Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJCX8K9)

• DOT Name: Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1)
• Synonyms: Mitotic arrest deficient 1-like protein 1; MAD1-like protein 1; Mitotic checkpoint MAD1 protein homolog; HsMAD1; hMAD1; Tax-binding protein 181
• Gene Name: MAD1L1
• Related Disease:
  Familial prostate carcinoma
  Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition
• UniProt ID: MD1L1_HUMAN
• PDB ID: 1GO4; 4DZO; 7B1F; 7B1H; 7B1J
• Pfam ID: PF05557
• Sequence:
  MEDLGENTMVLSTLRSLNNFISQRVEGGSGLDISTSAPGSLQMQYQQSMQLEERAEQIRS
  KSHLIQVEREKMQMELSHKRARVELERAASTSARNYEREVDRNQELLTRIRQLQEREAGA
  EEKMQEQLERNRQCQQNLDAASKRLREKEDSLAQAGETINALKGRISELQWSVMDQEMRV
  KRLESEKQELQEQLDLQHKKCQEANQKIQELQASQEARADHEQQIKDLEQKLSLQEQDAA
  IVKNMKSELVRLPRLERELKQLREESAHLREMRETNGLLQEELEGLQRKLGRQEKMQETL
  VGLELENERLLAKLQSWERLDQTMGLSIRTPEDLSRFVVELQQRELALKDKNSAVTSSAR
  GLEKARQQLQEELRQVSGQLLEERKKRETHEALARRLQKRVLLLTKERDGMRAILGSYDS
  ELTPAEYSPQLTRRMREAEDMVQKVHSHSAEMEAQLSQALEELGGQKQRADMLEMELKML
  KSQSSSAEQSFLFSREEADTLRLKVEELEGERSRLEEEKRMLEAQLERRALQGDYDQSRT
  KVLHMSLNPTSVARQRLREDHSQLQAECERLRGLLRAMERGGTVPADLEAAAASLPSSKE
  VAELKKQVESAELKNQRLKEVFQTKIQEFRKACYTLTGYQIDITTENQYRLTSLYAEHPG
  DCLIFKATSPSGSKMQLLETEFSHTVGELIEVHLRRQDSIPAFLSSLTLELFSRQTVA
• Function: Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. Forms a heterotetrameric complex with the closed conformation form of MAD2L1 (C-MAD2) at unattached kinetochores during prometaphase, recruits an open conformation of MAD2L1 (O-MAD2) and promotes the conversion of O-MAD2 to C-MAD2, which ensures mitotic checkpoint signaling ; [Isoform 3]: Sequesters MAD2L1 in the cytoplasm preventing its function as an activator of the mitotic spindle assembly checkpoint (SAC) resulting in SAC impairment and chromosomal instability in hepatocellular carcinomas.
• Tissue Specificity: .Expressed in hepatocellular carcinomas and hepatoma cell lines (at protein level).; [Isoform 3]: Expressed in hepatocellular carcinomas and hepatoma cell lines (at protein level).
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial prostate carcinoma	DISL9KNO	Limited	Unknown	[1]
Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition	DIS6ZW20	Limited	Autosomal recessive	[2]

5 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 Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[14]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[20]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Mitotic spindle assembly checkpoint protein MAD1 (MAD1L1).	[21]

References

• [1] Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Sci Adv. 2022 Nov 4;8(44):eabq5914. doi: 10.1126/sciadv.abq5914. Epub 2022 Nov 2.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [9] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] 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] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [14] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [15] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [16] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.