Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB2GM4G)

• DOT Name: Inhibitor of Bruton tyrosine kinase (IBTK)
• Synonyms: IBtk
• Gene Name: IBTK
• Related Disease:
  Rheumatoid arthritis
  Small lymphocytic lymphoma
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  B-cell lymphoma
  B-cell neoplasm
  Brain disease
  Central nervous system lymphoma
  Lymphoma
  Mantle cell lymphoma
  Neoplasm
  Pediatric lymphoma
  Wilms tumor
  Leukemia
  Lymphoproliferative syndrome
  Classic Hodgkin lymphoma
  Lymphoplasmacytic lymphoma
  Non-alcoholic steatohepatitis
  Pneumonia
  Pneumonitis
  Streptococcal pneumonia
  Waldenstrom macroglobulinemia
• UniProt ID: IBTK_HUMAN
• Pfam ID: PF12796 ; PF00651 ; PF00415
• Sequence:
  MSSPMPDCTSKCRSLKHALDVLSVVTKGSENQIKAFLSSHCYNAATIKDVFGRNALHLVS
  SCGKKGVLDWLIQKGVDLLVKDKESGWTALHRSIFYGHIDCVWSLLKHGVSLYIQDKEGL
  SALDLVMKDRPTHVVFKNTDPTDVYTWGDNTNFTLGHGSQNSKHHPELVDLFSRSGIYIK
  QVVLCKFHSVFLSQKGQVYTCGHGPGGRLGHGDEQTCLVPRLVEGLNGHNCSQVAAAKDH
  TVVLTEDGCVYTFGLNIFHQLGIIPPPSSCNVPRQIQAKYLKGRTIIGVAAGRFHTVLWT
  REAVYTMGLNGGQLGCLLDPNGEKCVTAPRQVSALHHKDIALSLVAASDGATVCVTTRGD
  IYLLADYQCKKMASKQLNLKKVLVSGGHMEYKVDPEHLKENGGQKICILAMDGAGRVFCW
  RSVNSSLKQCRWAYPRQVFISDIALNRNEILFVTQDGEGFRGRWFEEKRKSSEKKEILSN
  LHNSSSDVSYVSDINSVYERIRLEKLTFAHRAVSVSTDPSGCNFAILQSDPKTSLYEIPA
  VSSSSFFEEFGKLLREADEMDSIHDVTFQVGNRLFPAHKYILAVHSDFFQKLFLSDGNTS
  EFTDIYQKDEDSAGCHLFVVEKVHPDMFEYLLQFIYTDTCDFLTHGFKPRIHLNKNPEEY
  QGTLNSHLNKVNFHEDDNQKSAFEVYKSNQAQTVSERQKSKPKSCKKGKNIREDDPVRML
  QTVAKKFDFSNLSSRLDGVRFENEKINVIAKNTGNKLKLSQKKCSFLCDVTMKSVDGKEF
  PCHKCVLCARLEYFHSMLSSSWIEASSCAALEMPIHSDILKVILDYLYTDEAVVIKESQN
  VDFICSVLVVADQLLITRLKEICEVALTEKLTLKNAAMLLEFAAMYSAKQLKLSCLQFIG
  LNMAALLEARSLDVLSDGVLKDLSEFYRKMIPAMDRRVITPYQDGPDISYLEVEDGDIFL
  KEEINMEQNHSETMFKKAKTKAKKKPRKRSDSSGGYNLSDIIQSPSSTGLLKSGKTNSVE
  SLPELLTSDSEGSYAGVGSPRDLQSPDFTTGFHSDKIEAKVKPYVNGTSPVYSREDLKPW
  EKSPILKISAPQPIPSNRIDTTSSASWVAGSFSPVSPPVVDLRTIMEIEESRQKCGATPK
  SHLGKTVSHGVKLSQKQRKMIALTTKENNSGMNSMETVLFTPSKAPKPVNAWASSLHSVS
  SKSFRDFLLEEKKSVTSHSSGDHVKKVSFKGIENSQAPKIVRCSTHGTPGPEGNHISDLP
  LLDSPNPWLSSSVTAPSMVAPVTFASIVEEELQQEAALIRSREKPLALIQIEEHAIQDLL
  VFYEAFGNPEEFVIVERTPQGPLAVPMWNKHGC
• Function: Acts as an inhibitor of BTK tyrosine kinase activity, thereby playing a role in B-cell development. Down-regulates BTK kinase activity, leading to interference with BTK-mediated calcium mobilization and NF-kappa-B-driven transcription.
• Tissue Specificity: Expressed in DeFew, HEK293T, HeLa and in Jurkat, MC3 and NB4 lymphoid cells (at protein level). Isoform 1 is the predominant isoform expressed in all examined tissues and cell lines. Highly expressed in hemopoietic tissues (fetal liver, spleen, lymph node, thymus, peripheral blood leukocytes and bone marrow). Weakly or not expressed in other tissues.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Small lymphocytic lymphoma	DIS30POX	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[6]
B-cell neoplasm	DISVY326	Strong	Biomarker	[7]
Brain disease	DIS6ZC3X	Strong	Biomarker	[8]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[6]
Lymphoma	DISN6V4S	Strong	Biomarker	[4]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[4]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[10]
Leukemia	DISNAKFL	moderate	Altered Expression	[11]
Lymphoproliferative syndrome	DISMVL8O	moderate	Biomarker	[12]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Altered Expression	[2]
Lymphoplasmacytic lymphoma	DISMSQ11	Limited	Biomarker	[9]
Non-alcoholic steatohepatitis	DIST4788	Limited	Biomarker	[13]
Pneumonia	DIS8EF3M	Limited	Biomarker	[14]
Pneumonitis	DIS88E0K	Limited	Biomarker	[14]
Streptococcal pneumonia	DIS2EKMJ	Limited	Biomarker	[14]
Waldenstrom macroglobulinemia	DIS9O23I	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[20]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[21]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[24]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Inhibitor of Bruton tyrosine kinase (IBTK).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Inhibitor of Bruton tyrosine kinase (IBTK).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Inhibitor of Bruton tyrosine kinase (IBTK).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Inhibitor of Bruton tyrosine kinase (IBTK).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Inhibitor of Bruton tyrosine kinase (IBTK).	[17]

References

• [1] Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate.J Pharmacol Exp Ther. 2019 Oct;371(1):202-207. doi: 10.1124/jpet.119.257089. Epub 2019 Aug 1.
• [2] Late onset left ventricular dysfunction and cardiomyopathy induced with ibrutinib.J Oncol Pharm Pract. 2020 Mar;26(2):478-480. doi: 10.1177/1078155219852146. Epub 2019 May 29.
• [3] Abivertinib, a novel BTK inhibitor: Anti-Leukemia effects and synergistic efficacy with homoharringtonine in acute myeloid leukemia.Cancer Lett. 2019 Oct 1;461:132-143. doi: 10.1016/j.canlet.2019.07.008. Epub 2019 Jul 13.
• [4] IBTK contributes to B-cell lymphomagenesis in E-myc transgenic mice conferring resistance to apoptosis.Cell Death Dis. 2019 Apr 11;10(4):320. doi: 10.1038/s41419-019-1557-6.
• [5] Targeting Thioredoxin Reductase by Ibrutinib Promotes Apoptosis of SMMC-7721 Cells.J Pharmacol Exp Ther. 2019 May;369(2):212-222. doi: 10.1124/jpet.118.254862. Epub 2019 Feb 13.
• [6] Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap.Cancer Discov. 2017 Sep;7(9):940-942. doi: 10.1158/2159-8290.CD-17-0714.
• [7] Ibrutinib and Venetoclax for First-Line Treatment of CLL.N Engl J Med. 2019 May 30;380(22):2095-2103. doi: 10.1056/NEJMoa1900574.
• [8] Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus.Arthritis Res Ther. 2018 Jan 25;20(1):10. doi: 10.1186/s13075-017-1500-0.
• [9] Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis.PLoS One. 2019 Feb 20;14(2):e0211228. doi: 10.1371/journal.pone.0211228. eCollection 2019.
• [10] Proteomics analysis of siRNA-mediated silencing of Wilms' tumor 1 in the MDA-MB-468 breast cancer cell line.Oncol Rep. 2014 Apr;31(4):1754-60. doi: 10.3892/or.2014.3013. Epub 2014 Feb 5.
• [11] Ibrutinib: A Review in Chronic Lymphocytic Leukaemia.Drugs. 2017 Feb;77(2):225-236. doi: 10.1007/s40265-017-0695-3.
• [12] Increased Susceptibility for Atrial and Ventricular Cardiac Arrhythmias in Mice Treated With a Single High Dose of Ibrutinib.Can J Cardiol. 2018 Mar;34(3):337-341. doi: 10.1016/j.cjca.2017.12.001. Epub 2017 Dec 7.
• [13] Function of inhibitor of Bruton's tyrosine kinase isoform (IBTK) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response.J Biol Chem. 2017 Aug 25;292(34):14050-14065. doi: 10.1074/jbc.M117.799304. Epub 2017 Jul 14.
• [14] Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia.Mol Med. 2019 Jan 15;25(1):3. doi: 10.1186/s10020-018-0069-7.
• [15] 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.
• [16] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [23] 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.
• [24] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [25] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.