Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1EB8MT)

• DOT Name: Tyrosine-protein kinase Blk (BLK)
• Synonyms: EC 2.7.10.2; B lymphocyte kinase; p55-Blk
• Gene Name: BLK
• Related Disease:
  Maturity-onset diabetes of the young
  Maturity-onset diabetes of the young type 11
  Monogenic diabetes
• UniProt ID: BLK_HUMAN
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MGLVSSKKPDKEKPIKEKDKGQWSPLKVSAQDKDAPPLPPLVVFNHLTPPPPDEHLDEDK
  HFVVALYDYTAMNDRDLQMLKGEKLQVLKGTGDWWLARSLVTGREGYVPSNFVARVESLE
  MERWFFRSQGRKEAERQLLAPINKAGSFLIRESETNKGAFSLSVKDVTTQGELIKHYKIR
  CLDEGGYYISPRITFPSLQALVQHYSKKGDGLCQRLTLPCVRPAPQNPWAQDEWEIPRQS
  LRLVRKLGSGQFGEVWMGYYKNNMKVAIKTLKEGTMSPEAFLGEANVMKALQHERLVRLY
  AVVTKEPIYIVTEYMARGCLLDFLKTDEGSRLSLPRLIDMSAQIAEGMAYIERMNSIHRD
  LRAANILVSEALCCKIADFGLARIIDSEYTAQEGAKFPIKWTAPEAIHFGVFTIKADVWS
  FGVLLMEVVTYGRVPYPGMSNPEVIRNLERGYRMPRPDTCPPELYRGVIAECWRSRPEER
  PTFEFLQSVLEDFYTATERQYELQP
• Function: Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling. B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. Signaling through BLK plays an important role in transmitting signals through surface immunoglobulins and supports the pro-B to pre-B transition, as well as the signaling for growth arrest and apoptosis downstream of B-cell receptor. Specifically binds and phosphorylates CD79A at 'Tyr-188'and 'Tyr-199', as well as CD79B at 'Tyr-196' and 'Tyr-207'. Phosphorylates also the immunoglobulin G receptors FCGR2A, FCGR2B and FCGR2C. With FYN and LYN, plays an essential role in pre-B-cell receptor (pre-BCR)-mediated NF-kappa-B activation. Contributes also to BTK activation by indirectly stimulating BTK intramolecular autophosphorylation. In pancreatic islets, acts as a modulator of beta-cells function through the up-regulation of PDX1 and NKX6-1 and consequent stimulation of insulin secretion in response to glucose. Phosphorylates CGAS, promoting retention of CGAS in the cytosol.
• Tissue Specificity: Expressed in lymphatic organs, pancreatic islets, Leydig cells, striate ducts of salivary glands and hair follicles.
• KEGG Pathway: B cell receptor sig.ling pathway (hsa04662)
• Reactome Pathway:
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  RUNX1 regulates transcription of genes involved in BCR signaling (R-HSA-8939245)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[1]
Maturity-onset diabetes of the young type 11	DISYX7K7	Limited	Unknown	[2]
Monogenic diabetes	DISEB8Q0	Refuted	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Tyrosine-protein kinase Blk (BLK) decreases the response to substance of Afimoxifene.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein kinase Blk (BLK).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tyrosine-protein kinase Blk (BLK).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tyrosine-protein kinase Blk (BLK).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Tyrosine-protein kinase Blk (BLK).	[7]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Tyrosine-protein kinase Blk (BLK).	[8]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Tyrosine-protein kinase Blk (BLK).	[9]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase Blk (BLK).	[12]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Tyrosine-protein kinase Blk (BLK).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Tyrosine-protein kinase Blk (BLK).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein kinase Blk (BLK).	[11]

References

• [1] Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14460-5. doi: 10.1073/pnas.0906474106. Epub 2009 Aug 10.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] 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.
• [8] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [9] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [10] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [11] 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.
• [12] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [13] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [14] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.