Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6FQ1K3)

• DOT Name: Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)
• Synonyms: EC 2.7.11.1; Hematopoietic progenitor kinase; MAPK/ERK kinase kinase kinase 1; MEK kinase kinase 1; MEKKK 1
• Gene Name: MAP4K1
• UniProt ID: M4K1_HUMAN
• PDB ID: 6CQD; 6CQE; 6CQF; 6NFY; 6NFZ; 6NG0; 7KAC; 7L24; 7L25; 7L26; 7M0K; 7M0L; 7M0M; 7R9L; 7R9N; 7R9P; 7R9T; 7SIU; 8CDW; 8CIJ; 8FH4; 8FJZ; 8FKO
• EC Number: 2.7.11.1
• Pfam ID: PF00780 ; PF00069
• Sequence:
  MDVVDPDIFNRDPRDHYDLLQRLGGGTYGEVFKARDKVSGDLVALKMVKMEPDDDVSTLQ
  KEILILKTCRHANIVAYHGSYLWLQKLWICMEFCGAGSLQDIYQVTGSLSELQISYVCRE
  VLQGLAYLHSQKKIHRDIKGANILINDAGEVRLADFGISAQIGATLARRLSFIGTPYWMA
  PEVAAVALKGGYNELCDIWSLGITAIELAELQPPLFDVHPLRVLFLMTKSGYQPPRLKEK
  GKWSAAFHNFIKVTLTKSPKKRPSATKMLSHQLVSQPGLNRGLILDLLDKLKNPGKGPSI
  GDIEDEEPELPPAIPRRIRSTHRSSSLGIPDADCCRRHMEFRKLRGMETRPPANTARLQP
  PRDLRSSSPRKQLSESSDDDYDDVDIPTPAEDTPPPLPPKPKFRSPSDEGPGSMGDDGQL
  SPGVLVRCASGPPPNSPRPGPPPSTSSPHLTAHSEPSLWNPPSRELDKPPLLPPKKEKMK
  RKGCALLVKLFNGCPLRIHSTAAWTHPSTKDQHLLLGAEEGIFILNRNDQEATLEMLFPS
  RTTWVYSINNVLMSLSGKTPHLYSHSILGLLERKETRAGNPIAHISPHRLLARKNMVSTK
  IQDTKGCRACCVAEGASSGGPFLCGALETSVVLLQWYQPMNKFLLVRQVLFPLPTPLSVF
  ALLTGPGSELPAVCIGVSPGRPGKSVLFHTVRFGALSCWLGEMSTEHRGPVQVTQVEEDM
  VMVLMDGSVKLVTPEGSPVRGLRTPEIPMTEAVEAVAMVGGQLQAFWKHGVQVWALGSDQ
  LLQELRDPTLTFRLLGSPRLECSGTISPHCNLLLPGSSNSPASASRVAGITGL
• Function: Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate. Together with CLNK, it enhances CD3-triggered activation of T-cells and subsequent IL2 production.
• Tissue Specificity: Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[8]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[2]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[6]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[10]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[5]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide decreases the expression of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1).	[11]

References

• [1] 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.
• [2] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [3] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [6] 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.
• [7] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [10] 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.
• [11] Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.
• [12] Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study. Environ Health. 2014 Nov 13;13:94. doi: 10.1186/1476-069X-13-94.