Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWZZDQ9)

• DOT Name: Alpha-protein kinase 2 (ALPK2)
• Synonyms: EC 2.7.11.1; Heart alpha-protein kinase
• Gene Name: ALPK2
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Alzheimer disease
  Colorectal carcinoma
  Non-small-cell lung cancer
  Neoplasm
• UniProt ID: ALPK2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF02816 ; PF07679
• Sequence:
  MKDSEGPQRPPLCFLSTLLSQKVPEKSDAVLRCIISGQPKPEVTWYKNGQAIDGSGIISN
  YEFFENQYIHVLHLSCCTKNDAAVYQISAKNSFGMICCSASVEVECSSENPQLSPNLEDD
  RDRGWKHETGTHEEERANQIDEKEHPYKEEESISPGTPRSADSSPSKSNHSLSLQSLGNL
  DISVSSSENPLGVKGTRHTGEAYDPSNTEEIANGLLFLNSSHIYEKQDRCCHKTVHSMAS
  KFTDGDLNNDGPHDEGLRSSQQNPKVQKYISFSLPLSEATAHIYPGDSAVANKQPSPQLS
  SEDSDSDYELCPEITLTYTEEFSDDDLEYLECSDVMTDYSNAVWQRNLLGTEHVFLLESD
  DEEMEFGEHCLGGCEHFLSGMGCGSRVSGDAGPMVATAGFCGHHSQPQEVGVRSSRVSKH
  GPSSPQTGMTLILGPHQDGTSSVTEQGRYKLPTAPEAAENDYPGIQGETRDSHQAREEFA
  SDNLLNMDESVRETEMKLLSGESENSGMSQCWETAADKRVGGKDLWSKRGSRKSARVRQP
  GMKGNPKKPNANLRESTTEGTLHLCSAKESAEPPLTQSDKRETSHTTAAATGRSSHADAR
  ECAISTQAEQEAKTLQTSTDSVSKEGNTNCKGEGMQVNTLFETSQVPDWSDPPQVQVQET
  VRETISCSQMPAFSEPAGEESPFTGTTTISFSNLGGVHKENASLAQHSEVKPCTCGPQHE
  EKQDRDGNIPDNFREDLKYEQSISEANDETMSPGVFSRHLPKDARADFREPVAVSVASPE
  PTDTALTLENVCDEPRDREAVCAMECFEAGDQGTCFDTIDSLVGRPVDKYSPQEICSVDT
  ELAEGQNKVSDLCSSNDKTLEVFFQTQVSETSVSTCKSSKDGNSVMSPLFTSTFTLNISH
  TASEGATGENLAKVENSTYPLASTVHAGQEQPSPSNSGGLDETQLLSSENNPLVQFKEGG
  DKSPSPSAADTTATPASYSSIVSFPWEKPTTLTANNECFQATRETEDTSTVTIATEVHPA
  KYLAVSIPEDKHAGGTEERFPRASHEKVSQFPSQVQLDHILSGATIKSTKELLCRAPSVP
  GVPHHVLQLPEGEGFCSNSPLQVDNLSGDKSQTVDRADFRSYEENFQERGSETKQGVQQQ
  SLSQQGSLSAPDFQQSLPTTSAAQEERNLVPTAHSPASSREGAGQRSGWGTRVSVVAETA
  GEEDSQALSNVPSLSDILLEESKEYRPGNWEAGNKLKIITLEASASEIWPPRQLTNSESK
  ASDGGLIIPDKVWAVPDSLKADAVVPELAPSEIAALAHSPEDAESALADSRESHKGEEPT
  ISVHWRSLSSRGFSQPRLLESSVDPVDEKELSVTDSLSAASETGGKENVNNVSQDQEEKQ
  LKMDHTAFFKKFLTCPKILESSVDPIDEISVIEYTRAGKPEPSETTPQGAREGGQSNDGN
  MGHEAEIQPAILQVPCLQGTILSENRISRSQEGSMKQEAEQIQPEEAKTAIWQVLQPSEG
  GERIPSGCSIGQIQESSDGSLGEAEQSKKDKAELISPTSPLSSCLPIMTHASLGVDTHNS
  TGQIHDVPENDIVEPRKRQYVFPVSQKRGTIENERGKPLPSSPDLTRFPCTSSPEGNVTD
  FLISHKMEEPKIEVLQIGETKPPSSSSSSAKTLAFISGERELEKAPKLLQDPCQKGTLGC
  AKKSREREKSLEARAGKSPGTLTAVTGSEEVKRKPEAPGSGHLAEGVKKKILSRVAALRL
  KLEEKENIRKNSAFLKKMPKLETSLSHTEEKQDPKKPSCKREGRAPVLLKKIQAEMFPEH
  SGNVKLSCQFAEIHEDSTICWTKDSKSIAQVQRSAGDNSTVSFAIVQASPKDQGLYYCCI
  KNSYGKVTAEFNLTAEVLKQLSSRQDTKGCEEIEFSQLIFKEDFLHDSYFGGRLRGQIAT
  EELHFGEGVHRKAFRSTVMHGLMPVFKPGHACVLKVHNAIAYGTRNNDELIQRNYKLAAQ
  ECYVQNTARYYAKIYAAEAQPLEGFGEVPEIIPIFLIHRPENNIPYATVEEELIGEFVKY
  SIRDGKEINFLRRESEAGQKCCTFQHWVYQKTSGCLLVTDMQGVGMKLTDVGIATLAKGY
  KGFKGNCSMTFIDQFKALHQCNKYCKMLGLKSLQNNNQKQKQPSIGKSKVQTNSMTIKKA
  GPETPGEKKT
• Function: Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation. Regulates cardiac development and cardiomyocyte differentiation by negatively regulating Wnt/beta-catenin signaling.
• Tissue Specificity: Expressed in developing cardiac tissue and cardiomyocytes (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

2 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 Alpha-protein kinase 2 (ALPK2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-protein kinase 2 (ALPK2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-protein kinase 2 (ALPK2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-protein kinase 2 (ALPK2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alpha-protein kinase 2 (ALPK2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-protein kinase 2 (ALPK2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Alpha-protein kinase 2 (ALPK2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-protein kinase 2 (ALPK2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-protein kinase 2 (ALPK2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alpha-protein kinase 2 (ALPK2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Alpha-protein kinase 2 (ALPK2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alpha-protein kinase 2 (ALPK2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Alpha-protein kinase 2 (ALPK2).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Alpha-protein kinase 2 (ALPK2).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Alpha-protein kinase 2 (ALPK2).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Alpha-protein kinase 2 (ALPK2).	[17]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Alpha-protein kinase 2 (ALPK2).	[18]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Alpha-protein kinase 2 (ALPK2).	[19]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Alpha-protein kinase 2 (ALPK2).	[20]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Alpha-protein kinase 2 (ALPK2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-protein kinase 2 (ALPK2).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Alpha-protein kinase 2 (ALPK2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Alpha-protein kinase 2 (ALPK2).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Alpha-protein kinase 2 (ALPK2).	[16]

References

• [1] Side population cell fractions from hepatocellular carcinoma cell lines increased with tumor dedifferentiation, but lack characteristic features of cancer stem cells.J Gastroenterol Hepatol. 2014 May;29(5):1092-101. doi: 10.1111/jgh.12484.
• [2] An Alpha-kinase 2 Gene Variant Disrupts Filamentous Actin Localization in the Surface Cells of Colorectal Cancer Spheroids.Anticancer Res. 2017 Jul;37(7):3855-3862. doi: 10.21873/anticanres.11765.
• [3] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [4] miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression.Genes Chromosomes Cancer. 2013 Oct;52(10):895-911. doi: 10.1002/gcc.22085. Epub 2013 Aug 9.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [18] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [19] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.