Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG3CDVK)

• DOT Name: Tyrosine-protein kinase BTK (BTK)
• Synonyms: EC 2.7.10.2; Agammaglobulinemia tyrosine kinase; ATK; B-cell progenitor kinase; BPK; Bruton tyrosine kinase
• Gene Name: BTK
• Related Disease:
  Bruton-type agammaglobulinemia
  Isolated growth hormone deficiency type III
  Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
• UniProt ID: BTK_HUMAN
• PDB ID: 1AWW ; 1AWX ; 1B55 ; 1BTK ; 1BWN ; 1K2P ; 1QLY ; 2GE9 ; 2Z0P ; 3GEN ; 3K54 ; 3OCS ; 3OCT ; 3P08 ; 3PIX ; 3PIY ; 3PIZ ; 3PJ1 ; 3PJ2 ; 3PJ3 ; 4NWM ; 4OT5 ; 4OT6 ; 4OTF ; 4OTQ ; 4OTR ; 4RFY ; 4RFZ ; 4RG0 ; 4RX5 ; 4YHF ; 4Z3V ; 4ZLY ; 4ZLZ ; 5BPY ; 5BQ0 ; 5FBN ; 5FBO ; 5J87 ; 5JRS ; 5KUP ; 5P9F ; 5P9G ; 5P9H ; 5P9I ; 5P9J ; 5P9K ; 5P9L ; 5P9M ; 5T18 ; 5U9D ; 5VFI ; 5VGO ; 5XYZ ; 5ZZ4 ; 6AUA ; 6AUB ; 6BIK ; 6BKE ; 6BKH ; 6BKW ; 6BLN ; 6DI0 ; 6DI1 ; 6DI3 ; 6DI5 ; 6DI9 ; 6E4F ; 6EP9 ; 6HRP ; 6HRT ; 6HTF ; 6J6M ; 6N9P ; 6NFH ; 6NFI ; 6NZM ; 6O8I ; 6OMU ; 6S90 ; 6TFP ; 6TSE ; 6TT2 ; 6TUH ; 6TVN ; 6VXQ ; 6W06 ; 6W07 ; 6W7O ; 6W8I ; 6X3N ; 6X3O ; 6X3P ; 6XE4 ; 6YYF ; 6YYG ; 6YYK ; 7KXL ; 7KXM ; 7KXN ; 7KXO ; 7KXP ; 7KXQ ; 7L5O ; 7L5P ; 7LTY ; 7LTZ ; 7N4Q ; 7N4R ; 7N4S ; 7N5O ; 7N5R ; 7N5X ; 7N5Y ; 7R60 ; 7R61 ; 7YC9 ; 8DSO ; 8E2M ; 8EJB ; 8FLG ; 8FLH ; 8FLL ; 8FLN ; 8FLV
• EC Number: 2.7.10.2
• Pfam ID: PF00779 ; PF00169 ; PF07714 ; PF00017 ; PF00018
• Sequence:
  MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEK
  ITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEEL
  RKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSS
  HRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDE
  YFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGK
  EGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELIN
  YHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGK
  WRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANG
  CLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDF
  GLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER
  FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
• Function: Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK also plays a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Acts as an activator of NLRP3 inflammasome assembly by mediating phosphorylation of NLRP3. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.
• Tissue Specificity: Predominantly expressed in B-lymphocytes.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Platelet activation (hsa04611)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Epstein-Barr virus infection (hsa05169)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  MyD88 (R-HSA-166058)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  DAP12 signaling (R-HSA-2424491)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  G beta (R-HSA-8964315)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Potential therapeutics for SARS (R-HSA-9679191)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bruton-type agammaglobulinemia	DISQ5ZYP	Definitive	X-linked	[1]
Isolated growth hormone deficiency type III	DISRZSTR	Strong	X-linked	[2]
Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia	DIS32FL3	Supportive	X-linked	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibrutinib	DMHZCPO	Approved	Tyrosine-protein kinase BTK (BTK) decreases the response to substance of Ibrutinib.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine-protein kinase BTK (BTK).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tyrosine-protein kinase BTK (BTK).	[5]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Tyrosine-protein kinase BTK (BTK).	[6]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Tyrosine-protein kinase BTK (BTK).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Tyrosine-protein kinase BTK (BTK).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase BTK (BTK).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tyrosine-protein kinase BTK (BTK).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase BTK (BTK).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tyrosine-protein kinase BTK (BTK).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tyrosine-protein kinase BTK (BTK).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005 Feb;203:216-34. doi: 10.1111/j.0105-2896.2005.00233.x.
• [3] An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 1994 Jun 13;346(2-3):165-70. doi: 10.1016/0014-5793(94)00457-9.
• [4] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [5] Characterization of arsenic trioxide resistant clones derived from Jurkat leukemia T cell line: focus on PI3K/Akt signaling pathway. Chem Biol Interact. 2013 Oct 5;205(3):198-211. doi: 10.1016/j.cbi.2013.07.011. Epub 2013 Aug 2.
• [6] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [7] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [8] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [9] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015 Apr;29(4):895-900. doi: 10.1038/leu.2014.263. Epub 2014 Sep 5.