub 2012 Jan 11.
• [2] APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner.Gynecol Oncol. 2017 Dec;147(3):663-671. doi: 10.1016/j.ygyno.2017.10.016. Epub 2017 Oct 24.
• [3] Muscle-tendon weakness contributes to chronic fatigue syndrome in Gaucher's disease.J Orthop Surg Res. 2019 Nov 21;14(1):383. doi: 10.1186/s13018-019-1452-y.
• [4] Elastase-2, an angiotensin II-generating enzyme, contributes to increased angiotensin II in resistance arteries of mice with myocardial infarction.Br J Pharmacol. 2017 May;174(10):1104-1115. doi: 10.1111/bph.13755. Epub 2017 Apr 5.
• [5] Elastase-2, a Tissue Alternative Pathway for Angiotensin II Generation, Plays a Role in Circulatory Sympathovagal Balance in Mice.Front Physiol. 2017 Mar 23;8:170. doi: 10.3389/fphys.2017.00170. eCollection 2017.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [10] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.