Details of Drug Off-Target (DOT)

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

• DOT Name: Growth factor receptor-bound protein 10 (GRB10)
• Synonyms: GRB10 adapter protein; Insulin receptor-binding protein Grb-IR
• Gene Name: GRB10
• Related Disease:
  Acute myelogenous leukaemia
  Intervertebral disc degeneration
  Type-1 diabetes
  Achondroplasia
  Adrenal cortex neoplasm
  Alopecia
  Ewing sarcoma
  Fetal growth restriction
  Hyperinsulinemia
  Neoplasm
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
  Retinitis pigmentosa
  Schizophrenia
  Squamous cell carcinoma
  Systemic sclerosis
  Turner syndrome
  leukaemia
  Leukemia
  Beckwith-Wiedemann syndrome
  Castration-resistant prostate carcinoma
  Epithelial ovarian cancer
  Growth delay due to insulin-like growth factor I resistance
  Leber congenital amaurosis 1
  Neuroblastoma
  Pancreatic cancer
  Retinoblastoma
• UniProt ID: GRB10_HUMAN
• PDB ID: 1NRV; 3HK0
• Pfam ID: PF08947 ; PF00169 ; PF00788 ; PF00017
• Sequence:
  MALAGCPDSFLHHPYYQDKVEQTPRSQQDPAGPGLPAQSDRLANHQEDDVDLEALVNDMN
  ASLESLYSACSMQSDTVPLLQNGQHARSQPRASGPPRSIQPQVSPRQRVQRSQPVHILAV
  RRLQEEDQQFRTSSLPAIPNPFPELCGPGSPPVLTPGSLPPSQAAAKQDVKVFSEDGTSK
  VVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVESTMASE
  SKFLFRKNYAKYEFFKNPMNFFPEQMVTWCQQSNGSQTQLLQNFLNSSSCPEIQGFLHVK
  ELGKKSWKKLYVCLRRSGLYCSTKGTSKEPRHLQLLADLEDSNIFSLIAGRKQYNAPTDH
  GLCIKPNKVRNETKELRLLCAEDEQTRTCWMTAFRLLKYGMLLYQNYRIPQQRKALLSPF
  STPVRSVSENSLVAMDFSGQTGRVIENPAEAQSAALEEGHAWRKRSTRMNILGSQSPLHP
  STLSTVIHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIK
  NFQILPCEDDGQTFFSLDDGNTKFSDLIQLVDFYQLNKGVLPCKLKHHCIRVAL
• Function: Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.
• Tissue Specificity: Widely expressed in fetal and adult tissues, including fetal and postnatal liver, lung, kidney, skeletal muscle, heart, spleen, skin and brain.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway:
  IRS activation (R-HSA-74713)
  Signal attenuation (R-HSA-74749)
  Insulin receptor signalling cascade (R-HSA-74751)
  RET signaling (R-HSA-8853659)
  FLT3 Signaling (R-HSA-9607240)
  Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)
  Signaling by SCF-KIT (R-HSA-1433557)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Intervertebral disc degeneration	DISG3AIM	Definitive	Biomarker	[2]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Achondroplasia	DISYWN2O	Strong	Genetic Variation	[3]
Adrenal cortex neoplasm	DISO17X1	Strong	Altered Expression	[4]
Alopecia	DIS37HU4	Strong	Biomarker	[5]
Ewing sarcoma	DISQYLV3	Strong	Genetic Variation	[6]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[7]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[12]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[14]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[15]
Turner syndrome	DIS2035C	Strong	Biomarker	[16]
leukaemia	DISS7D1V	moderate	Biomarker	[17]
Leukemia	DISNAKFL	moderate	Biomarker	[17]
Beckwith-Wiedemann syndrome	DISH15GR	Limited	Genetic Variation	[18]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[19]
Growth delay due to insulin-like growth factor I resistance	DISWL710	Limited	Biomarker	[20]
Leber congenital amaurosis 1	DISY2B33	Limited	Altered Expression	[21]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[20]
Pancreatic cancer	DISJC981	Limited	Biomarker	[22]
Retinoblastoma	DISVPNPB	Limited	Altered Expression	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Growth factor receptor-bound protein 10 (GRB10).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Growth factor receptor-bound protein 10 (GRB10).	[31]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Growth factor receptor-bound protein 10 (GRB10).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Growth factor receptor-bound protein 10 (GRB10).	[43]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Growth factor receptor-bound protein 10 (GRB10).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Growth factor receptor-bound protein 10 (GRB10).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Growth factor receptor-bound protein 10 (GRB10).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[29]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Growth factor receptor-bound protein 10 (GRB10).	[30]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Growth factor receptor-bound protein 10 (GRB10).	[34]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[35]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[37]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[38]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[39]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Growth factor receptor-bound protein 10 (GRB10).	[34]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[40]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[41]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[42]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Growth factor receptor-bound protein 10 (GRB10).	[44]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[48]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[49]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Growth factor receptor-bound protein 10 (GRB10).	[50]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[51]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Growth factor receptor-bound protein 10 (GRB10).	[52]

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