Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVF5VZC)

• DOT Name: PHD finger protein 23 (PHF23)
• Synonyms: PDH-containing protein JUNE-1
• Gene Name: PHF23
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Leukemia
  Osteoarthritis
• UniProt ID: PHF23_HUMAN
• PDB ID: 6WXK
• Pfam ID: PF13831
• Sequence:
  MLEAMAEPSPEDPPPTLKPETQPPEKRRRTIEDFNKFCSFVLAYAGYIPPSKEESDWPAS
  GSSSPLRGESAADSDGWDSAPSDLRTIQTFVKKAKSSKRRAAQAGPTQPGPPRSTFSRLQ
  APDSATLLEKMKLKDSLFDLDGPKVASPLSPTSLTHTSRPPAALTPVPLSQGDLSHPPRK
  KDRKNRKLGPGAGAGFGVLRRPRPTPGDGEKRSRIKKSKKRKLKKAERGDRLPPPGPPQA
  PPSDTDSEEEEEEEEEEEEEEMATVVGGEAPVPVLPTPPEAPRPPATVHPEGVPPADSES
  KEVGSTETSQDGDASSSEGEMRVMDEDIMVESGDDSWDLITCYCRKPFAGRPMIECSLCG
  TWIHLSCAKIKKTNVPDFFYCQKCKELRPEARRLGGPPKSGEP
• Function: Acts as a negative regulator of autophagy, through promoting ubiquitination and degradation of LRSAM1, an E3 ubiquitin ligase that promotes autophagy in response to starvation or infecting bacteria.
• Tissue Specificity: Widely expressed in human tissues and various cell lines.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[2]
Leukemia	DISNAKFL	moderate	Biomarker	[3]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of PHD finger protein 23 (PHF23).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PHD finger protein 23 (PHF23).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of PHD finger protein 23 (PHF23).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PHD finger protein 23 (PHF23).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of PHD finger protein 23 (PHF23).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of PHD finger protein 23 (PHF23).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of PHD finger protein 23 (PHF23).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PHD finger protein 23 (PHF23).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of PHD finger protein 23 (PHF23).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PHD finger protein 23 (PHF23).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of PHD finger protein 23 (PHF23).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of PHD finger protein 23 (PHF23).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of PHD finger protein 23 (PHF23).	[14]

References

• [1] A cryptic translocation leading to NUP98-PHF23 fusion in AML.Best Pract Res Clin Haematol. 2016 Dec;29(4):320-323. doi: 10.1016/j.beha.2016.10.002. Epub 2016 Oct 18.
• [2] NUP98-PHF23 fusion is recurrent in acute myeloid leukemia and shares gene expression signature of leukemic stem cells.Leuk Res. 2016 Jun;45:1-7. doi: 10.1016/j.leukres.2016.03.006. Epub 2016 Mar 30.
• [3] NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function.Cancer Discov. 2014 May;4(5):564-77. doi: 10.1158/2159-8290.CD-13-0419. Epub 2014 Feb 17.
• [4] Plant homeodomain finger protein 23 inhibits autophagy and promotes apoptosis of chondrocytes in osteoarthritis.Chin Med J (Engl). 2019 Nov 5;132(21):2581-2587. doi: 10.1097/CM9.0000000000000402.
• [5] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.