Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8QKMT)

• DOT Name: Zinc finger protein 423
• Synonyms: Olf1/EBF-associated zinc finger protein; hOAZ; Smad- and Olf-interacting zinc finger protein
• Gene Name: ZNF423
• Related Disease:
  Joubert syndrome 17
  Nephronophthisis 14
  Joubert syndrome with oculorenal defect
  Nephronophthisis 2
  Nephronophthisis
• UniProt ID: ZN423_HUMAN
• PDB ID: 2MDG
• Pfam ID: PF00096 ; PF13912
• Sequence:
  MHKKRVEEGEASDFSLAWDSSVTAAGGLEGEPECDQKTSRALEDRNSVTSQEERNEDDED
  MEDESIYTCDHCQQDFESLADLTDHRAHRCPGDGDDDPQLSWVASSPSSKDVASPTQMIG
  DGCDLGLGEEEGGTGLPYPCQFCDKSFIRLSYLKRHEQIHSDKLPFKCTYCSRLFKHKRS
  RDRHIKLHTGDKKYHCHECEAAFSRSDHLKIHLKTHSSSKPFKCTVCKRGFSSTSSLQSH
  MQAHKKNKEHLAKSEKEAKKDDFMCDYCEDTFSQTEELEKHVLTRHPQLSEKADLQCIHC
  PEVFVDENTLLAHIHQAHANQKHKCPMCPEQFSSVEGVYCHLDSHRQPDSSNHSVSPDPV
  LGSVASMSSATPDSSASVERGSTPDSTLKPLRGQKKMRDDGQGWTKVVYSCPYCSKRDFN
  SLAVLEIHLKTIHADKPQQSHTCQICLDSMPTLYNLNEHVRKLHKNHAYPVMQFGNISAF
  HCNYCPEMFADINSLQEHIRVSHCGPNANPSDGNNAFFCNQCSMGFLTESSLTEHIQQAH
  CSVGSAKLESPVVQPTQSFMEVYSCPYCTNSPIFGSILKLTKHIKENHKNIPLAHSKKSK
  AEQSPVSSDVEVSSPKRQRLSASANSISNGEYPCNQCDLKFSNFESFQTHLKLHLELLLR
  KQACPQCKEDFDSQESLLQHLTVHYMTTSTHYVCESCDKQFSSVDDLQKHLLDMHTFVLY
  HCTLCQEVFDSKVSIQVHLAVKHSNEKKMYRCTACNWDFRKEADLQVHVKHSHLGNPAKA
  HKCIFCGETFSTEVELQCHITTHSKKYNCKFCSKAFHAIILLEKHLREKHCVFDAATENG
  TANGVPPMATKKAEPADLQGMLLKNPEAPNSHEASEDDVDASEPMYGCDICGAAYTMEVL
  LQNHRLRDHNIRPGEDDGSRKKAEFIKGSHKCNVCSRTFFSENGLREHLQTHRGPAKHYM
  CPICGERFPSLLTLTEHKVTHSKSLDTGTCRICKMPLQSEEEFIEHCQMHPDLRNSLTGF
  RCVVCMQTVTSTLELKIHGTFHMQKLAGSSAASSPNGQGLQKLYKCALCLKEFRSKQDLV
  KLDVNGLPYGLCAGCMARSANGQVGGLAPPEPADRPCAGLRCPECSVKFESAEDLESHMQ
  VDHRDLTPETSGPRKGTQTSPVPRKKTYQCIKCQMTFENEREIQIHVANHMIEEGINHEC
  KLCNQMFDSPAKLLCHLIEHSFEGMGGTFKCPVCFTVFVQANKLQQHIFAVHGQEDKIYD
  CSQCPQKFFFQTELQNHTMSQHAQ
• Function: Transcription factor that can both act as an activator or a repressor depending on the context. Plays a central role in BMP signaling and olfactory neurogenesis. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved in terminal olfactory receptor neurons differentiation; this interaction preventing EBF1 to bind DNA and activate olfactory-specific genes. Involved in olfactory neurogenesis by participating in a developmental switch that regulates the transition from differentiation to maturation in olfactory receptor neurons. Controls proliferation and differentiation of neural precursors in cerebellar vermis formation.
• Tissue Specificity: Expressed in brain, lung, skeletal muscle, heart, pancreas and kidney but not liver or placenta. Also expressed in aorta, ovary, pituitary, small intestine, fetal brain, fetal kidney and, within the adult brain, in the substantia nigra, medulla, amygdala, thalamus and cerebellum.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome 17	DIS9LHZ1	Strong	Autosomal dominant	[1]
Nephronophthisis 14	DIS4W4EA	Strong	Autosomal recessive	[2]
Joubert syndrome with oculorenal defect	DISU0IPO	Supportive	Autosomal recessive	[1]
Nephronophthisis 2	DIS5Y5KV	Supportive	Autosomal recessive	[1]
Nephronophthisis	DISXU4HY	Limited	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Zinc finger protein 423.	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Zinc finger protein 423.	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Zinc finger protein 423.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Zinc finger protein 423.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein 423.	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Zinc finger protein 423.	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Zinc finger protein 423.	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Zinc finger protein 423.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Zinc finger protein 423.	[10]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Zinc finger protein 423.	[13]

References

• [1] Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012 Aug 3;150(3):533-48. doi: 10.1016/j.cell.2012.06.028.
• [2] Zfp423 controls proliferation and differentiation of neural precursors in cerebellar vermis formation. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19424-9. doi: 10.1073/pnas.0609184103. Epub 2006 Dec 6.
• [3] 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.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] 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.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] 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.
• [10] Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in?neuroblastoma. Surgery. 2015 Sep;158(3):819-26. doi: 10.1016/j.surg.2015.04.017. Epub 2015 Jun 9.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.