Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQX7ATF)

• DOT Name: RNA-binding protein FXR2 (FXR2)
• Synonyms: FXR2P; FMR1 autosomal homolog 2
• Gene Name: FXR2
• Related Disease:
  Acute megakaryoblastic leukemia
  Childhood acute megakaryoblastic leukemia
  Fragile X syndrome
  Intellectual disability
• UniProt ID: FXR2_HUMAN
• PDB ID: 3H8Z
• Pfam ID: PF05641 ; PF12235 ; PF16096 ; PF00013 ; PF17904 ; PF18336
• Sequence:
  MGGLASGGDVEPGLPVEVRGSNGAFYKGFVKDVHEDSVTIFFENNWQSERQIPFGDVRLP
  PPADYNKEITEGDEVEVYSRANEQEPCGWWLARVRMMKGDFYVIEYAACDATYNEIVTLE
  RLRPVNPNPLATKGSFFKVTMAVPEDLREACSNENVHKEFKKALGANCIFLNITNSELFI
  LSTTEAPVKRASLLGDMHFRSLRTKLLLMSRNEEATKHLETSKQLAAAFQEEFTVREDLM
  GLAIGTHGANIQQARKVPGVTAIELGEETCTFRIYGETPEACRQARSYLEFSEDSVQVPR
  NLVGKVIGKNGKVIQEIVDKSGVVRVRVEGDNDKKNPREEGMVPFIFVGTRENISNAQAL
  LEYHLSYLQEVEQLRLERLQIDEQLRQIGLGFRPPGSGRGSGGSDKAGYSTDESSSSSLH
  ATRTYGGSYGGRGRGRRTGGPAYGPSSDVSTASETESEKREEPNRAGPGDRDPPTRGEES
  RRRPTGGRGRGPPPAPRPTSRYNSSSISSVLKDPDSNPYSLLDTSEPEPPVDSEPGEPPP
  ASARRRRSRRRRTDEDRTVMDGGLESDGPNMTENGLEDESRPQRRNRSRRRRNRGNRTDG
  SISGDRQPVTVADYISRAESQSRQRPPLERTKPSEDSLSGQKGDSVSKLPKGPSENGELS
  APLELGSMVNGVS
• Function: mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for adult hippocampal neurogenesis. Specifically binds to AU-rich elements (AREs) in the 3'-UTR of target mRNAs. Promotes formation of some phase-separated membraneless compartment by undergoing liquid-liquid phase separation upon binding to AREs-containing mRNAs: mRNAs storage into membraneless compartments regulates their translation and/or stability. Acts as a regulator of adult hippocampal neurogenesis by regulating translation and/or stability of NOG mRNA, thereby preventing NOG protein expression in the dentate gyrus.
• Tissue Specificity: Expressed in all tissues examined including heart, brain, kidney and testis . In brain, present at high level in neurons and especially in the Purkinje cells at the interface between the granular layer and the molecular layer (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Altered Expression	[1]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Altered Expression	[1]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Altered Expression	[1]

4 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 RNA-binding protein FXR2 (FXR2).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RNA-binding protein FXR2 (FXR2).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RNA-binding protein FXR2 (FXR2).	[12]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of RNA-binding protein FXR2 (FXR2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RNA-binding protein FXR2 (FXR2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein FXR2 (FXR2).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of RNA-binding protein FXR2 (FXR2).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of RNA-binding protein FXR2 (FXR2).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of RNA-binding protein FXR2 (FXR2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA-binding protein FXR2 (FXR2).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RNA-binding protein FXR2 (FXR2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RNA-binding protein FXR2 (FXR2).	[11]

References

• [1] Cloning and characterization of the novel chimeric gene p53/FXR2 in the acute megakaryoblastic leukemia cell line CMK11-5.Tohoku J Exp Med. 2006 Jul;209(3):169-80. doi: 10.1620/tjem.209.169.
• [2] Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice.Brain Sci. 2019 Jan 16;9(1):13. doi: 10.3390/brainsci9010013.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [8] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [12] 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.
• [13] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.