Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX8SZOT)

• DOT Name: Nucleotide triphosphate diphosphatase NUDT15 (NUDT15)
• Synonyms: EC 3.6.1.9; MutT homolog 2; MTH2; Nucleoside diphosphate-linked moiety X motif 15; Nudix motif 15; Nucleoside diphosphate-linked to another moiety X hydrolase 15; Nudix hydrolase 15
• Gene Name: NUDT15
• Related Disease:
  Acute lymphocytic leukaemia
  Advanced cancer
  Alopecia totalis
  Autoimmune disease
  Autoimmune hepatitis
  Crohn disease
  Irritable bowel syndrome
  Leukopenia
  Liver cirrhosis
  Pancreatitis
  Sjogren syndrome
  Systemic lupus erythematosus
  Agranulocytosis
  Alopecia
  Childhood acute lymphoblastic leukemia
  leukaemia
  Leukemia
  Skin disease
  Immune system disorder
  Inflammatory bowel disease
• UniProt ID: NUD15_HUMAN
• PDB ID: 5BON; 5LPG; 6T5J; 7AOM; 7AOP; 7B63; 7B64; 7B65; 7B66; 7B67; 7B7V; 7NR6; 7R0D
• EC Number: 3.6.1.9
• Pfam ID: PF00293
• Sequence:
  MTASAQPRGRRPGVGVGVVVTSCKHPRCVLLGKRKGSVGAGSFQLPGGHLEFGETWEECA
  QRETWEEAALHLKNVHFASVVNSFIEKENYHYVTILMKGEVDVTHDSEPKNVEPEKNESW
  EWVPWEELPPLDQLFWGLRCLKEQGYDPFKEDLNHLVGYKGNHL
• Function: May catalyze the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP. Could also catalyze the hydrolysis of some nucleoside diphosphate derivatives. Hydrolyzes oxidized nucleosides triphosphates like 8-oxo-dGTP in vitro, but the specificity and efficiency towards these substrates are low. Therefore, the potential in vivo sanitizing role of this enzyme, that would consist in removing oxidatively damaged forms of nucleosides to prevent their incorporation into DNA, is unclear. Through the hydrolysis of thioguanosine triphosphates may participate in the catabolism of thiopurine drugs. May also have a role in DNA synthesis and cell cycle progression by stabilizing PCNA. Exhibits decapping activity towards dpCoA-capped RNAs in vitro.
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Phosphate bond hydrolysis by NUDT proteins (R-HSA-2393930)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alopecia totalis	DISCNJPF	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[6]
Irritable bowel syndrome	DIS27206	Strong	Genetic Variation	[7]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[8]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[5]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[9]
Sjogren syndrome	DISUBX7H	Strong	Genetic Variation	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[11]
Agranulocytosis	DISJS4LS	moderate	Genetic Variation	[12]
Alopecia	DIS37HU4	moderate	Genetic Variation	[12]
Childhood acute lymphoblastic leukemia	DISJ5D6U	moderate	Biomarker	[1]
leukaemia	DISS7D1V	moderate	Genetic Variation	[8]
Leukemia	DISNAKFL	moderate	Genetic Variation	[8]
Skin disease	DISDW8R6	moderate	Genetic Variation	[12]
Immune system disorder	DISAEGPH	Limited	Genetic Variation	[13]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[14]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) affects the response to substance of Doxorubicin.	[23]
Paclitaxel	DMLB81S	Approved	Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) affects the response to substance of Paclitaxel.	[23]
Vinblastine	DM5TVS3	Approved	Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) affects the response to substance of Vinblastine.	[23]
Mercaptopurine	DMTM2IK	Approved	Nucleotide triphosphate diphosphatase NUDT15 (NUDT15) increases the response to substance of Mercaptopurine.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[21]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Nucleotide triphosphate diphosphatase NUDT15 (NUDT15).	[22]

References

• [1] The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia.J Pediatr. 2020 Jan;216:150-157.e1. doi: 10.1016/j.jpeds.2019.09.024. Epub 2019 Oct 18.
• [2] NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon.Pediatr Blood Cancer. 2017 Jan;64(1):146-150. doi: 10.1002/pbc.26189. Epub 2016 Aug 31.
• [3] NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease.Eur J Gastroenterol Hepatol. 2016 Apr;28(4):475-8. doi: 10.1097/MEG.0000000000000564.
• [4] Thiopurine intolerance-causing mutations in NUDT15 induce temperature-dependent destabilization of the catalytic site.Biochim Biophys Acta Proteins Proteom. 2019 Apr;1867(4):376-381. doi: 10.1016/j.bbapap.2019.01.006. Epub 2019 Jan 10.
• [5] NUDT15 Polymorphism Confer Increased Susceptibility to Thiopurine-Induced Leukopenia in Patients With Autoimmune Hepatitis and Related Cirrhosis.Front Pharmacol. 2019 Apr 9;10:346. doi: 10.3389/fphar.2019.00346. eCollection 2019.
• [6] Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping.J Gastroenterol. 2018 Feb;53(2):172-180. doi: 10.1007/s00535-017-1416-0. Epub 2017 Nov 30.
• [7] NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD.Pharmacogenomics J. 2016 Jun;16(3):280-5. doi: 10.1038/tpj.2015.43. Epub 2015 Jun 16.
• [8] Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15(R138C) knock-in mice.Leukemia. 2020 Mar;34(3):882-894. doi: 10.1038/s41375-019-0583-9. Epub 2019 Oct 24.
• [9] Update on thiopurine pharmacogenetics in inflammatory bowel disease.Pharmacogenomics. 2015 Jul;16(8):891-903. doi: 10.2217/pgs.15.29. Epub 2015 Jun 12.
• [10] NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects: Case report and literature review.Medicine (Baltimore). 2018 Apr;97(17):e0301. doi: 10.1097/MD.0000000000010301.
• [11] NUDT15 R139C Variants Increase the Risk of Azathioprine-Induced Leukopenia in Chinese Autoimmune Patients.Front Pharmacol. 2018 May 7;9:460. doi: 10.3389/fphar.2018.00460. eCollection 2018.
• [12] Severe thiopurine-induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case-control study.J Dermatol. 2018 Oct;45(10):1160-1165. doi: 10.1111/1346-8138.14588. Epub 2018 Aug 13.
• [13] Pharmacogeomic implications of population diversity in Latin America: TPMT and NUDT15 polymorphisms and thiopurine dosing.Pharmacogenet Genomics. 2020 Jan;30(1):1-4. doi: 10.1097/FPC.0000000000000388.
• [14] Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.JAMA. 2019 Feb 26;321(8):773-785. doi: 10.1001/jama.2019.0709.
• [15] 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.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [22] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [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.
• [24] A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017-20. doi: 10.1038/ng.3060. Epub 2014 Aug 10.