Details of Drug Off-Target (DOT)

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

• DOT Name: Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5)
• Synonyms: EC 2.7.11.1; Kinase homologous to SPS1/STE20; KHS; MAPK/ERK kinase kinase kinase 5; MEK kinase kinase 5; MEKKK 5
• Gene Name: MAP4K5
• Related Disease:
  Adult T-cell leukemia/lymphoma
  Cardiac failure
  Congestive heart failure
  Non-insulin dependent diabetes
  Obesity
  Type-1/2 diabetes
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: M4K5_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00069
• Sequence:
  MEAPLRPAADILRRNPQQDYELVQRVGSGTYGDVYKARNVHTGELAAVKIIKLEPGDDFS
  LIQQEIFMVKECKHCNIVAYFGSYLSREKLWICMEYCGGGSLQDIYHVTGPLSELQIAYV
  CRETLQGLAYLHTKGKMHRDIKGANILLTDHGDVKLADFGVAAKITATIAKRKSFIGTPY
  WMAPEVAAVEKNGGYNQLCDIWAVGITAIELGELQPPMFDLHPMRALFLMSKSNFQPPKL
  KDKTKWSSTFHNFVKIALTKNPKKRPTAERLLTHTFVAQPGLSRALAVELLDKVNNPDNH
  AHYTEADDDDFEPHAIIRHTIRSTNRNARAERTASEINFDKLQFEPPLRKETEARDEMGL
  SSDPNFMLQWNPFVDGANTGKSTSKRAIPPPLPPKPRISSYPEDNFPDEEKASTIKHCPD
  SESRAPQILRRQSSPSCGPVAETSSIGNGDGISKLMSENTEGSAQAPQLPRKKDKRDFPK
  PAINGLPPTPKVLMGACFSKVFDGCPLKINCATSWIHPDTKDQYIIFGTEDGIYTLNLNE
  LHEATMEQLFPRKCTWLYVINNTLMSLSVGKTFQLYSHNLIALFEHAKKPGLAAHIQTHR
  FPDRILPRKFALTTKIPDTKGCHKCCIVRNPYTGHKYLCGALQSGIVLLQWYEPMQKFML
  IKHFDFPLPSPLNVFEMLVIPEQEYPMVCVAISKGTESNQVVQFETINLNSASSWFTEIG
  AGSQQLDSIHVTQLERDTVLVCLDKFVKIVNLQGKLKSSKKLASELSFDFRIESVVCLQD
  SVLAFWKHGMQGKSFKSDEVTQEISDETRVFRLLGSDRVVVLESRPTENPTAHSNLYILA
  GHENSY
• Function: May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway.
• Tissue Specificity: Ubiquitously expressed in all tissues examined, with high levels in the ovary, testis and prostate.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[3]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[4]
Pancreatic cancer	DISJC981	Limited	Biomarker	[4]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[4]

12 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 Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5).	[16]

References

• [1] SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.Blood. 2013 May 2;121(18):3640-9. doi: 10.1182/blood-2012-07-441022. Epub 2013 Mar 12.
• [2] Sex- and age-dependent human transcriptome variability: implications for chronic heart failure.Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2754-9. doi: 10.1073/pnas.0436564100. Epub 2003 Feb 24.
• [3] The -822G/A polymorphism in the promoter region of the MAP4K5 gene is associated with reduced risk of type 2 diabetes in Chinese Hans from Shanghai.J Hum Genet. 2006;51(7):605-10. doi: 10.1007/s10038-006-0402-9. Epub 2006 May 13.
• [4] Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer.PLoS One. 2016 Mar 29;11(3):e0152300. doi: 10.1371/journal.pone.0152300. eCollection 2016.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] 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.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [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] 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.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] 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.