Details of Drug Off-Target (DOT)

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

• DOT Name: Paired box protein Pax-5 (PAX5)
• Synonyms: B-cell-specific transcription factor; BSAP
• Gene Name: PAX5
• Related Disease:
  Leukemia, acute lymphoblastic, susceptibility to, 3
  PAX5-related B lymphopenia and autism spectrum disorder
• UniProt ID: PAX5_HUMAN
• PDB ID: 1K78; 1MDM
• Pfam ID: PF00292 ; PF12403
• Sequence:
  MDLEKNYPTPRTSRTGHGGVNQLGGVFVNGRPLPDVVRQRIVELAHQGVRPCDISRQLRV
  SHGCVSKILGRYYETGSIKPGVIGGSKPKVATPKVVEKIAEYKRQNPTMFAWEIRDRLLA
  ERVCDNDTVPSVSSINRIIRTKVQQPPNQPVPASSHSIVSTGSVTQVSSVSTDSAGSSYS
  ISGILGITSPSADTNKRKRDEGIQESPVPNGHSLPGRDFLRKQMRGDLFTQQQLEVLDRV
  FERQHYSDIFTTTEPIKPEQTTEYSAMASLAGGLDDMKANLASPTPADIGSSVPGPQSYP
  IVTGRDLASTTLPGYPPHVPPAGQGSYSAPTLTGMVPGSEFSGSPYSHPQYSSYNDSWRF
  PNPGLLGSPYYYSAAARGAAPPAAATAYDRH
• Function: Transcription factor that plays an essential role in commitment of lymphoid progenitors to the B-lymphocyte lineage. Fulfills a dual role by repressing B-lineage inappropriate genes and simultaneously activating B-lineage-specific genes. In turn, regulates cell adhesion and migration, induces V(H)-to-D(H)J(H) recombination, facilitates pre-B-cell receptor signaling and promotes development to the mature B-cell stage. Repression of the cohesin-release factor WAPL causes global changes of the chromosomal architecture in pro-B cells to facilitate the generation of a diverse antibody repertoire ; (Microbial infection) Plays an essential role in the maintenance of Epstein-Barr virus genome copy number within the host cell by promoting EBNA1/oriP-dependent binding and transcription. Participates also in the inhibition of lytic EBV reactivation by modulating viral BZLF1 activity.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway: RUNX1 regulates transcription of genes involved in BCR signaling (R-HSA-8939245)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukemia, acute lymphoblastic, susceptibility to, 3	DIS87ANI	Moderate	Autosomal dominant	[1]
PAX5-related B lymphopenia and autism spectrum disorder	DISLUBYN	Moderate	Autosomal recessive	[2]

12 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 Paired box protein Pax-5 (PAX5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Paired box protein Pax-5 (PAX5).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Paired box protein Pax-5 (PAX5).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Paired box protein Pax-5 (PAX5).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Paired box protein Pax-5 (PAX5).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Paired box protein Pax-5 (PAX5).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Paired box protein Pax-5 (PAX5).	[9]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of Paired box protein Pax-5 (PAX5).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Paired box protein Pax-5 (PAX5).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Paired box protein Pax-5 (PAX5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Paired box protein Pax-5 (PAX5).	[14]
GW7604	DMCA4RM	Investigative	GW7604 increases the expression of Paired box protein Pax-5 (PAX5).	[7]

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 Paired box protein Pax-5 (PAX5).	[12]

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] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] 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.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res. 2002 Aug 1;62(15):4419-26.
• [8] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [11] 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.
• [12] 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.
• [13] Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013 Dec 9;24(6):777-90. doi: 10.1016/j.ccr.2013.11.003.
• [14] 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.