Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXZ25PZ)

• DOT Name: Homeobox protein aristaless-like 3 (ALX3)
• Synonyms: Proline-rich transcription factor ALX3
• Gene Name: ALX3
• Related Disease:
  Dysautonomia
  Frontorhiny
  Bifid nose
  Breast cancer
  Breast carcinoma
  Cerebral cavernous malformation
  Colon cancer
  Colon carcinoma
  Congenital nervous system disorder
  Craniosynostosis
  Dysplasia
  Estrogen-receptor positive breast cancer
  Isolated cleft palate
  Neoplasm
  Triple negative breast cancer
  Craniofrontonasal syndrome
  Neuroblastoma
  Coloboma
  Colorectal carcinoma
  Frontonasal dysplasia
  Hyperglycemia
  Neural tube defect
• UniProt ID: ALX3_HUMAN
• Pfam ID: PF00046
• Sequence:
  MDPEHCAPFRVGPAPGPYVASGDEPPGPQGTPAAAPHLHPAPPRGPRLTRFPACGPLEPY
  LPEPAKPPAKYLQDLGPGPALNGGHFYEGPAEAEEKTSKAASFPQLPLDCRGGPRDGPSN
  LQGSPGPCLASLHLPLSPGLPDSMELAKNKSKKRRNRTTFSTFQLEELEKVFQKTHYPDV
  YAREQLALRTDLTEARVQVWFQNRRAKWRKRERYGKIQEGRNPFTAAYDISVLPRTDSHP
  QLQNSLWASPGSGSPGGPCLVSPEGIPSPCMSPYSHPHGSVAGFMGVPAPSAAHPGIYSI
  HGFPPTLGGHSFEPSSDGDYKSPSLVSLRVKPKEPPGLLNWTT
• Function: Transcriptional regulator with a possible role in patterning of mesoderm during development.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dysautonomia	DISF4MT6	Definitive	Biomarker	[1]
Frontorhiny	DISYMQMD	Definitive	Autosomal recessive	[2]
Bifid nose	DISOZ09B	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cerebral cavernous malformation	DISLKNYA	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Congenital nervous system disorder	DIS2BIP8	Strong	Biomarker	[6]
Craniosynostosis	DIS6J405	Strong	Biomarker	[3]
Dysplasia	DISHPNVX	Strong	Biomarker	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[4]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Craniofrontonasal syndrome	DISSO9WK	moderate	Biomarker	[3]
Neuroblastoma	DISVZBI4	moderate	Posttranslational Modification	[9]
Coloboma	DISP39N5	Limited	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[11]
Frontonasal dysplasia	DISXV4YX	Limited	Genetic Variation	[12]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[13]
Neural tube defect	DIS5J95E	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein aristaless-like 3 (ALX3).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homeobox protein aristaless-like 3 (ALX3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein aristaless-like 3 (ALX3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein aristaless-like 3 (ALX3).	[17]

References

• [1] Processing of Emotion in Functional Neurological Disorder.Front Psychiatry. 2018 Oct 5;9:479. doi: 10.3389/fpsyt.2018.00479. eCollection 2018.
• [2] 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.
• [3] Potocki-Shaffer deletion encompassing ALX4 in a patient with frontonasal dysplasia phenotype.Am J Med Genet A. 2014 Feb;164A(2):346-52. doi: 10.1002/ajmg.a.36140. Epub 2013 Dec 13.
• [4] Induction of AMPK activation by N,N'-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers.PLoS One. 2019 Mar 15;14(3):e0209392. doi: 10.1371/journal.pone.0209392. eCollection 2019.
• [5] Stereotactic radiosurgery for cerebral cavernous malformations: A systematic review.Neurology. 2019 Nov 19;93(21):e1971-e1979. doi: 10.1212/WNL.0000000000008521. Epub 2019 Oct 28.
• [6] Frontonasal dysplasia, severe neuropsychological delay, and midline central nervous system anomalies: report of 10 Brazilian male patients.Am J Med Genet A. 2009 May;149A(5):1006-11. doi: 10.1002/ajmg.a.32717.
• [7] Frontonasal dysostosis in two successive generations.Am J Med Genet. 1999 Nov 26;87(3):251-3. doi: 10.1002/(sici)1096-8628(19991126)87:3<251::aid-ajmg10>3.0.co;2-g.
• [8] Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.PLoS One. 2009;4(4):e5385. doi: 10.1371/journal.pone.0005385. Epub 2009 Apr 29.
• [9] Combined restriction landmark genomic scanning and virtual genome scans identify a novel human homeobox gene, ALX3, that is hypermethylated in neuroblastoma.Genes Chromosomes Cancer. 2002 Mar;33(3):285-94. doi: 10.1002/gcc.10030.
• [10] Midline facial defects with ocular colobomata.Am J Med Genet. 1990 Sep;37(1):23-7. doi: 10.1002/ajmg.1320370107.
• [11] Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning.Endocr Relat Cancer. 2011 Jul 4;18(4):465-78. doi: 10.1530/ERC-11-0083. Print 2011 Aug.
• [12] Exome sequencing revealed a novel nonsense variant in ALX3 gene underlying frontorhiny.J Hum Genet. 2018 Jan;63(1):97-100. doi: 10.1038/s10038-017-0358-y. Epub 2017 Nov 16.
• [13] Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy.Sci Rep. 2017 Mar 24;7(1):389. doi: 10.1038/s41598-017-00334-1.
• [14] 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.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.