Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7VGO6G)

• DOT Name: Ankyrin repeat domain-containing protein 9 (ANKRD9)
• Gene Name: ANKRD9
• Related Disease:
  Advanced cancer
  Gastric cancer
  Juvenile idiopathic arthritis
  Neoplasm
  Stomach cancer
• UniProt ID: ANKR9_HUMAN
• Sequence:
  MPWDARRPGGGADGGPEASGAARSRAQKQCRKSSFAFYQAVRDLLPVWLLEDMRASEAFH
  WDERGRAAAYSPSEALLYALVHDHQAYAHYLLATFPRRALAPPSAGFRCCAAPGPHVALA
  VRYNRVGILRRILRTLRDFPAEERARVLDRRGCSRVEGGGTSLHVACELARPECLFLLLG
  HGASPGLRDGGGLTPLELLLRQLGRDAGATPSAAGAPASAPGEPRQRRLLLLDLLALYTP
  VGAAGSARQELLGDRPRWQRLLGEDKFQWLAGLAPPSLFARAMQVLVTAISPGRFPEALD
  ELPLPPFLQPLDLTGKG
• Function: Substrate receptor subunit of a cullin-RING superfamily E3 ligase complex (CUL5-based E3 ubiquitin ligase complex) which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Depending of the metabolic state of the cell, promotes the proteasomal degradation of IMPDH2, the rate-limiting enzyme in GTP biosynthesis or protects IMPDH2 by stabilizing IMPDH2 filaments assembly. Implicated in different cellular processes, like copper homeostasis and cell proliferation.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[1]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[1]

2 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 Ankyrin repeat domain-containing protein 9 (ANKRD9).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[10]

9 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 Ankyrin repeat domain-containing protein 9 (ANKRD9).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ankyrin repeat domain-containing protein 9 (ANKRD9).	[13]

References

• [1] ANKRD9 is associated with tumor suppression as a substrate receptor subunit of ubiquitin ligase.Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3145-3153. doi: 10.1016/j.bbadis.2018.07.001. Epub 2018 Jul 3.
• [2] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] 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.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.