Details of Drug Off-Target (DOT)

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

• DOT Name: Chordin-like protein 1 (CHRDL1)
• Synonyms: Neuralin-1; Neurogenesin-1; Ventroptin
• Gene Name: CHRDL1
• Related Disease:
  Isolated congenital megalocornea
  Alzheimer disease
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Classic Hodgkin lymphoma
  Cognitive impairment
  Lymphoproliferative syndrome
  Neoplasm
  Gastric cancer
  Kidney cancer
  Renal carcinoma
  Sensorineural hearing loss disorder
  Stomach cancer
  Epstein barr virus infection
  Megalocornea
  Membranous glomerulonephritis
• UniProt ID: CRDL1_HUMAN
• Pfam ID: PF19548 ; PF00093
• Sequence:
  MRKKWKMGGMKYIFSLLFFLLLEGGKTEQVKHSETYCMFQDKKYRVGERWHPYLEPYGLV
  YCVNCICSENGNVLCSRVRCPNVHCLSPVHIPHLCCPRCPDSLPPVNNKVTSKSCEYNGT
  TYQHGELFVAEGLFQNRQPNQCTQCSCSEGNVYCGLKTCPKLTCAFPVSVPDSCCRVCRG
  DGELSWEHSDGDIFRQPANREARHSYHRSHYDPPPSRQAGGLSRFPGARSHRGALMDSQQ
  ASGTIVQIVINNKHKHGQVCVSNGKTYSHGESWHPNLRAFGIVECVLCTCNVTKQECKKI
  HCPNRYPCKYPQKIDGKCCKVCPGKKAKELPGQSFDNKGYFCGEETMPVYESVFMEDGET
  TRKIALETERPPQVEVHVWTIRKGILQHFHIEKISKRMFEELPHFKLVTRTTLSQWKIFT
  EGEAQISQMCSSRVCRTELEDLVKVLYLERSEKGHC
• Function: Antagonizes the function of BMP4 by binding to it and preventing its interaction with receptors. Alters the fate commitment of neural stem cells from gliogenesis to neurogenesis. Contributes to neuronal differentiation of neural stem cells in the brain by preventing the adoption of a glial fate. May play a crucial role in dorsoventral axis formation. May play a role in embryonic bone formation. May also play an important role in regulating retinal angiogenesis through modulation of BMP4 actions in endothelial cells. Plays a role during anterior segment eye development.
• Tissue Specificity: Expressed in the developing cornea and in the eye anterior segment in addition to the retina. Differentially expressed in the fetal brain. There is high expression in cerebellum and neocortex. Expressed in retinal pericytes.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated congenital megalocornea	DIS5TEOS	Definitive	X-linked recessive	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[2]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[6]
Kidney cancer	DISBIPKM	moderate	Biomarker	[7]
Renal carcinoma	DISER9XT	moderate	Biomarker	[7]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[8]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[6]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[9]
Megalocornea	DISIMNF0	Limited	CausalMutation	[10]
Membranous glomerulonephritis	DISFSUKQ	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Chordin-like protein 1 (CHRDL1) affects the response to substance of Mitoxantrone.	[23]

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 Chordin-like protein 1 (CHRDL1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chordin-like protein 1 (CHRDL1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Chordin-like protein 1 (CHRDL1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Chordin-like protein 1 (CHRDL1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Chordin-like protein 1 (CHRDL1).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Chordin-like protein 1 (CHRDL1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Chordin-like protein 1 (CHRDL1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Chordin-like protein 1 (CHRDL1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chordin-like protein 1 (CHRDL1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Chordin-like protein 1 (CHRDL1).	[21]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Chordin-like protein 1 (CHRDL1).	[22]

References

• [1] X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am J Hum Genet. 2012 Feb 10;90(2):247-59. doi: 10.1016/j.ajhg.2011.12.019. Epub 2012 Jan 26.
• [2] Nicotine versus 6-hydroxy-l-nicotine against chlorisondamine induced memory impairment and oxidative stress in the rat hippocampus.Biomed Pharmacother. 2017 Feb;86:102-108. doi: 10.1016/j.biopha.2016.12.008. Epub 2016 Dec 9.
• [3] Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types.Cancer Sci. 2017 Jun;108(6):1271-1280. doi: 10.1111/cas.13249. Epub 2017 May 23.
• [4] Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion.Mol Cell Biol. 2016 May 2;36(10):1509-25. doi: 10.1128/MCB.00600-15. Print 2016 May 15.
• [5] Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells.Histopathology. 2018 Jun;72(7):1156-1163. doi: 10.1111/his.13475. Epub 2018 Mar 9.
• [6] Hypermethylation of the CHRDL1 promoter induces proliferation and metastasis by activating Akt and Erk in gastric cancer.Oncotarget. 2017 Apr 4;8(14):23155-23166. doi: 10.18632/oncotarget.15513.
• [7] De novo design of thioredoxin reductase-targeted heterometallic titanocene-gold compounds of chlorambucil for mechanistic insights into renal cancer.Chem Commun (Camb). 2019 Dec 19;56(2):297-300. doi: 10.1039/c9cc07406f.
• [8] Visual speech alters the discrimination and identification of non-intact auditory speech in children with hearing loss.Int J Pediatr Otorhinolaryngol. 2017 Mar;94:127-137. doi: 10.1016/j.ijporl.2017.01.009. Epub 2017 Jan 9.
• [9] Epidemiology and outcome of chronic high Epstein-Barr viral load carriage in pediatric kidney transplant recipients.Pediatr Transplant. 2018 May;22(3):e13147. doi: 10.1111/petr.13147. Epub 2018 Feb 6.
• [10] A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.Genet Med. 2016 Nov;18(11):1090-1096. doi: 10.1038/gim.2016.1. Epub 2016 Mar 3.
• [11] Chlormethine Hydrochloride is Not Inferior to Tacrolimus in Treating Steroid-Resistant Nephrotic Syndrome.Kidney Blood Press Res. 2018;43(1):68-79. doi: 10.1159/000486911. Epub 2018 Jan 24.
• [12] 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.
• [13] 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.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] 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.
• [19] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.