Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTLHL64)

• DOT Name: ALK and LTK ligand 2 (ALKAL2)
• Synonyms: Augmentor alpha; AUG-alpha
• Gene Name: ALKAL2
• Related Disease:
  Epithelial ovarian cancer
  Neoplasm
  Neuroblastoma
• UniProt ID: ALKL2_HUMAN
• PDB ID: 7LS0; 7MZX; 7N00; 7NWZ
• Pfam ID: PF15129
• Sequence:
  MRGPGHPLLLGLLLVLGAAGRGRGGAEPREPADGQALLRLVVELVQELRKHHSAEHKGLQ
  LLGRDCALGRAEAAGLGPSPEQRVEIVPRDLRMKDKFLKHLTGPLYFSPKCSKHFHRLYH
  NTRDCTIPAYYKRCARLLTRLAVSPVCMEDKQ
• Function: Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation. Cytokine-binding is sufficient to activate LTK. In contrast, ALKAL2-driven activation of ALK is coupled with heparin-binding to ALK. Stimulation of ALK signaling is involved in neural development and regulation of energy expenditure.
• Tissue Specificity: Widely expressed with highest levels in adrenal gland and modest levels in pancreas, testis and uterus.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ALK and LTK ligand 2 (ALKAL2).	[3]

10 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 ALK and LTK ligand 2 (ALKAL2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ALK and LTK ligand 2 (ALKAL2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ALK and LTK ligand 2 (ALKAL2).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of ALK and LTK ligand 2 (ALKAL2).	[7]
Malathion	DMXZ84M	Approved	Malathion increases the expression of ALK and LTK ligand 2 (ALKAL2).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of ALK and LTK ligand 2 (ALKAL2).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of ALK and LTK ligand 2 (ALKAL2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ALK and LTK ligand 2 (ALKAL2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ALK and LTK ligand 2 (ALKAL2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ALK and LTK ligand 2 (ALKAL2).	[11]

References

• [1] Genome-wide bioinformatics analysis reveals CTCFL is upregulated in high-grade epithelial ovarian cancer.Oncol Lett. 2019 Oct;18(4):4030-4039. doi: 10.3892/ol.2019.10736. Epub 2019 Aug 8.
• [2] Analysis of ALK, MYCN, and the ALK ligand ALKAL2 (FAM150B/AUG) in neuroblastoma patient samples with chromosome arm 2p rearrangements.Genes Chromosomes Cancer. 2020 Jan;59(1):50-57. doi: 10.1002/gcc.22790. Epub 2019 Sep 2.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] 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.
• [8] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [9] 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.
• [10] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [11] 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.