Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT860QF)

• DTT Name: LCK tyrosine protein kinase (LCK)
• Synonyms: p56-LCK; Tyrosine-protein kinase Lck; T cell-specific protein-tyrosine kinase; Proto-oncogene tyrosine-protein kinase LCK; Proto-oncogene Lck; Protein YT16; Lymphocyte cell-specific protein-tyrosine kinase; Leukocyte C-terminal Src kinase; LSK; LCK p59-Fyn; LCK Protooncogene Syn
• Gene Name: LCK
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: LCK_HUMAN
• TTD ID: T12499
• EC Number: EC 2.7.10.2
• Sequence:
  MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVTYEGSNPPASP
  LQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKAQSLTTGQEGFIPFNFVAKAN
  SLEPEPWFFKNLSRKDAERQLLAPGNTHGSFLIRESESTAGSFSLSVRDFDQNQGEVVKH
  YKIRNLDNGGFYISPRITFPGLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEV
  PRETLKLVERLGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL
  VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAEGMAFIEERNY
  IHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGAKFPIKWTAPEAINYGTFTIK
  SDVWSFGILLTEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYQLMRLCWKER
  PEDRPTFDYLRSVLEDFFTATEGQYQPQP
• Function: 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. 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.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  HTLV-I infection (hsa05166)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Regulation of KIT signaling (R-HSA-1433559)
  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)
  Interleukin-2 signaling (R-HSA-451927)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dasatinib	DMJV2EK	Blast phase chronic myelogenous leukemia, BCR-ABL1 positive		Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
ISIS-CRP	DMQDUG4	Cardiovascular disease	BA00-BE2Z	Phase 1	[2]
JNJ-26483327	DMSQ3AZ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

45 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(4-Phenoxy-phenyl)-quinazolin-4-yl-amine	DMFO8DR	Discovery agent	N.A.	Investigative	[4]
2-(3,4,5-Trihydroxy-benzylidene)-malononitrile	DM1I6SO	Discovery agent	N.A.	Investigative	[5]
3-(4-(o-toluidino)pyrimidin-2-ylamino)benzamide	DMX6ZHQ	Discovery agent	N.A.	Investigative	[6]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[7]
4-(3-Chloro-phenoxy)-6,7-dimethoxy-quinazoline	DMDS2LZ	Discovery agent	N.A.	Investigative	[8]
4-Phenylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine	DMHANXD	Discovery agent	N.A.	Investigative	[9]
6-o-tolylquinazolin-2-amine	DM4TX9O	Discovery agent	N.A.	Investigative	[10]
A-420983	DM7HSCI	Discovery agent	N.A.	Investigative	[11]
A-641359	DM5JSXI	Discovery agent	N.A.	Investigative	[12]
A-770041	DMP78JY	Discovery agent	N.A.	Investigative	[12]
AMP-PNP	DMTOK1D	Discovery agent	N.A.	Investigative	[13]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[14]
BMS-536924	DMXJB4N	Discovery agent	N.A.	Investigative	[15]
CEP-5104	DMV43GY	Discovery agent	N.A.	Investigative	[16]
CGP-57380	DMFPOUC	Discovery agent	N.A.	Investigative	[2]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[14]
GW-788388	DMIBUW5	Solid tumour/cancer	2A00-2F9Z	Investigative	[17]
HKI-9924129	DM5LR2B	Gram-positive bacterial infection	1B74-1G40	Investigative	[18]
JNJ-10198409	DM9GDP5	Discovery agent	N.A.	Investigative	[19]
JNJ-28312141	DMCMH7O	Discovery agent	N.A.	Investigative	[20]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[14]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[21]
LAVENDUSTIN A	DMH3X06	Discovery agent	N.A.	Investigative	[22]
Lck inhibitor	DME4TUQ	Discovery agent	N.A.	Investigative	[23]
NM-PP1	DMS8H5Q	Discovery agent	N.A.	Investigative	[2]
PD-0166326	DMD2CG9	Discovery agent	N.A.	Investigative	[18]
PD-0173952	DMSCQ9U	Discovery agent	N.A.	Investigative	[18]
PD-0173955	DMOZEW9	Discovery agent	N.A.	Investigative	[18]
PD-0173956	DM8RW92	Discovery agent	N.A.	Investigative	[18]
PD-0173958	DMZQ8YV	Discovery agent	N.A.	Investigative	[18]
PD-0179483	DMKO8LE	Discovery agent	N.A.	Investigative	[18]
PMID15546730C2	DMOPUIH	Discovery agent	N.A.	Investigative	[24]
PMID17280833C30	DMXHS4L	Discovery agent	N.A.	Investigative	[25]
PMID17600705C23	DMJFOGW	Discovery agent	N.A.	Investigative	[6]
PMID21855335C19a	DMTKJA9	Discovery agent	N.A.	Investigative	[26]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[14]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[14]
RPR-108518A	DMJ6RZI	Discovery agent	N.A.	Investigative	[8]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[14]
SU 6656	DMF1P6W	Discovery agent	N.A.	Investigative	[2]
TG-100435	DMIR3X2	Discovery agent	N.A.	Investigative	[27]
WH-4-023	DMJS8VQ	Discovery agent	N.A.	Investigative	[28]
Y-c[D-Pen-(3,5-diI)Tyr-GSFC]KR-NH2	DMF7S54	Discovery agent	N.A.	Investigative	[29]
Y-c[D-Pen-(3-I)Tyr-GSFC]KR-NH2	DMW1PSO	Discovery agent	N.A.	Investigative	[29]
ZM-336372	DMD5JYQ	Discovery agent	N.A.	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Multiple myeloma	2C82	Bone marrow	4.46E-02	-0.13	-1.09

References

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