Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWMQ67T)

• DOT Name: Nuclear protein AMMECR1 (AMMECR1)
• Synonyms: AMME syndrome candidate gene 1 protein
• Gene Name: AMMECR1
• Related Disease:
  Alport syndrome
  Hereditary elliptocytosis
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis
  Nephrocalcinosis
  Non-small-cell lung cancer
  Anemia
  Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome
• UniProt ID: AMMR1_HUMAN
• Pfam ID: PF01871
• Sequence:
  MAAGCCGVKKQKLSSSPPSGSGGGGGASSSSHCSGESQCRAGELGLGGAGTRLNGLGGLT
  GGGSGSGCTLSPPQGCGGGGGGIALSPPPSCGVGTLLSTPAAATSSSPSSSSAASSSSPG
  SRKMVVSAEMCCFCFDVLYCHLYGYQQPRTPRFTNEPYPLFVTWKIGRDKRLRGCIGTFS
  AMNLHSGLREYTLTSALKDSRFPPMTRDELPRLFCSVSLLTNFEDVCDYLDWEVGVHGIR
  IEFINEKGSKRTATYLPEVAKEQGWDHIQTIDSLLRKGGYKAPITNEFRKTIKLTRYRSE
  KMTLSYAEYLAHRQHHHFQNGIGHPLPPYNHYS

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alport syndrome	DIS25AB4	Strong	Biomarker	[1]
Hereditary elliptocytosis	DISA71F4	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis	DISUHMAR	Strong	X-linked	[3]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Anemia	DISTVL0C	moderate	Genetic Variation	[4]
Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome	DIS8ORO3	Supportive	X-linked	[3]

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 Nuclear protein AMMECR1 (AMMECR1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nuclear protein AMMECR1 (AMMECR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear protein AMMECR1 (AMMECR1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear protein AMMECR1 (AMMECR1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Nuclear protein AMMECR1 (AMMECR1).	[13]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Nuclear protein AMMECR1 (AMMECR1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nuclear protein AMMECR1 (AMMECR1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Nuclear protein AMMECR1 (AMMECR1).	[20]

References

• [1] Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis.Am J Med Genet A. 2019 Apr;179(4):650-654. doi: 10.1002/ajmg.a.61057. Epub 2019 Feb 8.
• [2] AMMECR1 Inhibits Apoptosis and Promotes Cell-cycle Progression and Proliferation of the A549 Human Lung Cancer Cell Line.Anticancer Res. 2019 Sep;39(9):4637-4642. doi: 10.21873/anticanres.13644.
• [3] AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. J Med Genet. 2017 Apr;54(4):269-277. doi: 10.1136/jmedgenet-2016-104100. Epub 2016 Nov 3.
• [4] X-linked elliptocytosis with impaired growth is related to mutated AMMECR1.Gene. 2017 Mar 30;606:47-52. doi: 10.1016/j.gene.2017.01.001. Epub 2017 Jan 9.
• [5] 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.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [14] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [15] 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.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.