Details of Drug Off-Target (DOT)

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

• DOT Name: SH3KBP1-binding protein 1 (SHKBP1)
• Synonyms: SETA-binding protein 1
• Gene Name: SHKBP1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Bone osteosarcoma
  Duchenne muscular dystrophy
  Narcolepsy
  Osteosarcoma
  Schizophrenia
• UniProt ID: SHKB1_HUMAN
• PDB ID: 4CRH
• Pfam ID: PF02214
• Sequence:
  MAAAATAAEGVPSRGPPGEVIHLNVGGKRFSTSRQTLTWIPDSFFSSLLSGRISTLKDET
  GAIFIDRDPTVFAPILNFLRTKELDPRGVHGSSLLHEAQFYGLTPLVRRLQLREELDRSS
  CGNVLFNGYLPPPVFPVKRRNRHSLVGPQQLGGRPAPVRRSNTMPPNLGNAGLLGRMLDE
  KTPPSPSGQPEEPGMVRLVCGHHNWIAVAYTQFLVCYRLKEASGWQLVFSSPRLDWPIER
  LALTARVHGGALGEHDKMVAAATGSEILLWALQAEGGGSEIGVFHLGVPVEALFFVGNQL
  IATSHTGRIGVWNAVTKHWQVQEVQPITSYDAAGSFLLLGCNNGSIYYVDVQKFPLRMKD
  NDLLVSELYRDPAEDGVTALSVYLTPKTSDSGNWIEIAYGTSSGGVRVIVQHPETVGSGP
  QLFQTFTVHRSPVTKIMLSEKHLISVCADNNHVRTWSVTRFRGMISTQPGSTPLASFKIL
  ALESADGHGGCSAGNDIGPYGERDDQQVFIQKVVPSASQLFVRLSSTGQRVCSVRSVDGS
  PTTAFTVLECEGSRRLGSRPRRYLLTGQANGSLAMWDLTTAMDGLGQAPAGGLTEQELME
  QLEHCELAPPAPSAPSWGCLPSPSPRISLTSLHSASSNTSLSGHRGSPSPPQAEARRRGG
  GSFVERCQELVRSGPDLRRPPTPAPWPSSGLGTPLTPPKMKLNETSF
• Function: Inhibits CBL-SH3KBP1 complex mediated down-regulation of EGFR signaling by sequestration of SH3KBP1. Binds to SH3KBP1 and prevents its interaction with CBL and inhibits translocation of SH3KBP1 to EGFR containing vesicles upon EGF stimulation.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[3]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[4]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	No Known	Unknown	[5]

1 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 SH3KBP1-binding protein 1 (SHKBP1).	[6]

9 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 SH3KBP1-binding protein 1 (SHKBP1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of SH3KBP1-binding protein 1 (SHKBP1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SH3KBP1-binding protein 1 (SHKBP1).	[15]

References

• [1] Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing.Leukemia. 2011 May;25(5):821-7. doi: 10.1038/leu.2011.19. Epub 2011 Feb 22.
• [2] The TGF-miR-499a-SHKBP1 pathway induces resistance to EGFR inhibitors in osteosarcoma cancer stem cell-like cells.J Exp Clin Cancer Res. 2019 May 28;38(1):226. doi: 10.1186/s13046-019-1195-y.
• [3] Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.Ann Neurol. 2018 Aug;84(2):234-245. doi: 10.1002/ana.25283. Epub 2018 Aug 25.
• [4] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [5] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] 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.
• [12] 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.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] 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.