Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE9BI32)

• DOT Name: NACHT, LRR and PYD domains-containing protein 7 (NLRP7)
• Synonyms: Nucleotide-binding oligomerization domain protein 12; PYRIN-containing APAF1-like protein 3
• Gene Name: NLRP7
• Related Disease:
  Beckwith-Wiedemann syndrome
  Endometrial cancer
  Endometrial carcinoma
  Fetal growth restriction
  Gestational trophoblastic neoplasia
  Hydatidiform mole, recurrent, 1
  Lung cancer
  Lung carcinoma
  Melanocytic nevus
  Seminoma
  Testicular germ cell tumor
  Ulcerative colitis
  Choriocarcinoma
  Complete hydatidiform mole
• UniProt ID: NALP7_HUMAN
• PDB ID: 2KM6
• Pfam ID: PF13516 ; PF05729 ; PF17776 ; PF17779 ; PF02758
• Sequence:
  MTSPQLEWTLQTLLEQLNEDELKSFKSLLWAFPLEDVLQKTPWSEVEEADGKKLAEILVN
  TSSENWIRNATVNILEEMNLTELCKMAKAEMMEDGQVQEIDNPELGDAEEDSELAKPGEK
  EGWRNSMEKQSLVWKNTFWQGDIDNFHDDVTLRNQRFIPFLNPRTPRKLTPYTVVLHGPA
  GVGKTTLAKKCMLDWTDCNLSPTLRYAFYLSCKELSRMGPCSFAELISKDWPELQDDIPS
  ILAQAQRILFVVDGLDELKVPPGALIQDICGDWEKKKPVPVLLGSLLKRKMLPRAALLVT
  TRPRALRDLQLLAQQPIYVRVEGFLEEDRRAYFLRHFGDEDQAMRAFELMRSNAALFQLG
  SAPAVCWIVCTTLKLQMEKGEDPVPTCLTRTGLFLRFLCSRFPQGAQLRGALRTLSLLAA
  QGLWAQMSVFHREDLERLGVQESDLRLFLDGDILRQDRVSKGCYSFIHLSFQQFLTALFY
  ALEKEEGEDRDGHAWDIGDVQKLLSGEERLKNPDLIQVGHFLFGLANEKRAKELEATFGC
  RMSPDIKQELLQCKAHLHANKPLSVTDLKEVLGCLYESQEEELAKVVVAPFKEISIHLTN
  TSEVMHCSFSLKHCQDLQKLSLQVAKGVFLENYMDFELDIEFERCTYLTIPNWARQDLRS
  LRLWTDFCSLFSSNSNLKFLEVKQSFLSDSSVRILCDHVTRSTCHLQKVEIKNVTPDTAY
  RDFCLAFIGKKTLTHLTLAGHIEWERTMMLMLCDLLRNHKCNLQYLRLGGHCATPEQWAE
  FFYVLKANQSLKHLRLSANVLLDEGAMLLYKTMTRPKHFLQMLSLENCRLTEASCKDLAA
  VLVVSKKLTHLCLAKNPIGDTGVKFLCEGLSYPDCKLQTLVLQQCSITKLGCRYLSEALQ
  EACSLTNLDLSINQIARGLWILCQALENPNCNLKHLRLKTYETNLEIKKLLEEVKEKNPK
  LTIDCNASGATAPPCCDFFC
• Function: Inhibits CASP1/caspase-1-dependent IL1B secretion.
• Tissue Specificity: Expressed in numerous tissues including uterus and ovary, with low levels in heart and brain. Not detected in skeletal muscle.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Genetic Variation	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[2]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[3]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Genetic Variation	[4]
Hydatidiform mole, recurrent, 1	DISXUJWE	Strong	Autosomal recessive	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Melanocytic nevus	DISYS32D	Strong	Genetic Variation	[7]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[8]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[9]
Choriocarcinoma	DISDBVNL	moderate	Biomarker	[10]
Complete hydatidiform mole	DIS5QPI0	Supportive	Autosomal recessive	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NACHT, LRR and PYD domains-containing protein 7 (NLRP7).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NACHT, LRR and PYD domains-containing protein 7 (NLRP7).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NACHT, LRR and PYD domains-containing protein 7 (NLRP7).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of NACHT, LRR and PYD domains-containing protein 7 (NLRP7).	[15]

References

• [1] Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). PLoS Genet. 2009 Mar;5(3):e1000423. doi: 10.1371/journal.pgen.1000423. Epub 2009 Mar 20.
• [2] Inflammasome as a Key Pathogenic Mechanism in Endometriosis.Curr Drug Targets. 2017;18(9):997-1002. doi: 10.2174/1389450117666160709013850.
• [3] NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation.J Mol Med (Berl). 2019 Mar;97(3):355-367. doi: 10.1007/s00109-018-01737-x. Epub 2019 Jan 8.
• [4] Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia: A case report.Medicine (Baltimore). 2018 Sep;97(38):e12424. doi: 10.1097/MD.0000000000012424.
• [5] A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod. 2008 Jan;14(1):33-40. doi: 10.1093/molehr/gam079. Epub 2007 Nov 26.
• [6] Generation of a humanized monoclonal antibody against human parathyroid hormone-related protein and its efficacy against humoral hypercalcemia of malignancy.Anticancer Res. 2004 Sep-Oct;24(5A):2665-73.
• [7] NLRP7 and KHDC3L variants in Chinese patients with recurrent hydatidiform moles.Jpn J Clin Oncol. 2019 Jul 1;49(7):620-627. doi: 10.1093/jjco/hyz036.
• [8] Oncogenic role of NALP7 in testicular seminomas.Cancer Sci. 2004 Dec;95(12):949-54. doi: 10.1111/j.1349-7006.2004.tb03182.x.
• [9] Exome Sequencing and Genotyping Identify a Rare Variant in NLRP7 Gene Associated With Ulcerative Colitis.J Crohns Colitis. 2018 Feb 28;12(3):321-326. doi: 10.1093/ecco-jcc/jjx157.
• [10] NLRP7 and the genetics of post-molar choriocarcinomas in Senegal.Mol Hum Reprod. 2012 Jan;18(1):52-6. doi: 10.1093/molehr/gar060. Epub 2011 Sep 26.
• [11] Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J Med Genet. 2009 Aug;46(8):569-75. doi: 10.1136/jmg.2008.064196. Epub 2009 Feb 25.
• [12] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [13] 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.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.