Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW3T4B2)

• DOT Name: Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1)
• Synonyms: IL-1-RAPL-1; IL-1RAPL-1; IL1RAPL-1; EC 3.2.2.6; Oligophrenin-4; Three immunoglobulin domain-containing IL-1 receptor-related 2; TIGIRR-2; X-linked interleukin-1 receptor accessory protein-like 1
• Gene Name: IL1RAPL1
• Related Disease:
  Advanced cancer
  Cognitive impairment
  Intellectual disability, X-linked 21
  Non-syndromic X-linked intellectual disability
  Autoimmune disease
  B-cell lymphoma
  B-cell neoplasm
  Brain neoplasm
  Breast neoplasm
  Cardiovascular disease
  Chromosomal disorder
  Coffin-Lowry syndrome
  Intellectual disability, X-linked 19
  Klinefelter syndrome
  Melanoma
  Pervasive developmental disorder
  Rheumatoid arthritis
  Vitiligo
  X-linked intellectual disability
  Bronchopulmonary dysplasia
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Asthma
  Autism
  Intellectual disability
  Intellectual disability, X-linked 1
  X-linked adrenal hypoplasia congenita
• UniProt ID: IRPL1_HUMAN
• PDB ID: 1T3G; 4M92; 5WY8
• EC Number: 3.2.2.6
• Pfam ID: PF00047 ; PF18452 ; PF01582
• Sequence:
  MKAPIPHLILLYATFTQSLKVVTKRGSADGCTDWSIDIKKYQVLVGEPVRIKCALFYGYI
  RTNYSLAQSAGLSLMWYKSSGPGDFEEPIAFDGSRMSKEEDSIWFRPTLLQDSGLYACVI
  RNSTYCMKVSISLTVGENDTGLCYNSKMKYFEKAELSKSKEISCRDIEDFLLPTREPEIL
  WYKECRTKTWRPSIVFKRDTLLIREVREDDIGNYTCELKYGGFVVRRTTELTVTAPLTDK
  PPKLLYPMESKLTIQETQLGDSANLTCRAFFGYSGDVSPLIYWMKGEKFIEDLDENRVWE
  SDIRILKEHLGEQEVSISLIVDSVEEGDLGNYSCYVENGNGRRHASVLLHKRELMYTVEL
  AGGLGAILLLLVCLVTIYKCYKIEIMLFYRNHFGAEELDGDNKDYDAYLSYTKVDPDQWN
  QETGEEERFALEILPDMLEKHYGYKLFIPDRDLIPTGTYIEDVARCVDQSKRLIIVMTPN
  YVVRRGWSIFELETRLRNMLVTGEIKVILIECSELRGIMNYQEVEALKHTIKLLTVIKWH
  GPKCNKLNSKFWKRLQYEMPFKRIEPITHEQALDVSEQGPFGELQTVSAISMAAATSTAL
  ATAHPDLRSTFHNTYHSQMRQKHYYRSYEYDVPPTGTLPLTSIGNQHTYCNIPMTLINGQ
  RPQTKSSREQNPDEAHTNSAILPLLPRETSISSVIW
• Function: May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel. May activate the MAP kinase JNK. Plays a role in neurite outgrowth. During dendritic spine formation can bidirectionally induce pre- and post-synaptic differentiation of neurons by trans-synaptically binding to PTPRD.
• Tissue Specificity: Detected at low levels in heart, skeletal muscle, ovary, skin, amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra and thalamus. Detected at very low levels in tonsil, prostate, testis, small intestine, placenta, colon and fetal liver.
• Reactome Pathway:
  Interleukin-38 signaling (R-HSA-9007892)
  Receptor-type tyrosine-protein phosphatases (R-HSA-388844)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[2]
Intellectual disability, X-linked 21	DISPKSPK	Definitive	X-linked	[3]
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[8]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[9]
Coffin-Lowry syndrome	DISMTBDA	Strong	Genetic Variation	[10]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Genetic Variation	[10]
Klinefelter syndrome	DISOUI7W	Strong	Genetic Variation	[11]
Melanoma	DIS1RRCY	Strong	Biomarker	[12]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[14]
Vitiligo	DISR05SL	Strong	Genetic Variation	[15]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[16]
Bronchopulmonary dysplasia	DISO0BY5	moderate	Genetic Variation	[17]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[18]
Asthma	DISW9QNS	Limited	Genetic Variation	[19]
Autism	DISV4V1Z	Limited	Biomarker	[16]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[20]
Intellectual disability, X-linked 1	DISET38E	Limited	Biomarker	[21]
X-linked adrenal hypoplasia congenita	DISNMXY8	Limited	Genetic Variation	[22]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) affects the response to substance of Topotecan.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[26]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1).	[27]

References

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• [15] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [16] IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway.PLoS One. 2013 Jun 13;8(6):e66254. doi: 10.1371/journal.pone.0066254. Print 2013.
• [17] Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2011 Nov 15;184(10):1164-70. doi: 10.1164/rccm.201103-0548OC. Epub 2011 Aug 11.
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• [19] Suggestive association between variants in IL1RAPL and asthma symptoms in Latin American children.Eur J Hum Genet. 2017 Apr;25(4):439-445. doi: 10.1038/ejhg.2016.197. Epub 2017 Jan 25.
• [20] The Synaptic and Neuronal Functions of the X-Linked Intellectual Disability Protein Interleukin-1 Receptor Accessory Protein Like 1 (IL1RAPL1).Dev Neurobiol. 2019 Jan;79(1):85-95. doi: 10.1002/dneu.22657. Epub 2018 Dec 21.
• [21] Novel mutation of IL1RAPL1 gene in a nonspecific X-linked mental retardation (MRX) family.Am J Med Genet A. 2008 Dec 15;146A(24):3167-72. doi: 10.1002/ajmg.a.32613.
• [22] Mental retardation in a boy with congenital adrenal hypoplasia: a clue to contiguous gene syndrome involving DAX1 and IL1RAPL.Endocr J. 2003 Jun;50(3):303-7. doi: 10.1507/endocrj.50.303.
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• [28] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
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• [30] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
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• [33] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.