Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25GBJM)

• DOT Name: Armadillo-like helical domain-containing protein 4 (ARMH4)
• Synonyms: Upstream of mTORC2 protein
• Gene Name: ARMH4
• Related Disease:
  Plasma cell myeloma
  Venous thromboembolism
• UniProt ID: ARMD4_HUMAN
• Pfam ID: PF15767
• Sequence:
  MRGPIVLHICLAFCSLLLFSVATQCLAFPKIERRREIAHVHAEKGQSDKMNTDDLENSSV
  TSKQTPQLVVSEDPMMMSAVPSATSLNKAFSINKETQPGQAGLMQTERPGVSTPTESGVP
  SAEEVFGSSQPERISPESGLAKAMLTIAITATPSLTVDEKEELLTSTNFQPIVEEITETT
  KGFLKYMDNQSFATESQEGVGLGHSPSSYVNTKEMLTTNPKTEKFEADTDHRTTSFPGAE
  STAGSEPGSLTPDKEKPSQMTADNTQAAATKQPLETSEYTLSVEPETDSLLGAPEVTVSV
  STAVPAASALSDEWDDTKLESVSRIRTPKLGDNEETQVRTEMSQTAQVSHEGMEGGQPWT
  EAAQVALGLPEGETHTGTALLIAHGNERSPAFTDQSSFTPTSLMEDMKVSIVNLLQSTGD
  FTESTKENDALFFLETTVSVSVYESEADQLLGNTMKDIITQEMTTAVQEPDATLSMVTQE
  QVATLELIRDSGKTEEEKEDPSPVSDVPGVTQLSRRWEPLATTISTTVVPLSFEVTPTVE
  EQMDTVTGPNEEFTPVLGSPVTPPGIMVGEPSISPALPALEASSERRTVVPSITRVNTAA
  SYGLDQLESEEGQEDEDEEDEEDEDEEEEDEEEDEEDKDADSLDEGLDGDTELPGFTLPG
  ITSQEPGLEEGNMDLLEGATYQVPDALEWEQQNQGLVRSWMEKLKDKAGYMSGMLVPVGV
  GIAGALFILGALYSIKVMNRRRRNGFKRHKRKQREFNSMQDRVMLLADSSEDEF
• Function: May modulate immune response and may play a role in inflammation. Down-modulates STAT3 signaling throught direct interaction with IL6ST, resulting in the inhibition of phosphorylation of STAT3 at 'Tyr-705'. May negatively regulates AKT signaling by modulating the activity of mTORC2 complex through RICTOR interaction.
• Tissue Specificity: Expressed in podocytes.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[1]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Armadillo-like helical domain-containing protein 4 (ARMH4).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Armadillo-like helical domain-containing protein 4 (ARMH4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Armadillo-like helical domain-containing protein 4 (ARMH4).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Armadillo-like helical domain-containing protein 4 (ARMH4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[6]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Armadillo-like helical domain-containing protein 4 (ARMH4).	[14]

References

• [1] Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy.J Clin Invest. 2016 Apr 1;126(4):1300-10. doi: 10.1172/JCI84620. Epub 2016 Feb 29.
• [2] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [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] 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.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] 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.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] 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.
• [14] 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.