Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JATFE)

• DOT Name: Activin receptor type-1 (ACVR1)
• Synonyms: EC 2.7.11.30; Activin receptor type I; ACTR-I; Activin receptor-like kinase 2; ALK-2; Serine/threonine-protein kinase receptor R1; SKR1; TGF-B superfamily receptor type I; TSR-I
• Gene Name: ACVR1
• Related Disease:
  Fibrodysplasia ossificans progressiva
  Congenital heart disease
• UniProt ID: ACVR1_HUMAN
• PDB ID: 3H9R ; 3MTF ; 3OOM ; 3Q4U ; 4BGG ; 4C02 ; 4DYM ; 5OXG ; 5OY6 ; 5S75 ; 5S76 ; 5S77 ; 5S78 ; 5S79 ; 5S7A ; 5S7B ; 5S7C ; 5S7D ; 5S7E ; 5S7F ; 5S7G ; 5S7H ; 5S7I ; 5S7J ; 5S7K ; 5S7L ; 5S7M ; 5S7N ; 5S7O ; 5S7P ; 5S7Q ; 5S7R ; 5S7S ; 5S7T ; 5S7U ; 5S7V ; 5S7W ; 5S7X ; 5S7Y ; 5S7Z ; 5S80 ; 5S81 ; 5S82 ; 5S83 ; 5S84 ; 5S85 ; 5S86 ; 5S87 ; 5S88 ; 5S89 ; 5S8A ; 5S8B ; 5S9K ; 6ACR ; 6EIX ; 6GI6 ; 6GIN ; 6GIP ; 6I1S ; 6JUX ; 6SRH ; 6SZM ; 6T6D ; 6T8N ; 6TN8 ; 6UNQ ; 6UNR ; 6UNS ; 6Z36 ; 6ZGC ; 7A21 ; 7C3G ; 7NNS ; 7YRU ; 8C7W ; 8C7Z
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF07714 ; PF08515
• Sequence:
  MVDGVMILPVLIMIALPSPSMEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFSSLSIN
  DGFHVYQKGCFQVYEQGKMTCKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNF
  HLEVGLIILSVVFAVCLLACLLGVALRKFKRRNQERLNPRDVEYGTIEGLITTNVGDSTL
  ADLLDHSCTSGSGSGLPFLVQRTVARQITLLECVGKGRYGEVWRGSWQGENVAVKIFSSR
  DEKSWFRETELYNTVMLRHENILGFIASDMTSRHSSTQLWLITHYHEMGSLYDYLQLTTL
  DTVSCLRIVLSIASGLAHLHIEIFGTQGKPAIAHRDLKSKNILVKKNGQCCIADLGLAVM
  HSQSTNQLDVGNNPRVGTKRYMAPEVLDETIQVDCFDSYKRVDIWAFGLVLWEVARRMVS
  NGIVEDYKPPFYDVVPNDPSFEDMRKVVCVDQQRPNIPNRWFSDPTLTSLAKLMKECWYQ
  NPSARLTALRIKKTLTKIDNSLDKLKTDC
• Function: Bone morphogenetic protein (BMP) type I receptor that is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. As a type I receptor, forms heterotetrameric receptor complexes with the type II receptors AMHR2, ACVR2A or ACVR2B. Upon binding of ligands such as BMP7 or GDF2/BMP9 to the heteromeric complexes, type II receptors transphosphorylate ACVR1 intracellular domain. In turn, ACVR1 kinase domain is activated and subsequently phosphorylates SMAD1/5/8 proteins that transduce the signal. In addition to its role in mediating BMP pathway-specific signaling, suppresses TGFbeta/activin pathway signaling by interfering with the binding of activin to its type II receptor. Besides canonical SMAD signaling, can activate non-canonical pathways such as p38 mitogen-activated protein kinases/MAPKs. May promote the expression of HAMP, potentially via its interaction with BMP6.
• Tissue Specificity: Expressed in normal parenchymal cells, endothelial cells, fibroblasts and tumor-derived epithelial cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Fluid shear stress and atherosclerosis (hsa05418)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrodysplasia ossificans progressiva	DISAT6WU	Definitive	Autosomal dominant	[1]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[1]

19 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 Activin receptor type-1 (ACVR1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Activin receptor type-1 (ACVR1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Activin receptor type-1 (ACVR1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Activin receptor type-1 (ACVR1).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Activin receptor type-1 (ACVR1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Activin receptor type-1 (ACVR1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Activin receptor type-1 (ACVR1).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Activin receptor type-1 (ACVR1).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Activin receptor type-1 (ACVR1).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Activin receptor type-1 (ACVR1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Activin receptor type-1 (ACVR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Activin receptor type-1 (ACVR1).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Activin receptor type-1 (ACVR1).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Activin receptor type-1 (ACVR1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Activin receptor type-1 (ACVR1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Activin receptor type-1 (ACVR1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Activin receptor type-1 (ACVR1).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Activin receptor type-1 (ACVR1).	[18]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Activin receptor type-1 (ACVR1).	[19]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] 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.
• [9] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [10] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [19] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.