Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP7KL47)

• DOT Name: Serine/threonine-protein kinase MARK1 (MARK1)
• Synonyms: EC 2.7.11.1; EC 2.7.11.26; MAP/microtubule affinity-regulating kinase 1; PAR1 homolog c; Par-1c; Par1c
• Gene Name: MARK1
• Related Disease:
  Rheumatoid arthritis
  Acute myelogenous leukaemia
  Autism
  Autism spectrum disorder
  Colorectal carcinoma
  Hemorrhoids
  Mental disorder
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Schizophrenia
  Advanced cancer
  Alcohol dependence
  Attention deficit hyperactivity disorder
  Autoimmune disease
  Melanoma
  Parkinson disease
  Alzheimer disease
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: MARK1_HUMAN
• PDB ID: 2HAK; 3OSE; 6C9D
• EC Number: 2.7.11.1; 2.7.11.26
• Pfam ID: PF02149 ; PF00069 ; PF00627
• Sequence:
  MSARTPLPTVNERDTENHTSVDGYTEPHIQPTKSSSRQNIPRCRNSITSATDEQPHIGNY
  RLQKTIGKGNFAKVKLARHVLTGREVAVKIIDKTQLNPTSLQKLFREVRIMKILNHPNIV
  KLFEVIETEKTLYLVMEYASGGEVFDYLVAHGRMKEKEARAKFRQIVSAVQYCHQKYIVH
  RDLKAENLLLDGDMNIKIADFGFSNEFTVGNKLDTFCGSPPYAAPELFQGKKYDGPEVDV
  WSLGVILYTLVSGSLPFDGQNLKELRERVLRGKYRIPFYMSTDCENLLKKLLVLNPIKRG
  SLEQIMKDRWMNVGHEEEELKPYTEPDPDFNDTKRIDIMVTMGFARDEINDALINQKYDE
  VMATYILLGRKPPEFEGGESLSSGNLCQRSRPSSDLNNSTLQSPAHLKVQRSISANQKQR
  RFSDHAGPSIPPAVSYTKRPQANSVESEQKEEWDKDVARKLGSTTVGSKSEMTASPLVGP
  ERKKSSTIPSNNVYSGGSMARRNTYVCERTTDRYVALQNGKDSSLTEMSVSSISSAGSSV
  ASAVPSARPRHQKSMSTSGHPIKVTLPTIKDGSEAYRPGTTQRVPAASPSAHSISTATPD
  RTRFPRGSSSRSTFHGEQLRERRSVAYNGPPASPSHETGAFAHARRGTSTGIISKITSKF
  VRRDPSEGEASGRTDTSRSTSGEPKERDKEEGKDSKPRSLRFTWSMKTTSSMDPNDMMRE
  IRKVLDANNCDYEQKERFLLFCVHGDARQDSLVQWEMEVCKLPRLSLNGVRFKRISGTSI
  AFKNIASKIANELKL
• Function: Serine/threonine-protein kinase. Involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3).
• Tissue Specificity: Highly expressed in heart, skeletal muscle, brain, fetal brain and fetal kidney.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Hemorrhoids	DISQ5G6G	Strong	Biomarker	[6]
Mental disorder	DIS3J5R8	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Altered Expression	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[5]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Genetic Variation	[3]
Autoimmune disease	DISORMTM	moderate	Biomarker	[11]
Melanoma	DIS1RRCY	moderate	Biomarker	[12]
Parkinson disease	DISQVHKL	Disputed	Biomarker	[13]
Alzheimer disease	DISF8S70	Limited	Biomarker	[14]
Gastric cancer	DISXGOUK	Limited	Biomarker	[15]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[15]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[15]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[16]

2 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 Serine/threonine-protein kinase MARK1 (MARK1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serine/threonine-protein kinase MARK1 (MARK1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein kinase MARK1 (MARK1).	[25]

References

• [1] CCR5 silencing reduces inflammatory response, inhibits viability, and promotes apoptosis of synovial cells in rat models of rheumatoid arthritis through the MAPK signaling pathway.J Cell Physiol. 2019 Aug;234(10):18748-18762. doi: 10.1002/jcp.28514. Epub 2019 May 7.
• [2] MEF2C Phosphorylation Is Required forChemotherapy Resistance in Acute Myeloid Leukemia.Cancer Discov. 2018 Apr;8(4):478-497. doi: 10.1158/2159-8290.CD-17-1271. Epub 2018 Feb 5.
• [3] Primate-accelerated evolutionary genes: novel routes to drug discovery in psychiatric disorders.Curr Med Chem. 2010;17(13):1300-16. doi: 10.2174/092986710790936338.
• [4] Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism.Hum Mol Genet. 2008 Aug 15;17(16):2541-51. doi: 10.1093/hmg/ddn154. Epub 2008 May 20.
• [5] MicroRNA-23a promotes colorectal cancer cell migration and proliferation by targeting at MARK1.Acta Biochim Biophys Sin (Shanghai). 2019 Jul 10;51(7):661-668. doi: 10.1093/abbs/gmz047.
• [6] Correction: Altered mental status and an acid-base disturbance.Cleve Clin J Med. 2017 Mar;84(3):214.
• [7] Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy.Dev Neurosci. 2013;35(4):306-16. doi: 10.1159/000350716. Epub 2013 Jun 8.
• [8] Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics.Sci Rep. 2017 Jan 3;7:39498. doi: 10.1038/srep39498.
• [9] Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFB signaling pathway in gastric cancer cells.J Biomed Sci. 2014 Jun 14;21(1):59. doi: 10.1186/1423-0127-21-59.
• [10] Fragile early visual percepts mark genetic liability specific to schizophrenia.Schizophr Bull. 2013 Jul;39(4):839-47. doi: 10.1093/schbul/sbs041. Epub 2012 Mar 23.
• [11] On the mark: genetically engineered immunotherapies for autoimmunity.Curr Opin Immunol. 2019 Dec;61:69-73. doi: 10.1016/j.coi.2019.08.005. Epub 2019 Sep 26.
• [12] MDA-9/syntenin is essential for factor VIIa-induced signaling, migration, and metastasis in melanoma cells.J Biol Chem. 2015 Feb 6;290(6):3333-48. doi: 10.1074/jbc.M114.606913. Epub 2014 Dec 10.
• [13] Unbiased Proteomics of Early Lewy Body Formation Model Implicates Active Microtubule Affinity-Regulating Kinases (MARKs) in Synucleinopathies.J Neurosci. 2017 Jun 14;37(24):5870-5884. doi: 10.1523/JNEUROSCI.2705-16.2017. Epub 2017 May 18.
• [14] Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain.Structure. 2018 Aug 7;26(8):1137-1143.e3. doi: 10.1016/j.str.2018.05.008. Epub 2018 Jun 28.
• [15] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [16] Increased CYP24A1 expression is associated with BRAF(V600E) mutation and advanced stages in papillary thyroid carcinoma.Clin Endocrinol (Oxf). 2014 Jul;81(1):109-16. doi: 10.1111/cen.12396. Epub 2014 Jan 21.
• [17] 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.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] 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.
• [24] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [25] 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.