Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY4HPWB)

• DOT Name: NHL repeat-containing protein 2 (NHLRC2)
• Gene Name: NHLRC2
• Related Disease:
  Fibrosis, neurodegeneration, and cerebral angiomatosis
  Neural tube defect
  Alzheimer disease
  Colon cancer
  Colon carcinoma
  Fibrosis
• UniProt ID: NHLC2_HUMAN
• PDB ID: 6G7W; 6GC1
• Pfam ID: PF01436 ; PF13905
• Sequence:
  MAAPGGRGRSLSGLLPAQTSLEYALLDAVTQQEKDSLVYQYLQKVDGWEQDLSVPEFPEG
  LEWLNTEEPISVYKDLCGKIVVLDFFTYCCINCIHLLPDLHALEHTYSDKDGLLIIGVHS
  AKFPNEKVLDNIKSAVLRYNITHPMVNDADASLWQELEVSCWPTLVILGPRGNMLFSLIG
  EGHKDKLFLYTSIALKYYKDRGQIRDNKIGIKLYKDSLPPSPLLFPGKVTVDQVTDRLVI
  ADTGHHRILVVWKNGQIQYSIGGPNPGRKDGIFSESTFNSPQGVAIMNNIIYVADTENHL
  IRKIDLEAEKVSTVAGIGIQGTDKEGGAKGEQQPISSPWDVVFGTSGSEVQRGDILWIAM
  AGTHQIWALLLDSGKLPKKNELTKGTCLRFAGSGNEENRNNAYPHKAGFAQPSGLSLASE
  DPWSCLFVADSESSTVRTVSLKDGAVKHLVGGERDPMNLFAFGDVDGVGINAKLQHPLGV
  TWDKKRNLLYVADSYNHKIKVVDPKTKNCTTLAGTGDTNNVTSSSFTESTFNEPGGLCIG
  ENGELLYVADTNNHQIKVMDLETKMVSVLPIFRSENAVVDGPFLVEKQKTLPKLPKSAPS
  IRLSPVTACAGQTLQFKLRLDLPSGSKLTEGVSSCWFLTAEGNEWLLQGQIAAGDIENIS
  SQPTISLQIPDDCLSLEAIVSVSVFLYYCSADSSACMMKAILFSQPLQITDTQQGCIAPV
  ELRYVF
• Function: Required for normal embryonic development.
• Tissue Specificity: Ubiquitous. Detected in heart, kidney, muscle, brain, lung, liver and in skin fibroblasts (at protein level).
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrosis, neurodegeneration, and cerebral angiomatosis	DIS9YQSP	Definitive	Autosomal recessive	[1]
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Fibrosis	DIS6FM27	Limited	Genetic Variation	[5]

15 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 NHL repeat-containing protein 2 (NHLRC2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NHL repeat-containing protein 2 (NHLRC2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of NHL repeat-containing protein 2 (NHLRC2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[13]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of NHL repeat-containing protein 2 (NHLRC2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of NHL repeat-containing protein 2 (NHLRC2).	[19]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of NHL repeat-containing protein 2 (NHLRC2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NHL repeat-containing protein 2 (NHLRC2).	[18]

References

• [1] Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome. J Hum Genet. 2020 Oct;65(10):911-915. doi: 10.1038/s10038-020-0776-0. Epub 2020 May 21.
• [2] Notomelia and related neural tube defects in a baby born in Niger: case report and literature review.Childs Nerv Syst. 2017 Mar;33(3):529-534. doi: 10.1007/s00381-017-3337-x. Epub 2017 Jan 12.
• [3] Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens.Nat Genet. 2018 Dec;50(12):1716-1727. doi: 10.1038/s41588-018-0254-1. Epub 2018 Nov 5.
• [4] ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line.Cell Death Dis. 2017 Dec 14;8(12):3218. doi: 10.1038/s41419-017-0006-7.
• [5] NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.Acta Neuropathol. 2018 May;135(5):727-742. doi: 10.1007/s00401-018-1817-z. Epub 2018 Feb 8.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [15] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.