Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT883FG9)

• DOT Name: Tyrosine-protein kinase Lck (LCK)
• Synonyms: EC 2.7.10.2; Leukocyte C-terminal Src kinase; LSK; Lymphocyte cell-specific protein-tyrosine kinase; Protein YT16; Proto-oncogene Lck; T cell-specific protein-tyrosine kinase; p56-LCK
• Gene Name: LCK
• Related Disease: Severe combined immunodeficiency due to LCK deficiency
• UniProt ID: LCK_HUMAN
• PDB ID: 1BHF ; 1BHH ; 1CWD ; 1CWE ; 1FBZ ; 1H92 ; 1IJR ; 1KIK ; 1LCJ ; 1LCK ; 1LKK ; 1LKL ; 1Q68 ; 1Q69 ; 1QPC ; 1QPD ; 1QPE ; 1QPJ ; 1X27 ; 2IIM ; 2OF2 ; 2OF4 ; 2OFU ; 2OFV ; 2OG8 ; 2PL0 ; 2ZM1 ; 2ZM4 ; 2ZYB ; 3AC1 ; 3AC2 ; 3AC3 ; 3AC4 ; 3AC5 ; 3AC8 ; 3ACJ ; 3ACK ; 3AD4 ; 3AD5 ; 3AD6 ; 3B2W ; 3BRH ; 3BYM ; 3BYO ; 3BYS ; 3BYU ; 3KMM ; 3KXZ ; 3LCK ; 3MPM ; 4C3F ; 4D8K ; 5MTM ; 5MTN ; 6H6A ; 6PDJ ; 8X2P
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVTYEGSNPPASP
  LQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKAQSLTTGQEGFIPFNFVAKAN
  SLEPEPWFFKNLSRKDAERQLLAPGNTHGSFLIRESESTAGSFSLSVRDFDQNQGEVVKH
  YKIRNLDNGGFYISPRITFPGLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEV
  PRETLKLVERLGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL
  VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAEGMAFIEERNY
  IHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGAKFPIKWTAPEAINYGTFTIK
  SDVWSFGILLTEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYQLMRLCWKER
  PEDRPTFDYLRSVLEDFFTATEGQYQPQP
• Function: Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2.
• Tissue Specificity: Expressed specifically in lymphoid cells.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Yersinia infection (hsa05135)
  Human T-cell leukemia virus 1 infection (hsa05166)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by SCF-KIT (R-HSA-1433557)
  Regulation of KIT signaling (R-HSA-1433559)
  Nef and signal transduction (R-HSA-164944)
  Nef Mediated CD4 Down-regulation (R-HSA-167590)
  Downstream TCR signaling (R-HSA-202424)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Generation of second messenger molecules (R-HSA-202433)
  PECAM1 interactions (R-HSA-210990)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  DAP12 signaling (R-HSA-2424491)
  CD28 co-stimulation (R-HSA-389356)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  CTLA4 inhibitory signaling (R-HSA-389513)
  PD-1 signaling (R-HSA-389948)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  RHOH GTPase cycle (R-HSA-9013407)
  Interleukin-2 signaling (R-HSA-9020558)
  Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants (R-HSA-9670439)
  FLT3 signaling through SRC family kinases (R-HSA-9706374)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe combined immunodeficiency due to LCK deficiency	DISE5YMB	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Tyrosine-protein kinase Lck (LCK) affects the response to substance of Methotrexate.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tyrosine-protein kinase Lck (LCK).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Tyrosine-protein kinase Lck (LCK).	[5]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Tyrosine-protein kinase Lck (LCK).	[9]
Imatinib	DM7RJXL	Approved	Imatinib decreases the phosphorylation of Tyrosine-protein kinase Lck (LCK).	[10]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Tyrosine-protein kinase Lck (LCK).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tyrosine-protein kinase Lck (LCK).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein kinase Lck (LCK).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase Lck (LCK).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tyrosine-protein kinase Lck (LCK).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Tyrosine-protein kinase Lck (LCK).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Tyrosine-protein kinase Lck (LCK).	[7]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Tyrosine-protein kinase Lck (LCK).	[8]
Crizotinib	DM4F29C	Approved	Crizotinib decreases the activity of Tyrosine-protein kinase Lck (LCK).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tyrosine-protein kinase Lck (LCK).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tyrosine-protein kinase Lck (LCK).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Tyrosine-protein kinase Lck (LCK).	[3]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Tyrosine-protein kinase Lck (LCK).	[4]
UCN-01	DMUNJZB	Phase 2	UCN-01 decreases the activity of Tyrosine-protein kinase Lck (LCK).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase Lck (LCK).	[16]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Tyrosine-protein kinase Lck (LCK).	[18]
KENPAULLONE	DMAGVXW	Patented	KENPAULLONE decreases the activity of Tyrosine-protein kinase Lck (LCK).	[19]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the activity of Tyrosine-protein kinase Lck (LCK).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tyrosine-protein kinase Lck (LCK).	[20]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Tyrosine-protein kinase Lck (LCK).	[21]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE decreases the expression of Tyrosine-protein kinase Lck (LCK).	[22]
Indirubin-3'-monoxime	DMLRQH0	Investigative	Indirubin-3'-monoxime decreases the activity of Tyrosine-protein kinase Lck (LCK).	[19]
Purvalanol A	DMNQ7TM	Investigative	Purvalanol A decreases the activity of Tyrosine-protein kinase Lck (LCK).	[19]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol decreases the expression of Tyrosine-protein kinase Lck (LCK).	[4]
9-Nitropaullone	DM8LUYM	Investigative	9-Nitropaullone decreases the activity of Tyrosine-protein kinase Lck (LCK).	[19]

References

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• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
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• [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] 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.
• [19] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [22] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [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.