Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX1DKRA)

• DOT Name: Pancreas/duodenum homeobox protein 1 (PDX1)
• Synonyms: PDX-1; Glucose-sensitive factor; GSF; Insulin promoter factor 1; IPF-1; Insulin upstream factor 1; IUF-1; Islet/duodenum homeobox-1; IDX-1; Somatostatin-transactivating factor 1; STF-1
• Gene Name: PDX1
• Related Disease:
  Maturity-onset diabetes of the young type 4
  Pancreatic agenesis 1
  Permanent neonatal diabetes mellitus
  Monogenic diabetes
  Maturity-onset diabetes of the young
  Pancreatic agenesis
• UniProt ID: PDX1_HUMAN
• PDB ID: 6F8F; 7KPK
• Pfam ID: PF00046
• Sequence:
  MNGEEQYYAATQLYKDPCAFQRGPAPEFSASPPACLYMGRQPPPPPPHPFPGALGALEQG
  SPPDISPYEVPPLADDPAVAHLHHHLPAQLALPHPPAGPFPEGAEPGVLEEPNRVQLPFP
  WMKSTKAHAWKGQWAGGAYAAEPEENKRTRTAYTRAQLLELEKEFLFNKYISRPRRVELA
  VMLNLTERHIKIWFQNRRMKWKKEEDKKRGGGTAVGGGGVAEPEQDCAVTSGEELLALPP
  PPPPGGAVPPAAPVAAREGRLPPGLSASPQPSSVAPRRPQEPR
• Function: Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. As part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Binds preferentially the DNA motif 5'-[CT]TAAT[TG]-3'. During development, specifies the early pancreatic epithelium, permitting its proliferation, branching and subsequent differentiation. At adult stage, required for maintaining the hormone-producing phenotype of the beta-cell.
• Tissue Specificity: Duodenum and pancreas (Langerhans islet beta cells and small subsets of endocrine non-beta-cells, at low levels in acinar cells).
• KEGG Pathway:
  Insulin secretion (hsa04911)
  Type II diabetes mellitus (hsa04930)
  Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Regulation of gene expression in early pancreatic precursor cells (R-HSA-210747)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maturity-onset diabetes of the young type 4	DISN46VD	Definitive	Autosomal dominant	[1]
Pancreatic agenesis 1	DISMAF1O	Definitive	Autosomal recessive	[2]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal recessive	[3]
Monogenic diabetes	DISEB8Q0	Moderate	Autosomal dominant	[2]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[4]
Pancreatic agenesis	DISTVEYC	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Pancreas/duodenum homeobox protein 1 (PDX1).	[6]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Amiloride	DMRTSGP	Approved	Amiloride decreases the uptake of Pancreas/duodenum homeobox protein 1 (PDX1).	[7]
D-glucose	DMMG2TO	Investigative	D-glucose affects the localization of Pancreas/duodenum homeobox protein 1 (PDX1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Pancreas/duodenum homeobox protein 1 (PDX1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Pancreas/duodenum homeobox protein 1 (PDX1).	[9]
Harmine	DMPA5WD	Patented	Harmine increases the expression of Pancreas/duodenum homeobox protein 1 (PDX1).	[10]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the expression of Pancreas/duodenum homeobox protein 1 (PDX1).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [5] Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997 Jan;15(1):106-10. doi: 10.1038/ng0197-106.
• [6] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
• [7] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
• [8] Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism. J Biol Chem. 2011 Feb 25;286(8):6049-60. doi: 10.1074/jbc.M110.176842. Epub 2010 Dec 16.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015 Apr;21(4):383-8. doi: 10.1038/nm.3820. Epub 2015 Mar 9.
• [11] PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets. Biochem Biophys Res Commun. 2008 Feb 22;366(4):1096-101. doi: 10.1016/j.bbrc.2007.12.088. Epub 2007 Dec 26.
• [12] Phosphorylation-dependent nucleocytoplasmic shuttling of pancreatic duodenal homeobox-1. Diabetes. 2001 Oct;50(10):2244-52. doi: 10.2337/diabetes.50.10.2244.