Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJU2I5H)

• DOT Name: Chordin-like protein 2 (CHRDL2)
• Synonyms: Breast tumor novel factor 1; BNF-1; Chordin-related protein 2
• Gene Name: CHRDL2
• Related Disease:
  Breast neoplasm
  Colon cancer
  Colonic neoplasm
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Huntington disease
  Mediastinal large B-cell lymphoma
  Neoplasm
• UniProt ID: CRDL2_HUMAN
• Pfam ID: PF19548 ; PF00093
• Sequence:
  MVPEVRVLSSLLGLALLWFPLDSHARARPDMFCLFHGKRYSPGESWHPYLEPQGLMYCLR
  CTCSEGAHVSCYRLHCPPVHCPQPVTEPQQCCPKCVEPHTPSGLRAPPKSCQHNGTMYQH
  GEIFSAHELFPSRLPNQCVLCSCTEGQIYCGLTTCPEPGCPAPLPLPDSCCQACKDEASE
  QSDEEDSVQSLHGVRHPQDPCSSDAGRKRGPGTPAPTGLSAPLSFIPRHFRPKGAGSTTV
  KIVLKEKHKKACVHGGKTYSHGEVWHPAFRAFGPLPCILCTCEDGRQDCQRVTCPTEYPC
  RHPEKVAGKCCKICPEDKADPGHSEISSTRCPKAPGRVLVHTSVSPSPDNLRRFALEHEA
  SDLVEIYLWKLVKGIFHLTQIKKVRKQDFQKEAQHFRLLAGPHEGHWNVFLAQTLELKVT
  ASPDKVTKT
• Function: May inhibit BMPs activity by blocking their interaction with their receptors. Has a negative regulator effect on the cartilage formation/regeneration from immature mesenchymal cells, by preventing or reducing the rate of matrix accumulation. Implicated in tumor angiogenesis. May play a role during myoblast and osteoblast differentiation, and maturation.
• Tissue Specificity: Highly expressed in uterus. Moderately expressed in heart, liver, prostate, testis and ovary. Weakly expressed in skeletal muscle, kidney, spleen, small intestine and colon. Expressed in the secretory epithelial cells of uterine endometrium, fallopian tubes, endocervical glands, bladder and prostate, as well as the transitional epithelium of the urinary bladder, and in bone osteoblasts (at protein level). In normal cartilage, expression was confined in a few chondrocytes in the superficial zone as well as in the middle zone. In diseased cartilage coming from osteoarthritic patients, expression was limited to the middle zone of chondrocytes. Isoform 1 and isoform 2 are expressed in fetal cerebellum and heart, while only isoform 2 is detected in fetal spleen. Isoform 2 present in plasma.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Genetic Variation	[2]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[1]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[2]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[2]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[2]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Huntington disease	DISQPLA4	Strong	Biomarker	[3]
Mediastinal large B-cell lymphoma	DISAUA10	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]

3 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 Chordin-like protein 2 (CHRDL2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Chordin-like protein 2 (CHRDL2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chordin-like protein 2 (CHRDL2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chordin-like protein 2 (CHRDL2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chordin-like protein 2 (CHRDL2).	[8]

References

• [1] BNF-1, a novel gene encoding a putative extracellular matrix protein, is overexpressed in tumor tissues.Gene. 2003 Jun 5;311:105-10. doi: 10.1016/s0378-1119(03)00563-8.
• [2] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [3] Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.Hum Mol Genet. 2007 Aug 1;16(15):1845-61. doi: 10.1093/hmg/ddm133. Epub 2007 May 21.
• [4] Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma.Diagn Pathol. 2019 Dec 12;14(1):133. doi: 10.1186/s13000-019-0918-x.
• [5] Overexpression of colorectal cancer oncogene CHRDL2 predicts a poor prognosis.Oncotarget. 2017 Feb 14;8(7):11489-11506. doi: 10.18632/oncotarget.14039.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [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] 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.