Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD5QPCI)

• DOT Name: Notch homolog 2 N-terminal-like protein A (NOTCH2NLA)
• Synonyms: Notch homolog 2 N-terminal-like protein
• Gene Name: NOTCH2NLA
• Related Disease:
  Autism
  Isolated congenital microcephaly
  Leukopenia
  Megalencephaly
  Schizophrenia
• UniProt ID: NT2NA_HUMAN
• Pfam ID: PF00008 ; PF07645
• Sequence:
  MCVTYHNGTGYCKCPEGFLGEYCQHRDPCEKNRCQNGGTCVAQAMLGKATCRCASGFTGE
  DCQYSTSHPCFVSRPCLNGGTCHMLSRDTYECTCQVGFTGKECQWTDACLSHPCANGSTC
  TTVANQFSCKCLTGFTGQKCETDVNECDIPGHCQHGGTCLNLPGSYQCQCLQGFTGQYCD
  SLYVPCAPSPCVNGGTCRQTGDFTFECNCLPETVRRGTELWERDREVWNGKEHDEN
• Function: Human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway. Able to promote neural progenitor self-renewal, possibly by down-regulating neuronal differentiation genes, thereby delaying the differentiation of neuronal progenitors and leading to an overall final increase in neuronal production. Acts by enhancing the Notch signaling pathway via two different mechanisms that probably work in parallel to reach the same effect. Enhances Notch signaling pathway in a non-cell-autonomous manner via direct interaction with NOTCH2. Also promotes Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions, which promotes neuronal differentiation.
• Tissue Specificity: Widely expressed with higher levels in leukocytes and lymph nodes . Expressed in radial glia neural stem cells during cortical development .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Genetic Variation	[1]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[1]
Leukopenia	DISJMBMM	Strong	Biomarker	[2]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Notch homolog 2 N-terminal-like protein A (NOTCH2NLA) affects the response to substance of Temozolomide.	[11]
DTI-015	DMXZRW0	Approved	Notch homolog 2 N-terminal-like protein A (NOTCH2NLA) affects the response to substance of DTI-015.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Notch homolog 2 N-terminal-like protein A (NOTCH2NLA).	[10]

References

• [1] Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.Cell. 2018 May 31;173(6):1356-1369.e22. doi: 10.1016/j.cell.2018.03.051. Epub 2018 May 31.
• [2] A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Mol Cell Biol. 2004 Jan;24(1):58-70. doi: 10.1128/MCB.24.1.58-70.2004.
• [3] 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.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] 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.
• [6] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [7] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [8] 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.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.