Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT93MVIC)

• DOT Name: Serine/threonine-protein kinase LMTK2 (LMTK2)
• Synonyms: EC 2.7.11.1; Apoptosis-associated tyrosine kinase 2; Brain-enriched kinase; hBREK; CDK5/p35-regulated kinase; CPRK; Kinase/phosphatase/inhibitor 2; Lemur tyrosine kinase 2; Serine/threonine-protein kinase KPI-2
• Gene Name: LMTK2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Azoospermia
  Cerebral infarction
  Cystic fibrosis
  Hepatocellular carcinoma
  Lafora disease
  Lewy body dementia
  Nasopharyngeal carcinoma
  Neoplasm
  Prostate carcinoma
  Prostate neoplasm
  Colon cancer
  Colon carcinoma
  Adenocarcinoma
  Castration-resistant prostate carcinoma
  Prostate cancer
• UniProt ID: LMTK2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF07714
• Sequence:
  MPGPPALRRRLLLLLLVLLIAGSAGAAPLPQTGAGEAPPAAEVSSSFVILCVCSLIILIV
  LIANCVSCCKDPEIDFKEFEDNFDDEIDFTPPAEDTPSVQSPAEVFTLSVPNISLPAPSQ
  FQPSVEGLKSQVARHSLNYIQEIGNGWFGKVLLGEIYTGTSVARVIVKELKASANPKEQD
  TFLKNGEPYYILQHPNILQCVGQCVEAIPYLLVFEFCDLGDLKAYLRSEQEHMRGDSQTM
  LLQRMACEVAAGLAAMHKLHFLHSDLALRNCFLTSDLNVKVGDYGIGFSRYKEDYIETDD
  KKVFPLRWTAPELVTSFQDRLLTADQTKYSNIWSLGVTLWELFDNAAQPYSNLSNLDVLN
  QVIRERDTKLPKPQLEQPYSDRWYEVLQFCWLSPEKRPAAEDVHRLLTYLRLQSQRDSEV
  DFEQQWNALKPNTNSRDSSNNAAFPILDHFARDRLGREMEEVLTVTETSQGLSFEYVWEA
  AKHDHFDERSRGHLDEGLSYTSIFYPVEVFESSLSDPGPGKQDDSGQDVPLRVPGVVPVF
  DAHNLSVGSDYYIQLEEKSGSNLELDYPPALLTTDMDNPERTGPELSQLTALRSVELEES
  STDEDFFQSSTDPKDSSLPGDLHVTSGPESPFNNIFNDVDKSEDLPSHQKIFDLMELNGV
  QADFKPATLSSSLDNPKESVITGHFEKEKPRKIFDSEPLCLSDNLMHQDNFDPLNVQELS
  ENFLFLQEKNLLKGSLSSKEHINDLQTELKNAGFTEAMLETSCRNSLDTELQFAENKPGL
  SLLQENVSTKGDDTDVMLTGDTLSTSLQSSPEVQVPPTSFETEETPRRVPPDSLPTQGET
  QPTCLDVIVPEDCLHQDISPDAVTVPVEILSTDARTHSLDNRSQDSPGESEETLRLTESD
  SVLADDILASRVSVGSSLPELGQELHNKPFSEDHHSHRRLEKNLEAVETLNQLNSKDAAK
  EAGLVSALSSDSTSQDSLLEDSLSAPFPASEPSLETPDSLESVDVHEALLDSLGSHTPQK
  LVPPDKPADSGYETENLESPEWTLHPAPEGTADSEPATTGDGGHSGLPPNPVIVISDAGD
  GHRGTEVTPETFTAGSQGSYRDSAYFSDNDSEPEKRSEEVPGTSPSALVLVQEQPLPEPV
  LPEQSPAAQDSCLEARKSQPDESCLSALHNSSDLELRATPEPAQTGVPQQVHPTEDEASS
  PWSVLNAELSSGDDFETQDDRPCTLASTGTNTNELLAYTNSALDKSLSSHSEGPKLKEPD
  IEGKYLGKLGVSGMLDLSEDGMDADEEDENSDDSDEDLRAFNLHSLSSESEDETEHPVPI
  ILSNEDGRHLRSLLKPTAANAPDPLPEDWKKEKKAVTFFDDVTVYLFDQETPTKELGPCG
  GEACGPDLSGPAPASGSPYLSRCINSESSTDEEGGGFEWDDDFSPDPFMSKTTSNLLSSK
  PSLQTSKYFSPPPPARSTEQSWPHSAPYSRFSISPANIASFSLTHLTDSDIEQGGSSEDG
  EKD
• Function: Phosphorylates PPP1C, phosphorylase b and CFTR.
• Tissue Specificity: Mainly expressed in skeletal muscle, and weakly in brain and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Azoospermia	DIS94181	Strong	Genetic Variation	[3]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Lafora disease	DIS83JHH	Strong	Biomarker	[2]
Lewy body dementia	DISAE66J	Strong	Biomarker	[2]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Colon cancer	DISVC52G	moderate	Biomarker	[10]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[10]
Adenocarcinoma	DIS3IHTY	Limited	Genetic Variation	[11]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[12]
Prostate cancer	DISF190Y	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Serine/threonine-protein kinase LMTK2 (LMTK2) affects the response to substance of Temozolomide.	[21]
DTI-015	DMXZRW0	Approved	Serine/threonine-protein kinase LMTK2 (LMTK2) affects the response to substance of DTI-015.	[21]

3 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 Serine/threonine-protein kinase LMTK2 (LMTK2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase LMTK2 (LMTK2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase LMTK2 (LMTK2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase LMTK2 (LMTK2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase LMTK2 (LMTK2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase LMTK2 (LMTK2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein kinase LMTK2 (LMTK2).	[20]

References

• [1] Unraveling the Function of Lemur Tyrosine Kinase 2 Network.Front Pharmacol. 2019 Jan 29;10:24. doi: 10.3389/fphar.2019.00024. eCollection 2019.
• [2] Neuropathological characterization of Lemur tyrosine kinase 2 (LMTK2) in Alzheimer's disease and neocortical Lewy body disease.Sci Rep. 2019 Nov 20;9(1):17222. doi: 10.1038/s41598-019-53638-9.
• [3] LMTK2 and PARP-2 gene polymorphism and azoospermia secondary to meiotic arrest.J Assist Reprod Genet. 2009 Sep-Oct;26(9-10):545-52. doi: 10.1007/s10815-009-9347-1. Epub 2009 Oct 6.
• [4] Overexpression of lemur tyrosine kinase-2 protects neurons from oxygen-glucose deprivation/reoxygenation-induced injury through reinforcement of Nrf2 signaling by modulating GSK-3 phosphorylation.Biochem Biophys Res Commun. 2020 Jan 22;521(4):964-970. doi: 10.1016/j.bbrc.2019.11.002. Epub 2019 Nov 10.
• [5] The LMTK-family of kinases: Emerging important players in cell physiology and pathogenesis.Biochim Biophys Acta Mol Basis Dis. 2021 Sep 1;1867(9):165372. doi: 10.1016/j.bbadis.2018.12.023. Epub 2018 Dec 29.
• [6] Silencing of lemur tyrosine kinase 2 restricts the proliferation and invasion of hepatocellular carcinoma through modulation of GSK-3/Wnt/-catenin signaling.Biochem Biophys Res Commun. 2019 Oct 1;517(4):722-728. doi: 10.1016/j.bbrc.2019.07.122. Epub 2019 Aug 5.
• [7] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [8] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [9] Multiple newly identified loci associated with prostate cancer susceptibility.Nat Genet. 2008 Mar;40(3):316-21. doi: 10.1038/ng.90. Epub 2008 Feb 10.
• [10] Lemur tyrosine kinase 2 acts as a positive regulator of NF-B activation and colon cancer cell proliferation.Cancer Lett. 2019 Jul 10;454:70-77. doi: 10.1016/j.canlet.2019.04.011. Epub 2019 Apr 10.
• [11] Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer.BMC Cancer. 2010 Jun 22;10:315. doi: 10.1186/1471-2407-10-315.
• [12] Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy.Oncotarget. 2015 Jun 10;6(16):14233-46. doi: 10.18632/oncotarget.3899.
• [13] Systematic meta-analyses of gene-specific genetic association studies in prostate cancer.Oncotarget. 2016 Apr 19;7(16):22271-84. doi: 10.18632/oncotarget.7926.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.