Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WRCBH)

• DOT Name: Kalirin (KALRN)
• Synonyms: EC 2.7.11.1; Huntingtin-associated protein-interacting protein; Protein Duo; Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain
• Gene Name: KALRN
• Related Disease:
  B-cell lymphoma
  Brucellosis
  Marginal zone lymphoma
  Neoplasm
  Systemic lupus erythematosus
  Advanced cancer
  Alzheimer disease
  Alzheimer disease 3
  Arteriosclerosis
  Atherosclerosis
  Attention deficit hyperactivity disorder
  Cardiovascular disease
  Cocaine addiction
  Coronary atherosclerosis
  High blood pressure
  Huntington disease
  Irritable bowel syndrome
  Knee osteoarthritis
  Major depressive disorder
  Narcolepsy
  Sarcoidosis
  Stroke
  Vascular disease
  Schizophrenia
  Asthma
  Coronary heart disease
  Intellectual disability
  Non-insulin dependent diabetes
  Osteoarthritis
  Psychotic disorder
• UniProt ID: KALRN_HUMAN
• PDB ID: 5QQD; 5QQE; 5QQF; 5QQG; 5QQH; 5QQI; 5QQJ; 5QQK; 5QQL; 5QQM; 5QQN; 5QU9
• EC Number: 2.7.11.1
• Pfam ID: PF13716 ; PF00041 ; PF07679 ; PF00169 ; PF00069 ; PF00621 ; PF16609 ; PF00435
• Sequence:
  MTDRFWDQWYLWYLRLLRLLDRGSFRNDGLKASDVLPILKEKVAFVSGGRDKRGGPILTF
  PARSNHDRIRQEDLRKLVTYLASVPSEDVCKRGFTVIIDMRGSKWDLIKPLLKTLQEAFP
  AEIHVALIIKPDNFWQKQKTNFGSSKFIFETSMVSVEGLTKLVDPSQLTEEFDGSLDYNH
  EEWIELRLSLEEFFNSAVHLLSRLEDLQEMLARKEFPVDVEGSRRLIDEHTQLKKKVLKA
  PVEELDREGQRLLQCIRCSDGFSGRNCIPGSADFQSLVPKITSLLDKLHSTRQHLHQMWH
  VRKLKLDQCFQLRLFEQDAEKMFDWISHNKELFLQSHTEIGVSYQYALDLQTQHNHFAMN
  SMNAYVNINRIMSVASRLSEAGHYASQQIKQISTQLDQEWKSFAAALDERSTILAMSAVF
  HQKAEQFLSGVDAWCKMCSEGGLPSEMQDLELAIHHHQTLYEQVTQAYTEVSQDGKALLD
  VLQRPLSPGNSESLTATANYSKAVHQVLDVVHEVLHHQRRLESIWQHRKVRLHQRLQLCV
  FQQDVQQVLDWIENHGEAFLSKHTGVGKSLHRARALQKRHDDFEEVAQNTYTNADKLLEA
  AEQLAQTGECDPEEIYKAARHLEVRIQDFVRRVEQRKLLLDMSVSFHTHTKELWTWMEDL
  QKEMLEDVCADSVDAVQELIKQFQQQQTATLDATLNVIKEGEDLIQQLRSAPPSLGEPSE
  ARDSAVSNNKTPHSSSISHIESVLQQLDDAQVQMEELFHERKIKLDIFLQLRIFEQYTIE
  VTAELDAWNEDLLRQMNDFNTEDLTLAEQRLQRHTERKLAMNNMTFEVIQQGQDLHQYIT
  EVQASGIELICEKDIDLAAQVQELLEFLHEKQHELELNAEQTHKRLEQCLQLRHLQAEVK
  QVLGWIRNGESMLNASLVNASSLSEAEQLQREHEQFQLAIESLFHATSLQKTHQSALQVQ
  QKAEVLLQAGHYDADAIRECAEKVALHWQQLMLKMEDRLKLVNASVAFYKTSEQVCSVLE
  SLEQEYRRDEDWCGGRDKLGPAAEIDHVIPLISKHLEQKEAFLKACTLARRNAEVFLKYI
  HRNNVSMPSVASHTRGPEQQVKAILSELLQRENRVLHFWTLKKRRLDQCQQYVVFERSAK
  QALDWIQETGEFYLSTHTSTGETTEETQELLKEYGEFRVPAKQTKEKVKLLIQLADSFVE
  KGHIHATEIRKWVTTVDKHYRDFSLRMGKYRYSLEKALGVNTEDNKDLELDIIPASLSDR
  EVKLRDANHEVNEEKRKSARKKEFIMAELLQTEKAYVRDLHECLETYLWEMTSGVEEIPP
  GILNKEHIIFGNIQEIYDFHNNIFLKELEKYEQLPEDVGHCFVTWADKFQMYVTYCKNKP
  DSNQLILEHAGTFFDEIQQRHGLANSISSYLIKPVQRITKYQLLLKELLTCCEEGKGELK
  DGLEVMLSVPKKANDAMHVSMLEGFDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFL
  FEISLVFSKEIKDSSGHTKYVYKNKLLTSELGVTEHVEGDPCKFALWSGRTPSSDNKTVL
  KASNIETKQEWIKNIREVIQERIIHLKGALKEPLQLPKTPAKQRNNSKRDGVEDIDSQGD
  GSSQPDTISIASRTSQNTVDSDKLSGGCELTVVLQDFSAGHSSELTIQVGQTVELLERPS
  ERPGWCLVRTTERSPPLEGLVPSSALCISHSRSSVEMDCFFPLVKDAYSHSSSENGGKSE
  SVANLQAQPSLNSIHSSPGPKRSTNTLKKWLTSPVRRLNSGKADGNIKKQKKVRDGRKSF
  DLGSPKPGDETTPQGDSADEKSKKGWGEDEPDEESHTPLPPPMKIFDNDPTQDEMSSSLL
  AARQASTEVPTAADLVNAIEKLVKNKLSLEGSSYRGSLKDPAGCLNEGMAPPTPPKNPEE
  EQKAKALRGRMFVLNELVQTEKDYVKDLGIVVEGFMKRIEEKGVPEDMRGKDKIVFGNIH
  QIYDWHKDFFLAELEKCIQEQDRLAQLFIKHERKLHIYVWYCQNKPRSEYIVAEYDAYFE
  EVKQEINQRLTLSDFLIKPIQRITKYQLLLKDFLRYSEKAGLECSDIEKAVELMCLVPKR
  CNDMMNLGRLQGFEGTLTAQGKLLQQDTFYVIELDAGMQSRTKERRVFLFEQIVIFSELL
  RKGSLTPGYMFKRSIKMNYLVLEENVDNDPCKFALMNRETSERVVLQAANADIQQAWVQD
  INQVLETQRDFLNALQSPIEYQRKERSTAVMRSQPARLPQASPRPYSSVPAGSEKPPKGS
  SYNPPLPPLKISTSNGSPGFEYHQPGDKFEASKQNDLGGCNGTSSMAVIKDYYALKENEI
  CVSQGEVVQVLAVNQQNMCLVYQPASDHSPAAEGWVPGSILAPLTKATAAESSDGSIKKS
  CSWHTLRMRKRAEVENTGKNEATGPRKPKDILGNKVSVKETNSSEESECDDLDPNTSMEI
  LNPNFIQEVAPEFLVPLVDVTCLLGDTVILQCKVCGRPKPTITWKGPDQNILDTDNSSAT
  YTVSSCDSGEITLKICNLMPQDSGIYTCIATNDHGTTSTSATVKVQGVPAAPNRPIAQER
  SCTSVILRWLPPSSTGNCTISGYTVEYREEGSQIWQQSVASTLDTYLVIEDLSPGCPYQF
  RVSASNPWGISLPSEPSEFVRLPEYDAAADGATISWKENFDSAYTELNEIGRGRFSIVKK
  CIHKATRKDVAVKFVSKKMKKKEQAAHEAALLQHLQHPQYITLHDTYESPTSYILILELM
  DDGRLLDYLMNHDELMEEKVAFYIRDIMEALQYLHNCRVAHLDIKPENLLIDLRIPVPRV
  KLIDLEDAVQISGHFHIHHLLGNPEFAAPEVIQGIPVSLGTDIWSIGVLTYVMLSGVSPF
  LDESKEETCINVCRVDFSFPHEYFCGVSNAARDFINVILQEDFRRRPTAATCLQHPWLQP
  HNGSYSKIPLDTSRLACFIERRKHQNDVRPIPNVKSYIVNRVNQGT
• Function: Promotes the exchange of GDP by GTP. Activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, through their effects on the actin cytoskeleton. Induces lamellipodia independent of its GEF activity.
• Tissue Specificity: Isoform 2 is brain specific. Highly expressed in cerebral cortex, putamen, amygdala, hippocampus and caudate nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4 is expressed in skeletal muscle.
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  RHOA GTPase cycle (R-HSA-8980692)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOG GTPase cycle (R-HSA-9013408)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Definitive	Genetic Variation	[1]
Brucellosis	DISEAYGH	Definitive	Genetic Variation	[2]
Marginal zone lymphoma	DISLZ4AO	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[8]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[9]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[6]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[10]
Huntington disease	DISQPLA4	Strong	Biomarker	[9]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[11]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[12]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[13]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[14]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[15]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Vascular disease	DISVS67S	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[16]
Asthma	DISW9QNS	Limited	Biomarker	[17]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[18]
Intellectual disability	DISMBNXP	Limited	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[18]
Osteoarthritis	DIS05URM	Limited	Biomarker	[20]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[21]

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 Kalirin (KALRN).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kalirin (KALRN).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kalirin (KALRN).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Kalirin (KALRN).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kalirin (KALRN).	[37]

12 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 Kalirin (KALRN).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kalirin (KALRN).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kalirin (KALRN).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Kalirin (KALRN).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kalirin (KALRN).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kalirin (KALRN).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Kalirin (KALRN).	[30]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Kalirin (KALRN).	[31]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Kalirin (KALRN).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kalirin (KALRN).	[34]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Kalirin (KALRN).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kalirin (KALRN).	[29]

References

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• [4] Kalirin-7 prevents dendritic spine dysgenesis induced by amyloid beta-derived oligomers.Eur J Neurosci. 2019 May;49(9):1091-1101. doi: 10.1111/ejn.14311. Epub 2019 Jan 20.
• [5] Under-expression of Kalirin-7 Increases iNOS activity in cultured cells and correlates to elevated iNOS activity in Alzheimer's disease hippocampus.J Alzheimers Dis. 2007 Nov;12(3):271-81. doi: 10.3233/jad-2007-12309.
• [6] KALRN Rare and Common Variants and Susceptibility to Ischemic Stroke in Chinese Han Population.Neuromolecular Med. 2015 Sep;17(3):241-50. doi: 10.1007/s12017-015-8352-z. Epub 2015 Apr 28.
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• [13] A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness.Nat Commun. 2014 Sep 16;5:4858. doi: 10.1038/ncomms5858.
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• [18] Association of KALRN, ADIPOQ, and FTO gene polymorphism in type 2 diabetic patients with coronary artery disease: possible predisposing markers.Coron Artery Dis. 2016 Sep;27(6):490-6. doi: 10.1097/MCA.0000000000000386.
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• [28] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
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• [31] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [32] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [33] 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.
• [34] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [35] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [36] 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.
• [37] 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.