Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEYFN5O)

• DOT Name: Microtubule-associated serine/threonine-protein kinase 1 (MAST1)
• Synonyms: EC 2.7.11.1; Syntrophin-associated serine/threonine-protein kinase
• Gene Name: MAST1
• Related Disease:
  Intellectual disability
  Neoplasm
  Advanced cancer
  Autism
  Breast carcinoma
  Isolated congenital microcephaly
  Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations
  Megalencephaly
  Hereditary breast carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: MAST1_HUMAN
• PDB ID: 2M9X; 3PS4
• EC Number: 2.7.11.1
• Pfam ID: PF08926 ; PF17820 ; PF00069
• Sequence:
  MSDSLWTALSNFSMPSFPGGSMFRRTKSCRTSNRKSLILTSTSPTLPRPHSPLPGHLGSS
  PLDSPRNFSPNTPAHFSFASSRRADGRRWSLASLPSSGYGTNTPSSTVSSSCSSQERLHQ
  LPYQPTVDELHFLSKHFGSTESITDEDGGRRSPAVRPRSRSLSPGRSPSSYDNEIVMMNH
  VYKERFPKATAQMEEKLRDFTRAYEPDSVLPLADGVLSFIHHQIIELARDCLTKSRDGLI
  TTVYFYELQENLEKLLQDAYERSESLEVAFVTQLVKKLLIIISRPARLLECLEFNPEEFY
  HLLEAAEGHAKEGHLVKTDIPRYIIRQLGLTRDPFPDVVHLEEQDSGGSNTPEQDDLSEG
  RSSKAKKPPGENDFDTIKLISNGAYGAVYLVRHRDTRQRFAMKKINKQNLILRNQIQQAF
  VERDILTFAENPFVVGMFCSFETRRHLCMVMEYVEGGDCATLLKNIGALPVEMARMYFAE
  TVLALEYLHNYGIVHRDLKPDNLLITSMGHIKLTDFGLSKMGLMSLTTNLYEGHIEKDAR
  EFLDKQVCGTPEYIAPEVILRQGYGKPVDWWAMGIILYEFLVGCVPFFGDTPEELFGQVI
  SDDILWPEGDEALPTEAQLLISSLLQTNPLVRLGAGGAFEVKQHSFFRDLDWTGLLRQKA
  EFIPHLESEDDTSYFDTRSDRYHHVNSYDEDDTTEEEPVEIRQFSSCSPRFSKVYSSMEQ
  LSQHEPKTPVAAAGSSKREPSTKGPEEKVAGKREGLGGLTLREKTWRGGSPEIKRFSASE
  ASFLEGEASPPLGARRRFSALLEPSRFSAPQEDEDEARLRRPPRPSSDPAGSLDARAPKE
  ETQGEGTSSAGDSEATDRPRPGDLCPPSKDGDASGPRATNDLVLRRARHQQMSGDVAVEK
  RPSRTGGKVIKSASATALSVMIPAVDPHGSSPLASPMSPRSLSSNPSSRDSSPSRDYSPA
  VSGLRSPITIQRSGKKYGFTLRAIRVYMGDTDVYSVHHIVWHVEEGGPAQEAGLCAGDLI
  THVNGEPVHGMVHPEVVELILKSGNKVAVTTTPFENTSIRIGPARRSSYKAKMARRNKRP
  SAKEGQESKKRSSLFRKITKQSNLLHTSRSLSSLNRSLSSSDSLPGSPTHGLPARSPTHS
  YRSTPDSAYLGASSQSSSPASSTPNSPASSASHHIRPSTLHGLSPKLHRQYRSARCKSAG
  NIPLSPLAHTPSPTQASPPPLPGHTVGSSHTTQSFPAKLHSSPPVVRPRPKSAEPPRSPL
  LKRVQSAEKLGASLSADKKGALRKHSLEVGHPDFRKDFHGELALHSLAESDGETPPVEGL
  GAPRQVAVRRLGRQESPLSLGADPLLPEGASRPPVSSKEKESPGGAEACTPPRATTPGGR
  TLERDVGCTRHQSVQTEDGTGGMARAVAKAALSPVQEHETGRRSSSGEAGTPLVPIVVEP
  ARPGAKAVVPQPLGADSKGLQEPAPLAPSVPEAPRGRERWVLEVVEERTTLSGPRSKPAS
  PKLSPEPQTPSLAPAKCSAPSSAVTPVPPASLLGSGTKPQVGLTSRCPAEAVPPAGLTKK
  GVSSPAPPGP
• Function: Microtubule-associated protein essential for correct brain development. Appears to link the dystrophin/utrophin network with microtubule filaments via the syntrophins. Phosphorylation of DMD or UTRN may modulate their affinities for associated proteins.
• Tissue Specificity: Expressed in fetal brain.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations	DISKA7UB	Strong	Autosomal dominant	[4]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[4]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[6]
Lung cancer	DISCM4YA	moderate	Biomarker	[7]
Lung carcinoma	DISTR26C	moderate	Biomarker	[7]

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 Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[11]

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 Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Microtubule-associated serine/threonine-protein kinase 1 (MAST1).	[16]

References

• [1] Evaluating the Role of MAST1 as an Intellectual Disability Disease Gene: Identification of a Novel De Novo Variant in a Patient with Developmental Disabilities.J Mol Neurosci. 2020 Mar;70(3):320-327. doi: 10.1007/s12031-019-01415-8.
• [2] Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation.J Clin Invest. 2019 Oct 1;129(10):4110-4123. doi: 10.1172/JCI125963.
• [3] Pulling a MAST1 on Cisplatin Resistance.Cancer Cell. 2018 Aug 13;34(2):183-185. doi: 10.1016/j.ccell.2018.07.010.
• [4] Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. Neuron. 2018 Dec 19;100(6):1354-1368.e5. doi: 10.1016/j.neuron.2018.10.044. Epub 2018 Nov 15.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.Int J Cancer. 2019 Apr 15;144(8):1962-1974. doi: 10.1002/ijc.31921. Epub 2018 Nov 13.
• [7] Germline mutations causing familial lung cancer.J Hum Genet. 2015 Oct;60(10):597-603. doi: 10.1038/jhg.2015.75. Epub 2015 Jul 16.
• [8] 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.
• [9] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] 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.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.