Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2UBXO)

• DOT Name: Adhesion G-protein coupled receptor G6 (ADGRG6)
• Synonyms: Developmentally regulated G-protein-coupled receptor; G-protein coupled receptor 126; Vascular inducible G protein-coupled receptor
• Gene Name: ADGRG6
• Related Disease:
  Lethal congenital contracture syndrome 9
  Pulmonary disease
  Androgen insensitivity syndrome
  Chronic obstructive pulmonary disease
  Intervertebral disc degeneration
  Lung adenocarcinoma
  Multiple sclerosis
  Neoplasm
  Neuromuscular disease
  Non-small-cell lung cancer
  Testicular germ cell tumor
  Arthrogryposis
  Bladder cancer
  Intellectual disability
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: AGRG6_HUMAN
• Pfam ID: PF00002 ; PF00431 ; PF01825 ; PF00354
• Sequence:
  MMFRSDRMWSCHWKWKPSPLLFLFALYIMCVPHSVWGCANCRVVLSNPSGTFTSPCYPND
  YPNSQACMWTLRAPTGYIIQITFNDFDIEEAPNCIYDSLSLDNGESQTKFCGATAKGLSF
  NSSANEMHVSFSSDFSIQKKGFNASYIRVAVSLRNQKVILPQTSDAYQVSVAKSISIPEL
  SAFTLCFEATKVGHEDSDWTAFSYSNASFTQLLSFGKAKSGYFLSISDSKCLLNNALPVK
  EKEDIFAESFEQLCLVWNNSLGSIGVNFKRNYETVPCDSTISKVIPGNGKLLLGSNQNEI
  VSLKGDIYNFRLWNFTMNAKILSNLSCNVKGNVVDWQNDFWNIPNLALKAESNLSCGSYL
  IPLPAAELASCADLGTLCQATVNSPSTTPPTVTTNMPVTNRIDKQRNDGIIYRISVVIQN
  ILRHPEVKVQSKVAEWLNSTFQNWNYTVYVVNISFHLSAGEDKIKVKRSLEDEPRLVLWA
  LLVYNATNNTNLEGKIIQQKLLKNNESLDEGLRLHTVNVRQLGHCLAMEEPKGYYWPSIQ
  PSEYVLPCPDKPGFSASRICFYNATNPLVTYWGPVDISNCLKEANEVANQILNLTADGQN
  LTSANITNIVEQVKRIVNKEENIDITLGSTLMNIFSNILSSSDSDLLESSSEALKTIDEL
  AFKIDLNSTSHVNITTRNLALSVSSLLPGTNAISNFSIGLPSNNESYFQMDFESGQVDPL
  ASVILPPNLLENLSPEDSVLVRRAQFTFFNKTGLFQDVGPQRKTLVSYVMACSIGNITIQ
  NLKDPVQIKIKHTRTQEVHHPICAFWDLNKNKSFGGWNTSGCVAHRDSDASETVCLCNHF
  THFGVLMDLPRSASQLDARNTKVLTFISYIGCGISAIFSAATLLTYVAFEKLRRDYPSKI
  LMNLSTALLFLNLLFLLDGWITSFNVDGLCIAVAVLLHFFLLATFTWMGLEAIHMYIALV
  KVFNTYIRRYILKFCIIGWGLPALVVSVVLASRNNNEVYGKESYGKEKGDEFCWIQDPVI
  FYVTCAGYFGVMFFLNIAMFIVVMVQICGRNGKRSNRTLREEVLRNLRSVVSLTFLLGMT
  WGFAFFAWGPLNIPFMYLFSIFNSLQGLFIFIFHCAMKENVQKQWRQHLCCGRFRLADNS
  DWSKTATNIIKKSSDNLGKSLSSSSIGSNSTYLTSKSKSSSTTYFKRNSHTDNVSYEHSF
  NKSGSLRQCFHGQVLVKTGPC
• Function: G-protein coupled receptor which is activated by type IV collagen, a major constituent of the basement membrane. Couples to G(i)-proteins as well as G(s)-proteins. Essential for normal differentiation of promyelinating Schwann cells and for normal myelination of axons. Regulates neural, cardiac and ear development via G-protein- and/or N-terminus-dependent signaling. May act as a receptor for PRNP which may promote myelin homeostasis.
• Tissue Specificity: Expressed in placenta and to a lower extent in pancreas and liver. Detected in aortic endothelial cells but not in skin microvascular endothelial cells.
• Reactome Pathway: EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lethal congenital contracture syndrome 9	DIS2KD4T	Definitive	Autosomal recessive	[1]
Pulmonary disease	DIS6060I	Definitive	Genetic Variation	[2]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[4]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[8]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[6]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[10]
Arthrogryposis	DISC81CM	moderate	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Limited	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[11]
Urinary bladder cancer	DISDV4T7	Limited	Genetic Variation	[8]
Urinary bladder neoplasm	DIS7HACE	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Adhesion G-protein coupled receptor G6 (ADGRG6) affects the response to substance of Fluorouracil.	[29]
Chlorothiazide	DMLHESP	Approved	Adhesion G-protein coupled receptor G6 (ADGRG6) increases the Metabolic disorder ADR of Chlorothiazide.	[30]

16 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 Adhesion G-protein coupled receptor G6 (ADGRG6).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[21]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[27]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Adhesion G-protein coupled receptor G6 (ADGRG6).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Adhesion G-protein coupled receptor G6 (ADGRG6).	[26]

References

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• [2] Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli.Ann N Y Acad Sci. 2019 Nov;1456(1):96-108. doi: 10.1111/nyas.14135. Epub 2019 Jun 19.
• [3] A Genetic Variant in GPR126 Causing a Decreased Inclusion of Exon 6 Is Associated with Cartilage Development in Adolescent Idiopathic Scoliosis Population.Biomed Res Int. 2019 Feb 11;2019:4678969. doi: 10.1155/2019/4678969. eCollection 2019.
• [4] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [5] Dysregulation of STAT3 signaling is associated with endplate-oriented herniations of the intervertebral disc in Adgrg6 mutant mice.PLoS Genet. 2019 Oct 25;15(10):e1008096. doi: 10.1371/journal.pgen.1008096. eCollection 2019 Oct.
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• [18] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
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