Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3NZSX3)

• DOT Name: Leucine-rich repeat-containing protein 17 (LRRC17)
• Synonyms: p37NB
• Gene Name: LRRC17
• Related Disease:
  Bone osteosarcoma
  Neuroblastoma
  Osteosarcoma
• UniProt ID: LRC17_HUMAN
• Pfam ID: PF13855
• Sequence:
  MRVVTIVILLCFCKAAELRKASPGSVRSRVNHGRAGGGRRGSNPVKRYAPGLPCDVYTYL
  HEKYLDCQERKLVYVLPGWPQDLLHMLLARNKIRTLKNNMFSKFKKLKSLDLQQNEISKI
  ESEAFFGLNKLTTLLLQHNQIKVLTEEVFIYTPLLSYLRLYDNPWHCTCEIETLISMLQI
  PRNRNLGNYAKCESPQEQKNKKLRQIKSEQLCNEEEKEQLDPKPQVSGRPPVIKPEVDST
  FCHNYVFPIQTLDCKRKELKKVPNNIPPDIVKLDLSYNKINQLRPKEFEDVHELKKLNLS
  SNGIEFIDPAAFLGLTHLEELDLSNNSLQNFDYGVLEDLYFLKLLWLRDNPWRCDYNIHY
  LYYWLKHHYNVHFNGLECKTPEEYKGWSVGKYIRSYYEECPKDKLPAYPESFDQDTEDDE
  WEKKHRDHTAKKQSVIITIVG
• Function: Involved in bone homeostasis. Acts as a negative regulator of RANKL-induced osteoclast precursor differentiation from bone marrow precursors.
• Tissue Specificity: Expressed in osteoblast cell lines. Well expressed in ovary, heart, pancreas, skeletal muscle, lung, and fetal kidney and lung and only at the basal levels in the other tissues examined including adult kidney. More expressed in S-type neuroblastoma cells than in N-type neuroblastoma cells.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[2]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]

14 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 Leucine-rich repeat-containing protein 17 (LRRC17).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[5]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[11]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucine-rich repeat-containing protein 17 (LRRC17).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Leucine-rich repeat-containing protein 17 (LRRC17).	[13]

References

• [1] MicroRNA profiling with correlation to gene expression revealed the oncogenic miR-17-92 cluster to be up-regulated in osteosarcoma.Cancer Genet. 2012 May;205(5):212-9. doi: 10.1016/j.cancergen.2012.03.001.
• [2] A cDNA encoding a putative 37 kDa leucine-rich repeat (LRR) protein, p37NB, isolated from S-type neuroblastoma cell has a differential tissue distribution.Biochim Biophys Acta. 1996 Dec 11;1309(3):183-8. doi: 10.1016/s0167-4781(96)00158-3.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [11] 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.
• [12] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [13] 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.
• [14] 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.
• [15] 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.