Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ7YKK5)

• DOT Name: Serine/threonine-protein kinase greatwall (MASTL)
• Synonyms: GW; GWL; hGWL; EC 2.7.11.1; Microtubule-associated serine/threonine-protein kinase-like; MAST-L
• Gene Name: MASTL
• Related Disease:
  Estrogen-receptor positive breast cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Gray platelet syndrome
  Hepatocellular carcinoma
  Non-small-cell lung cancer
  Thrombocytopenia
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Gastric cancer
  Liver cancer
  Stomach cancer
  Obsolete autosomal thrombocytopenia with normal platelets
  Neoplasm
  Neuroblastoma
  Thrombocytopenia 2
• UniProt ID: GWL_HUMAN
• PDB ID: 5LOH
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MDPTAGSKKEPGGGAATEEGVNRIAVPKPPSIEEFSIVKPISRGAFGKVYLGQKGGKLYA
  VKVVKKADMINKNMTHQVQAERDALALSKSPFIVHLYYSLQSANNVYLVMEYLIGGDVKS
  LLHIYGYFDEEMAVKYISEVALALDYLHRHGIIHRDLKPDNMLISNEGHIKLTDFGLSKV
  TLNRDINMMDILTTPSMAKPRQDYSRTPGQVLSLISSLGFNTPIAEKNQDPANILSACLS
  ETSQLSQGLVCPMSVDQKDTTPYSSKLLKSCLETVASNPGMPVKCLTSNLLQSRKRLATS
  SASSQSHTFISSVESECHSSPKWEKDCQESDEALGPTMMSWNAVEKLCAKSANAIETKGF
  NKKDLELALSPIHNSSALPTTGRSCVNLAKKCFSGEVSWEAVELDVNNINMDTDTSQLGF
  HQSNQWAVDSGGISEEHLGKRSLKRNFELVDSSPCKKIIQNKKTCVEYKHNEMTNCYTNQ
  NTGLTVEVQDLKLSVHKSQQNDCANKENIVNSFTDKQQTPEKLPIPMIAKNLMCELDEDC
  EKNSKRDYLSSSFLCSDDDRASKNISMNSDSSFPGISIMESPLESQPLDSDRSIKESSFE
  ESNIEDPLIVTPDCQEKTSPKGVENPAVQESNQKMLGPPLEVLKTLASKRNAVAFRSFNS
  HINASNNSEPSRMNMTSLDAMDISCAYSGSYPMAITPTQKRRSCMPHQQTPNQIKSGTPY
  RTPKSVRRGVAPVDDGRILGTPDYLAPELLLGRAHGPAVDWWALGVCLFEFLTGIPPFND
  ETPQQVFQNILKRDIPWPEGEEKLSDNAQSAVEILLTIDDTKRAGMKELKRHPLFSDVDW
  ENLQHQTMPFIPQPDDETDTSYFEARNTAQHLTVSGFSL
• Function: Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.
• Reactome Pathway: MASTL Facilitates Mitotic Progression (R-HSA-2465910)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Estrogen-receptor positive breast cancer	DIS1H502	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Gray platelet syndrome	DISLOTCW	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[7]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[8]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[8]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[9]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[10]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[11]
Liver cancer	DISDE4BI	moderate	Altered Expression	[10]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[11]
Obsolete autosomal thrombocytopenia with normal platelets	DISHFIE8	Supportive	Autosomal dominant	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Thrombocytopenia 2	DISBLVLV	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[22]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[23]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[25]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[28]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[32]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Serine/threonine-protein kinase greatwall (MASTL).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Serine/threonine-protein kinase greatwall (MASTL).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine/threonine-protein kinase greatwall (MASTL).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein kinase greatwall (MASTL).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein kinase greatwall (MASTL).	[29]

References

• [1] MASTL is a potential poor prognostic indicator in ER+ breast cancer.Eur Rev Med Pharmacol Sci. 2017 May;21(10):2413-2420.
• [2] Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer.Cell Death Differ. 2018 May;25(5):828-840. doi: 10.1038/s41418-017-0024-0. Epub 2017 Dec 11.
• [3] MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/-catenin signaling.Mol Cancer. 2018 Aug 1;17(1):111. doi: 10.1186/s12943-018-0848-3.
• [4] Thrombocytopenias due to gray platelet syndrome or THC2 mutations.Semin Thromb Hemost. 2011 Sep;37(6):690-7. doi: 10.1055/s-0031-1291379. Epub 2011 Nov 18.
• [5] Inflammatory cytokine-induced expression of MASTL is involved in hepatocarcinogenesis by regulating cell cycle progression.Oncol Lett. 2019 Mar;17(3):3163-3172. doi: 10.3892/ol.2019.9983. Epub 2019 Jan 29.
• [6] Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC.Mol Cancer Ther. 2015 Jun;14(6):1434-44. doi: 10.1158/1535-7163.MCT-14-0846. Epub 2015 Mar 25.
• [7] Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets.J Clin Invest. 2018 Dec 3;128(12):5351-5367. doi: 10.1172/JCI121876. Epub 2018 Oct 29.
• [8] Mitosis perturbation by MASTL depletion impairs the viability of thyroid tumor cells.Cancer Lett. 2019 Feb 1;442:362-372. doi: 10.1016/j.canlet.2018.11.010. Epub 2018 Nov 14.
• [9] The Oncogenic Functions of MASTL Kinase.Front Cell Dev Biol. 2018 Nov 23;6:162. doi: 10.3389/fcell.2018.00162. eCollection 2018.
• [10] ENSA expression correlates with attenuated tumor propagation in liver cancer.Biochem Biophys Res Commun. 2013 Dec 6;442(1-2):56-61. doi: 10.1016/j.bbrc.2013.10.165. Epub 2013 Nov 8.
• [11] Mastl overexpression is associated with epithelial to mesenchymal transition and predicts a poor clinical outcome in gastric cancer.Oncol Lett. 2017 Dec;14(6):7283-7287. doi: 10.3892/ol.2017.7155. Epub 2017 Oct 10.
• [12] FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003;55(1):66-70. doi: 10.1159/000071812.
• [13] Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma.Cancer Lett. 2016 Feb 1;371(1):79-89. doi: 10.1016/j.canlet.2015.11.025. Epub 2015 Nov 23.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [21] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [22] 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.
• [23] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [24] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [25] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [26] 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.
• [27] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [28] 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.
• [29] 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.
• [30] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [31] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.