Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9RA64U)

• DOT Name: PAK4-inhibitor INKA2 (INKA2)
• Synonyms: Induced in neural crest by AP2-alpha protein-related homolog; Inca-r; Inka-box actin regulator 2
• Gene Name: INKA2
• Related Disease:
  Advanced cancer
  Crohn disease
• UniProt ID: INKA2_HUMAN
• Pfam ID: PF15342
• Sequence:
  MTMESREMDCYLRRLKQELMSMKEVGDGLQDQMNCMMGALQELKLLQVQTALEQLEISGG
  GPVPGSPEGPRTQCEHPCWEGGRGPARPTVCSPSSQPSLGSSTKFPSHRSVCGRDLAPLP
  RTQPHQSCAQQGPERVEPDDWTSTLMSRGRNRQPLVLGDNVFADLVGNWLDLPELEKGGE
  KGETGGAREPKGEKGQPQELGRRFALTANIFKKFLRSVRPDRDRLLKEKPGWVTPMVPES
  RTGRSQKVKKRSLSKGSGHFPFPGTGEHRRGENPPTSCPKALEHSPSGFDINTAVWV
• Function: Inhibitor of the serine/threonine-protein kinase PAK4. Acts by binding PAK4 in a substrate-like manner, inhibiting the protein kinase activity.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PAK4-inhibitor INKA2 (INKA2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PAK4-inhibitor INKA2 (INKA2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of PAK4-inhibitor INKA2 (INKA2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of PAK4-inhibitor INKA2 (INKA2).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of PAK4-inhibitor INKA2 (INKA2).	[8]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of PAK4-inhibitor INKA2 (INKA2).	[9]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of PAK4-inhibitor INKA2 (INKA2).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of PAK4-inhibitor INKA2 (INKA2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of PAK4-inhibitor INKA2 (INKA2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of PAK4-inhibitor INKA2 (INKA2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PAK4-inhibitor INKA2 (INKA2).	[6]

References

• [1] INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4.Int J Oncol. 2019 Jun;54(6):1907-1920. doi: 10.3892/ijo.2019.4786. Epub 2019 Apr 15.
• [2] A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals.J Crohns Colitis. 2019 Apr 26;13(5):648-658. doi: 10.1093/ecco-jcc/jjy197.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [6] 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.
• [7] 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.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.