Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN59BZS)

• DOT Name: A-kinase anchor protein 6 (AKAP6)
• Synonyms: AKAP-6; A-kinase anchor protein 100 kDa; AKAP 100; Protein kinase A-anchoring protein 6; PRKA6; mAKAP
• Gene Name: AKAP6
• Related Disease:
  Anorexia nervosa cachexia
  Arrhythmogenic right ventricular cardiomyopathy
  Atrial fibrillation
  Central nervous system neoplasm
  Dementia
  Epithelial ovarian cancer
  Familial focal epilepsy with variable foci
  Glioma
  Intellectual disability
  Narcolepsy
  Non-insulin dependent diabetes
  Schizophrenia
  Asthma
  Familial atrial fibrillation
  Bipolar disorder
• UniProt ID: AKAP6_HUMAN
• Pfam ID: PF00435
• Sequence:
  MLTMSVTLSPLRSQDLDPMATDASPMAINMTPTVEQGEGEEAMKDMDSDQQYEKPPPLHT
  GADWKIVLHLPEIETWLRMTSERVRDLTYSVQQDSDSKHVDVHLVQLKDICEDISDHVEQ
  IHALLETEFSLKLLSYSVNVIVDIHAVQLLWHQLRVSVLVLRERILQGLQDANGNYTRQT
  DILQAFSEETKEGRLDSLTEVDDSGQLTIKCSQNYLSLDCGITAFELSDYSPSEDLLSGL
  GDMTSSQVKTKPFDSWSYSEMEKEFPELIRSVGLLTVAADSISTNGSEAVTEEVSQVSLS
  VDDKGGCEEDNASAVEEQPGLTLGVSSSSGEALTNAAQPSSETVQQESSSSSHHDAKNQQ
  PVPCENATPKRTIRDCFNYNEDSPTQPTLPKRGLFLKEETFKNDLKGNGGKRQMVDLKPE
  MSRSTPSLVDPPDRSKLCLVLQSSYPNSPSAASQSYECLHKVGNGNLENTVKFHIKEISS
  SLGRLNDCYKEKSRLKKPHKTSEEVPPCRTPKRGTGSGKQAKNTKSSAVPNGELSYTSKA
  IEGPQTNSASTSSLEPCNQRSWNAKLQLQSETSSSPAFTQSSESSVGSDNIMSPVPLLSK
  HKSKKGQASSPSHVTRNGEVVEAWYGSDEYLALPSHLKQTEVLALKLENLTKLLPQKPRG
  ETIQNIDDWELSEMNSDSEIYPTYHVKKKHTRLGRVSPSSSSDIASSLGESIESGPLSDI
  LSDEESSMPLAGMKKYADEKSERASSSEKNESHSATKSALIQKLMQDIQHQDNYEAIWEK
  IEGFVNKLDEFIQWLNEAMETTENWTPPKAEMDDLKLYLETHLSFKLNVDSHCALKEAVE
  EEGHQLLELIASHKAGLKDMLRMIASQWKELQRQIKRQHSWILRALDTIKAEILATDVSV
  EDEEGTGSPKAEVQLCYLEAQRDAVEQMSLKLYSEQYTSSSKRKEEFADMSKVHSVGSNG
  LLDFDSEYQELWDWLIDMESLVMDSHDLMMSEEQQQHLYKRYSVEMSIRHLKKTELLSKV
  EALKKGGVLLPNDLLEKVDSINEKWELLGKTLGEKIQDTMAGHSGSSPRDLLSPESGSLV
  RQLEVRIKELKGWLRDTELFIFNSCLRQEKEGTMNTEKQLQYFKSLCREIKQRRRGVASI
  LRLCQHLLDDRETCNLNADHQPMQLIIVNLERRWEAIVMQAVQWQTRLQKKMGKESETLN
  VIDPGLMDLNGMSEDALEWDEMDISNKLISLNEESNDLDQELQPVIPSLKLGETSNEDPG
  YDEEADNHGGSQYASNITAPSSPHIYQVYSLHNVELYEDNHMPFLKNNPKVTGMTQPNVL
  TKSLSKDSSFSSTKSLPDLLGGSNLVKPCACHGGDMSQNSGSESGIVSEGDTETTTNSEM
  CLLNAVDGSPSNLETEHLDPQMGDAVNVLKQKFTDEGESIKLPNSSQSSISPVGCVNGKV
  GDLNSITKHTPDCLGEELQGKHDVFTFYDYSYLQGSKLKLPMIMKQSQSEKAHVEDPLLR
  GFYFDKKSCKSKHQTTELQPDVPPHERILASASHEMDRISYKSGNIEKTFTGMQNAKQLS
  LLSHSSSIESLSPGGDLFGLGIFKNGSDSLQRSTSLESWLTSYKSNEDLFSCHSSGDISV
  SSGSVGELSKRTLDLLNRLENIQSPSEQKIKRSVSDITLQSSSQKMSFTGQMSLDIASSI
  NEDSAASLTELSSSDELSLCSEDIVLHKNKIPESNASFRKRLTRSVADESDVNVSMIVNV
  SCTSACTDDEDDSDLLSSSTLTLTEEELCIKDEDDDSSIATDDEIYEDCTLMSGLDYIKN
  ELQTWIRPKLSLTRDKKRCNVSDEMKGSKDISSSEMTNPSDTLNIETLLNGSVKRVSENN
  GNGKNSSHTHELGTKRENKKTIFKVNKDPYVADMENGNIEGIPERQKGKPNVTSKVSENL
  GSHGKEISESEHCKCKALMDSLDDSNTAGKEFVSQDVRHLPKKCPNHHHFENQSTASTPT
  EKSFSELALETRFNNRQDSDALKSSDDAPSMAGKSAGCCLALEQNGTEENASISNISCCN
  CEPDVFHQKDAEDCSVHNFVKEIIDMASTALKSKSQPENEVAAPTSLTQIKEKVLEHSHR
  PIQLRKGDFYSYLSLSSHDSDCGEVTNYIEEKSSTPLPLDTTDSGLDDKEDIECFFEACV
  EGDSDGEEPCFSSAPPNESAVPSEAAMPLQATACSSEFSDSSLSADDADTVALSSPSSQE
  RAEVGKEVNGLPQTSSGCAENLEFTPSKLDSEKESSGKPGESGMPEEHNAASAKSKVQDL
  SLKANQPTDKAALHPSPKTLTCEENLLNLHEKRHRNMHR
• Function: Binds to type II regulatory subunits of protein kinase A and anchors/targets them to the nuclear membrane or sarcoplasmic reticulum. May act as an adapter for assembling multiprotein complexes.
• Tissue Specificity: Highly expressed in cardiac and skeletal muscle, followed by brain.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[1]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[3]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[6]
Familial focal epilepsy with variable foci	DIS50BKW	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Asthma	DISW9QNS	moderate	Genetic Variation	[11]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[3]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A-kinase anchor protein 6 (AKAP6).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of A-kinase anchor protein 6 (AKAP6).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of A-kinase anchor protein 6 (AKAP6).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of A-kinase anchor protein 6 (AKAP6).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A-kinase anchor protein 6 (AKAP6).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A-kinase anchor protein 6 (AKAP6).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of A-kinase anchor protein 6 (AKAP6).	[19]

References

• [1] Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases.PLoS One. 2016 Aug 2;11(8):e0159593. doi: 10.1371/journal.pone.0159593. eCollection 2016.
• [2] Predicting disease genes using protein-protein interactions.J Med Genet. 2006 Aug;43(8):691-8. doi: 10.1136/jmg.2006.041376. Epub 2006 Apr 12.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.Nat Genet. 2017 May;49(5):789-794. doi: 10.1038/ng.3823. Epub 2017 Mar 27.
• [5] Association of AKAP6 and MIR2113 with cognitive performance in a population-based sample of older adults.Genes Brain Behav. 2017 Apr;16(4):472-478. doi: 10.1111/gbb.12368. Epub 2017 Jan 26.
• [6] Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.PLoS One. 2018 Jul 6;13(7):e0197561. doi: 10.1371/journal.pone.0197561. eCollection 2018.
• [7] Impact of AKAP6 polymorphisms on Glioma susceptibility and prognosis.BMC Neurol. 2019 Nov 23;19(1):296. doi: 10.1186/s12883-019-1504-2.
• [8] The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum Genet. 2017 Aug;136(8):921-939. doi: 10.1007/s00439-017-1821-8. Epub 2017 Jun 9.
• [9] 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.
• [10] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [11] HLA-DQ strikes again: genome-wide association study further confirms HLA-DQ in the diagnosis of asthma among adults.Clin Exp Allergy. 2012 Dec;42(12):1724-33. doi: 10.1111/cea.12000.
• [12] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [13] 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.
• [14] 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.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [17] 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.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.