Details of Drug Off-Target (DOT)

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

• DOT Name: Activity-dependent neuroprotector homeobox protein (ADNP)
• Synonyms: Activity-dependent neuroprotective protein
• Gene Name: ADNP
• Related Disease:
  ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
  Multiple sclerosis
  Neurodevelopmental disorder
  Alzheimer disease
  Autism
  Autism spectrum disorder
  Blepharophimosis, ptosis, and epicanthus inversus syndrome
  Brain infarction
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Diabetic retinopathy
  Epithelial ovarian cancer
  Movement disorder
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pervasive developmental disorder
  Ptosis
  Schizophrenia
  Tauopathy
  Trichohepatoenteric syndrome
  Advanced cancer
  Cognitive impairment
  Exanthem
  Intellectual disability
  Ischemia
  Prostate carcinoma
• UniProt ID: ADNP_HUMAN
• Pfam ID: PF19627 ; PF00046
• Sequence:
  MFQLPVNNLGSLRKARKTVKKILSDIGLEYCKEHIEDFKQFEPNDFYLKNTTWEDVGLWD
  PSLTKNQDYRTKPFCCSACPFSSKFFSAYKSHFRNVHSEDFENRILLNCPYCTFNADKKT
  LETHIKIFHAPNASAPSSSLSTFKDKNKNDGLKPKQADSVEQAVYYCKKCTYRDPLYEIV
  RKHIYREHFQHVAAPYIAKAGEKSLNGAVPLGSNAREESSIHCKRCLFMPKSYEALVQHV
  IEDHERIGYQVTAMIGHTNVVVPRSKPLMLIAPKPQDKKSMGLPPRIGSLASGNVRSLPS
  QQMVNRLSIPKPNLNSTGVNMMSSVHLQQNNYGVKSVGQGYSVGQSMRLGLGGNAPVSIP
  QQSQSVKQLLPSGNGRSYGLGSEQRSQAPARYSLQSANASSLSSGQLKSPSLSQSQASRV
  LGQSSSKPAAAATGPPPGNTSSTQKWKICTICNELFPENVYSVHFEKEHKAEKVPAVANY
  IMKIHNFTSKCLYCNRYLPTDTLLNHMLIHGLSCPYCRSTFNDVEKMAAHMRMVHIDEEM
  GPKTDSTLSFDLTLQQGSHTNIHLLVTTYNLRDAPAESVAYHAQNNPPVPPKPQPKVQEK
  ADIPVKSSPQAAVPYKKDVGKTLCPLCFSILKGPISDALAHHLRERHQVIQTVHPVEKKL
  TYKCIHCLGVYTSNMTASTITLHLVHCRGVGKTQNGQDKTNAPSRLNQSPSLAPVKRTYE
  QMEFPLLKKRKLDDDSDSPSFFEEKPEEPVVLALDPKGHEDDSYEARKSFLTKYFNKQPY
  PTRREIEKLAASLWLWKSDIASHFSNKRKKCVRDCEKYKPGVLLGFNMKELNKVKHEMDF
  DAEWLFENHDEKDSRVNASKTADKKLNLGKEDDSSSDSFENLEEESNESGSPFDPVFEVE
  PKISNDNPEEHVLKVIPEDASESEEKLDQKEDGSKYETIHLTEEPTKLMHNASDSEVDQD
  DVVEWKDGASPSESGPGSQQVSDFEDNTCEMKPGTWSDESSQSEDARSSKPAAKKKATMQ
  GDREQLKWKNSSYGKVEGFWSKDQSQWKNASENDERLSNPQIEWQNSTIDSEDGEQFDNM
  TDGVAEPMHGSLAGVKLSSQQA
• Function: May be involved in transcriptional regulation. May mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. Positively modulates WNT-beta-catenin/CTNN1B signaling, acting by regulating phosphorylation of, and thereby stabilizing, CTNNB1. May be required for neural induction and neuronal differentiation. May be involved in erythroid differentiation.
• Tissue Specificity: Widely expressed. Strong expression in heart, skeletal muscle, kidney and placenta. In brain, expression is stronger in the cerebellum and cortex regions. No expression detected in the colon. Strong increase of expression in colon and breast cancer tissues.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	DIS81XMM	Definitive	Autosomal dominant	[1]
Multiple sclerosis	DISB2WZI	Definitive	Altered Expression	[2]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Blepharophimosis, ptosis, and epicanthus inversus syndrome	DISN43YC	Strong	Genetic Variation	[6]
Brain infarction	DISPPGYK	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[5]
Ptosis	DISJZNIY	Strong	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Tauopathy	DISY2IPA	Strong	Genetic Variation	[12]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[14]
Cognitive impairment	DISH2ERD	Disputed	Biomarker	[15]
Exanthem	DISAFOQN	Limited	Biomarker	[16]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[5]
Ischemia	DIS5XOOY	Limited	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[18]

6 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 Activity-dependent neuroprotector homeobox protein (ADNP).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Activity-dependent neuroprotector homeobox protein (ADNP).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Activity-dependent neuroprotector homeobox protein (ADNP).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Activity-dependent neuroprotector homeobox protein (ADNP).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Activity-dependent neuroprotector homeobox protein (ADNP).	[30]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Activity-dependent neuroprotector homeobox protein (ADNP).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[26]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Activity-dependent neuroprotector homeobox protein (ADNP).	[32]

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] Expression of activity-dependent neuroprotective protein in the immune system: possible functions and relevance to multiple sclerosis.Neuroimmunomodulation. 2010;17(2):120-5. doi: 10.1159/000258695. Epub 2009 Nov 17.
• [3] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [4] Direct evidence for binding of aluminum to NAP anti-amyloid peptide and its analogs.Eur J Mass Spectrom (Chichester). 2020 Apr;26(2):106-116. doi: 10.1177/1469066719877714. Epub 2019 Sep 24.
• [5] Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.Biol Psychiatry. 2019 Feb 15;85(4):287-297. doi: 10.1016/j.biopsych.2018.02.1173. Epub 2018 Mar 15.
• [6] Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene.Am J Med Genet A. 2017 Jun;173(6):1631-1634. doi: 10.1002/ajmg.a.38126. Epub 2017 Apr 13.
• [7] NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death.Stroke. 2002 Apr;33(4):1085-92. doi: 10.1161/01.str.0000014207.05597.d7.
• [8] ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer.Clin Cancer Res. 2017 Jun 1;23(11):2769-2780. doi: 10.1158/1078-0432.CCR-16-1604. Epub 2016 Nov 30.
• [9] NAP counteracts hyperglycemia/hypoxia induced retinal pigment epithelial barrier breakdown through modulation of HIFs and VEGF expression.J Cell Physiol. 2018 Feb;233(2):1120-1128. doi: 10.1002/jcp.25971. Epub 2017 Sep 28.
• [10] Integrative proteogenomic analyses of human tumours identifies ADNP as a novel oncogenic mediator of cell cycle progression in high-grade serous ovarian cancer with poor prognosis.EBioMedicine. 2019 Dec;50:191-202. doi: 10.1016/j.ebiom.2019.11.009. Epub 2019 Nov 22.
• [11] The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse.Transl Psychiatry. 2019 Jan 15;9(1):2. doi: 10.1038/s41398-018-0357-6.
• [12] Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study.Mol Psychiatry. 2021 May;26(5):1619-1633. doi: 10.1038/s41380-019-0563-5. Epub 2019 Oct 30.
• [13] The Eight and a Half Year Journey of Undiagnosed AD: Gene Sequencing and Funding of Advanced Genetic Testing Has Led to Hope and New Beginnings.Front Endocrinol (Lausanne). 2017 May 19;8:107. doi: 10.3389/fendo.2017.00107. eCollection 2017.
• [14] Activity-dependent neuroprotective protein recruits HP1 and CHD4 to control lineage-specifying genes.Nature. 2018 May;557(7707):739-743. doi: 10.1038/s41586-018-0153-8. Epub 2018 May 23.
• [15] D-NAP prophylactic treatment in the SOD mutant mouse model of amyotrophic lateral sclerosis: review of discovery and treatment of tauopathy.J Mol Neurosci. 2012 Nov;48(3):597-602. doi: 10.1007/s12031-012-9882-6.
• [16] Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children.Transl Psychiatry. 2017 Feb 21;7(2):e1043. doi: 10.1038/tp.2017.27.
• [17] The neuropeptide NAP provides neuroprotection against retinal ganglion cell damage after retinal ischemia and optic nerve crush.Graefes Arch Clin Exp Ophthalmol. 2008 Sep;246(9):1255-63. doi: 10.1007/s00417-007-0746-7. Epub 2008 Apr 15.
• [18] A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.Nat Genet. 2014 Oct;46(10):1103-9. doi: 10.1038/ng.3094. Epub 2014 Sep 14.
• [19] 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.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] 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.
• [22] 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.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [25] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [26] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [27] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [32] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [33] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.