Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZVARA5)

• DOT Name: ALX homeobox protein 1 (ALX1)
• Synonyms: Cartilage homeoprotein 1; CART-1
• Gene Name: ALX1
• Related Disease:
  Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome
  Breast cancer
  Breast carcinoma
  Cervical carcinoma
  Chondrosarcoma
  Craniofrontonasal syndrome
  Craniosynostosis
  Frontonasal dysplasia
  Melanoma
  Neoplasm
  Neural tube defect
  Bone osteosarcoma
  Metastatic malignant neoplasm
  Microphthalmia
  Osteosarcoma
• UniProt ID: ALX1_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MEFLSEKFALKSPPSKNSDFYMGAGGPLEHVMETLDNESFYSKASAGKCVQAFGPLPRAE
  HHVRLERTSPCQDSSVNYGITKVEGQPLHTELNRAMDNCNSLRMSPVKGMQEKGELDELG
  DKCDSNVSSSKKRRHRTTFTSLQLEELEKVFQKTHYPDVYVREQLALRTELTEARVQVWF
  QNRRAKWRKRERYGQIQQAKSHFAATYDISVLPRTDSYPQIQNNLWAGNASGGSVVTSCM
  LPRDTSSCMTPYSHSPRTDSSYTGFSNHQNQFSHVPLNNFFTDSLLTGATNGHAFETKPE
  FERRSSSIAVLRMKAKEHTANISWAM
• Function: Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes. Most probably regulates the expression of genes involved in the development of mesenchyme-derived craniofacial structures. Early on in development, it plays a role in forebrain mesenchyme survival. May also induce epithelial to mesenchymal transition (EMT) through the expression of SNAI1.
• Tissue Specificity: Cartilage and cervix tissue.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome	DISH4NN3	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[3]
Craniofrontonasal syndrome	DISSO9WK	Strong	Biomarker	[4]
Craniosynostosis	DIS6J405	Strong	Biomarker	[4]
Frontonasal dysplasia	DISXV4YX	Strong	Genetic Variation	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neural tube defect	DIS5J95E	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[8]
Microphthalmia	DISGEBES	moderate	Biomarker	[9]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ALX homeobox protein 1 (ALX1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ALX homeobox protein 1 (ALX1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ALX homeobox protein 1 (ALX1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of ALX homeobox protein 1 (ALX1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of ALX homeobox protein 1 (ALX1).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of ALX homeobox protein 1 (ALX1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of ALX homeobox protein 1 (ALX1).	[17]

2 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 affects the methylation of ALX homeobox protein 1 (ALX1).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ALX homeobox protein 1 (ALX1).	[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] Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer.Cancer Res. 1996 Sep 1;56(17):3886-90.
• [3] Human Cart-1: structural organization, chromosomal localization, and functional analysis of a cartilage-specific homeodomain cDNA.DNA Cell Biol. 1996 Jul;15(7):531-41. doi: 10.1089/dna.1996.15.531.
• [4] 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.
• [5] Exome sequencing revealed a novel splice site variant in the ALX1 gene underlying frontonasal dysplasia. Clin Genet. 2017 Mar;91(3):494-498. doi: 10.1111/cge.12822. Epub 2016 Jul 12.
• [6] Knockdown of aristaless-like homeobox1 inhibits epithelial-mesenchymal transition through Wnt/-catenin signaling pathway in melanoma cells.Biochem Biophys Res Commun. 2019 Mar 26;511(1):105-110. doi: 10.1016/j.bbrc.2019.02.050. Epub 2019 Feb 14.
• [7] Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study.BMC Med Genet. 2010 Oct 8;11:141. doi: 10.1186/1471-2350-11-141.
• [8] Depletion of ALX1 causes inhibition of migration and induction of apoptosis in human osteosarcoma.Tumour Biol. 2015 Aug;36(8):5965-70. doi: 10.1007/s13277-015-3271-z. Epub 2015 Mar 4.
• [9] Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet. 2010 May 14;86(5):789-96. doi: 10.1016/j.ajhg.2010.04.002. Epub 2010 May 6.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.