Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0WH38E)

• DOT Name: Guanine nucleotide exchange factor C9orf72 (C9ORF72)
• Gene Name: C9ORF72
• Related Disease:
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
  Progressive myoclonus epilepsy
• UniProt ID: CI072_HUMAN
• PDB ID: 6LT0; 6V4U; 7MGE; 7O2W
• Pfam ID: PF15019
• Sequence:
  MSTLCPPPSPAVAKTEIALSGKSPLLAATFAYWDNILGPRVRHIWAPKTEQVLLSDGEIT
  FLANHTLNGEILRNAESGAIDVKFFVLSEKGVIIVSLIFDGNWNGDRSTYGLSIILPQTE
  LSFYLPLHRVCVDRLTHIIRKGRIWMHKERQENVQKIILEGTERMEDQGQSIIPMLTGEV
  IPVMELLSSMKSHSVPEEIDIADTVLNDDDIGDSCHEGFLLNAISSHLQTCGCSVVVGSS
  AEKVNKIVRTLCLFLTPAERKCSRLCEAESSFKYESGLFVQGLLKDSTGSFVLPFRQVMY
  APYPTTHIDVDVNTVKQMPPCHEHIYNQRRYMRSELTAFWRATSEEDMAQDTIIYTDESF
  TPDLNIFQDVLHRDTLVKAFLDQVFQLKPGLSLRSTFLAQFLLVLHRKALTLIKYIEDDT
  QKGKKPFKSLRNLKIDLDLTAEGDLNIIMALAEKIKPGLHSFIFGRPFYTSVQERDVLMT
  F
• Function: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy. In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity. As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro. Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes. Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism. Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus. Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity; [Isoform 1]: Regulates stress granule assembly in response to cellular stress; [Isoform 2]: Does not play a role in regulation of stress granule assembly in response to cellular stress.
• Tissue Specificity: Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level).
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1	DIS8SB8X	Definitive	Autosomal dominant	[1]
Progressive myoclonus epilepsy	DISAMCNS	Limited	Autosomal dominant	[2]

1 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 Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[3]

14 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 Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Guanine nucleotide exchange factor C9orf72 (C9ORF72).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [15] 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.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.