LCK

Summary

LCK (LCK proto-oncogene, Src family tyrosine kinase, HGNC:6524) is a protein-coding gene on chromosome 1p35.2, encoding Tyrosine-protein kinase Lck (P06239). 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.

This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein is a key signaling molecule in the selection and maturation of developing T-cells. It contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to the plasma membrane and pericentrosomal vesicles, and binds to cell surface receptors, including CD4 and CD8, and other signaling molecules. Multiple alternatively spliced variants encoding different isoforms have been described.

Source: NCBI Gene 3932 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe combined immunodeficiency due to LCK deficiency (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 328 total — 9 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes — 126 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6524
Approved symbol	LCK
Name	LCK proto-oncogene, Src family tyrosine kinase
Location	1p35.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000182866
Ensembl biotype	protein_coding
OMIM	153390
Entrez	3932

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 20 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000333070, ENST00000336890, ENST00000355928, ENST00000373557, ENST00000373562, ENST00000461712, ENST00000469765, ENST00000469956, ENST00000476457, ENST00000477031, ENST00000482949, ENST00000495610, ENST00000696990, ENST00000696991, ENST00000885193, ENST00000885194, ENST00000885195, ENST00000885196, ENST00000885197, ENST00000915389, ENST00000915390, ENST00000915391, ENST00000915392, ENST00000915393, ENST00000915394, ENST00000961403

RefSeq mRNA: 3 — MANE Select: NM_005356 NM_001042771, NM_001330468, NM_005356

CCDS: CCDS359, CCDS90908

Canonical transcript exons

ENST00000336890 — 13 exons

Exon	Start	End
ENSE00001292351	32279671	32279747
ENSE00001312604	32251265	32251371
ENSE00001952500	32279841	32279994
ENSE00003460083	32275914	32276063
ENSE00003461657	32275569	32275672
ENSE00003562461	32274993	32275083
ENSE00003690851	32276607	32276786
ENSE00003969212	32274325	32274434
ENSE00003969213	32275321	32275419
ENSE00003969214	32276337	32276489
ENSE00003969219	32280079	32280210
ENSE00003969221	32285514	32286165
ENSE00003969226	32274737	32274818

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 99.21.

FANTOM5 (CAGE): breadth broad, TPM avg 15.0201 / max 685.0126, expressed in 383 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1972	10.7765	216
1973	2.2046	114
1974	1.4902	157
1970	0.2393	114
1975	0.2151	55
1971	0.0737	48
1976	0.0207	11

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	99.21	gold quality
granulocyte	CL:0000094	98.71	gold quality
lymph node	UBERON:0000029	96.76	gold quality
blood	UBERON:0000178	95.56	gold quality
vermiform appendix	UBERON:0001154	94.65	gold quality
spleen	UBERON:0002106	91.55	gold quality
caecum	UBERON:0001153	90.40	gold quality
epithelium of nasopharynx	UBERON:0001951	89.82	gold quality
ileal mucosa	UBERON:0000331	86.93	gold quality
superficial temporal artery	UBERON:0001614	84.64	gold quality
tonsil	UBERON:0002372	83.98	gold quality
amniotic fluid	UBERON:0000173	83.95	gold quality
bone marrow	UBERON:0002371	83.47	gold quality
bone marrow cell	CL:0002092	82.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.89	gold quality
jejunal mucosa	UBERON:0000399	81.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.78	gold quality
gall bladder	UBERON:0002110	81.63	gold quality
small intestine	UBERON:0002108	80.71	gold quality
palpebral conjunctiva	UBERON:0001812	80.38	gold quality
mucosa of transverse colon	UBERON:0004991	80.12	gold quality
colonic epithelium	UBERON:0000397	79.35	gold quality
corpus epididymis	UBERON:0004359	77.92	gold quality
rectum	UBERON:0001052	77.27	gold quality
duodenum	UBERON:0002114	77.25	gold quality
decidua	UBERON:0002450	77.15	gold quality
mucosa of urinary bladder	UBERON:0001259	76.22	gold quality
upper lobe of left lung	UBERON:0008952	75.90	gold quality
cervix squamous epithelium	UBERON:0006922	75.02	gold quality
upper lobe of lung	UBERON:0008948	74.22	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	701.40
E-MTAB-9067	yes	504.19
E-CURD-112	yes	387.26
E-HCAD-4	yes	113.67
E-MTAB-6701	yes	98.11
E-HCAD-1	yes	75.90
E-CURD-122	yes	74.06
E-MTAB-10553	yes	47.60
E-MTAB-6678	yes	43.62
E-CURD-88	yes	37.74
E-MTAB-8410	yes	31.74
E-HCAD-10	yes	27.76
E-CURD-46	yes	16.13
E-MTAB-10042	yes	15.34
E-MTAB-7606	no	1872.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL3, ETS1, ETS2, FOS, IRF1, LMO2, MYB, NFKB, NOTO, PARP1, TCF12, TP53

miRNA regulators (miRDB)

24 targeting LCK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-3944-5P	98.50	67.55	997
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-4700-3P	97.74	68.64	1014
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-597-5P	96.82	67.57	732
HSA-MIR-10525-3P	96.32	68.04	699

Literature-anchored findings (GeneRIF, showing 40)

• The association of Lck with c-Cbl in vivo required a functional SH3 domain. These results suggest a model whereby the SH3 domain negatively regulates basal localization of Lck to lipid rafts via association with c-Cbl. (PMID:11741956)
• p56(Lck) targets CD4 to specialized lipid microdomains preferentially localized on microvilli (PMID:11854499)
• Negative regulation of Lck by Cbl ubiquitin ligase (PMID:11904433)
• Lck is required for stromal cell-derived factor 1 alpha (CXCL12)-induced lymphoid cell chemotaxis. (PMID:12036857)
• The activation of Lck in T cells activates apoptotic pathways which are counteracted by Vav and suggests a novel role for costimulation in protecting T cells from CD4-mediated cell death. (PMID:12055221)
• Anti-CD45RO suppressed Src family protein tyrosine kinase p56lck expression in PMNs. (PMID:12100025)
• the distinct potential of Fyn and Lck to phosphorylate Sam68 is likely controlled by the interaction of the kinase SH3 domain with the linker and Sam68, possibly on a competitive binding basis. (PMID:12370810)
• no association between polymorphisms and protein level in type 1 diabetes (PMID:12401726)
• We conclude that the Lck deficiency influences early steps during radiation-induced mitochondrial alterations (PMID:12527887)
• evaluated the role of Lck tyrosine kinase, an early effector of T cell activation, in regulation of the membrane-cytoskeleton linker protein ezrin; results identify ezrin as the first cytoskeletal substrate for Lck (PMID:12560083)
• The exon 7-spliced Lck isoform in T lymphocytes: a potential regulator of p56lck signaling pathways. (PMID:12565834)
• interaction of linker of activated T cells with open-active form of Lck in lipid rafts reveals a new mechanism for the regulation of Lck in T cells (PMID:12570875)
• lck phosphorylation has a role in costimulation with the T-cell receptor during lymphocyte activation (PMID:12589038)
• The costimulatory effects of HCV E2 on T cells depend on CD81 cross-linking that activates Lck through raft aggregation and thus leads to enhanced TCR signaling. (PMID:12645944)
• Analysis of the three-dimensional structure of Lck protein domains. (PMID:12734017)
• protein tyrosine kinase Lck phosphorylates TCRzeta (PMID:12755691)
• lck serine phosphorylation is inhibited by T cell receptor-stimulated generation of hydrogen peroxide (PMID:12899942)
• examined the folding and solution structures of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes;coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains (PMID:14500983)
• CD38 initiates and propagates several activating signaling pathways including those with Lck and CD3-zeta (PMID:14523017)
• p56lck in the presence of hypoxia/reoxygenation regulates NFkappaB activation, uPA secretion, and cell motility through tyrosine phosphorylation of IkappaBalpha (PMID:14534291)
• By turning off Lck, Yersinia pestis phosphatase YopH blocks T cell antigen receptor signaling at its very first step, effectively preventing the development of a protective immune response against this lethal bacterium. (PMID:14623872)
• the SD10 region in Lck, which is a novel site involved in substrate recognition, binds to CD45-D2 (PMID:14625311)
• Not only is Lck dispensable for T cell activation by bacterial superantigens, but it actively inhibits this signaling pathway. (PMID:14688329)
• p56(lck) in presence of H/R regulates MEK-1-dependent ERK1/2 phosphorylation and uPA secretion through tyrosine phosphorylation of EGF receptor (PMID:14699120)
• Lck and ZAP-70 have roles in the interaction of human MUC1 and beta-catenin in activated Jurkat T cells (PMID:14766232)
• apoptotic effect of Herpesvirus saimiri Tip protein in T cells is mediated by Fas and requires the presence of active Lck in the cell (PMID:15016553)
• direct binding of the hepatitis C virus core to gC1qR on T cells leads to impaired Lck/Akt activation and T-cell function (PMID:15163734)
• following TCR stimulation, activated Lck in human T cells is degraded in the presence of an Hsp90 inhibitor; active Lck levels are influenced by two opposing processes, targeting for degradation by ubiquitination and rescue by Hsp90 monitoring. (PMID:15199125)
• In human, the cytoplasmic domain of ADAM15v2 strongly interacts with Lck and Hck and regulates leukocyte function. (PMID:15263807)
• major role for the common LCK polymorphisms in type 1 diabetes is unlikely. (PMID:15331563)
• Loss of expression of lymphocyte-specific protein tyrosine kinase lck is associated with tumor-infiltrating lymphocytes in renal cancer (PMID:15641485)
• Data suggest that, in addition to their established roles in the initiation of T cell receptor (TCR) signaling, CD45 and Lck may also influence the type of TCR signal generated. (PMID:15687496)
• calculation of the equilibrium binding constant of the phosphotyrosine peptide pYEEI to the Src homology 2 domain of human Lck (PMID:15867154)
• lck degradation plays an important role in the development of activation-induced nonresponsiveness in human cytotoxic T lymphocytes (PMID:15958529)
• intracellular M. leprae activates Erk1/2 directly by p56Lck by means of a PKCepsilon-dependent and MEK-independent signaling pathway (PMID:15967991)
• Lck enhanced Bcl-3-mediated activation of a p52/Bcl-3-responsive promoter in reporter gene assays independent of its tyrosine kinase activity, but requiring the Lck SH3 protein interaction domain (PMID:16099425)
• data suggest that flexibility between SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environments and distinct functions (PMID:16185072)
• The difference in the spatio-temporal localization of LCK and ZAP70 proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways (PMID:16219325)
• The data show that Shc is connected to the activated TCR via direct interaction with Lck. (PMID:16257509)
• Analysis of the ligand binding specificity of the lymphocyte specific kinase (Lck) SH3 domain. (PMID:16274251)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lck	ENSMUSG00000000409
rattus_norvegicus	Lck	ENSRNOG00000009705

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Tyrosine-protein kinase Lck — P06239 (reviewed: P06239)

Alternative names: Leukocyte C-terminal Src kinase, Lymphocyte cell-specific protein-tyrosine kinase, Protein YT16, Proto-oncogene Lck, T cell-specific protein-tyrosine kinase, p56-LCK

All UniProt accessions (11): P06239, A0A0S2Z3T3, A0A0S2Z3Y8, A0A8V8TKX3, A0A8V8TM09, E9PAP0, E9PI33, E9PJ92, E9PKQ8, E9PQ10, F8W6B9

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3’-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B and PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocyte migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70. Interacts with UNC119; this interaction plays a crucial role in activation of LCK. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70. Interacts with CD160. Interacts with CD48. (Microbial infection) Interacts with herpes simplex virus 1 UL46; this interaction activates LCK. (Microbial infection) Interacts with HIV-1 Nef through its SH3 domain.

Subcellular location. Cell membrane. Cytoplasm. Cytosol.

Tissue specificity. Expressed specifically in lymphoid cells.

Post-translational modifications. Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cell receptor signaling. Dephosphorylation at Tyr-394 by DUSP22 negatively regulates T-cell receptor signaling. Myristoylation is required prior to palmitoylation. Palmitoylation regulates association with the plasma membrane and could be mediated by ZDHHC2. ‘Lys-63’-linked ubiquitinated at Lys-99 and Lys-276 by UBR2; this modification is required for autophosphorylation at Tyr-394.

Disease relevance. A chromosomal aberration involving LCK is found in leukemias. Translocation t(1;7)(p34;q34) with TCRB. Immunodeficiency 22 (IMD22) [MIM:615758] A primary immunodeficiency characterized by T-cell dysfunction. Affected individuals present with lymphopenia, recurrent infections, severe diarrhea, and failure to thrive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation.

Domain organisation. The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P06239-1	Long	yes
P06239-2	Short
P06239-3	3

RefSeq proteins (3): NP_001036236, NP_001317397, NP_005347* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR035749	Lck_SH3	Domain
IPR035850	Lck_SH2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, PF00018, PF07714

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (102 total): strand 27, helix 18, sequence conflict 10, turn 9, modified residue 7, mutagenesis site 7, sequence variant 6, lipid moiety-binding region 3, domain 3, splice variant 3, cross-link 2, region of interest 2, binding site 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

57 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1LKK	X-RAY DIFFRACTION	1
2IIM	X-RAY DIFFRACTION	1
8X2P	X-RAY DIFFRACTION	1.4
1QPC	X-RAY DIFFRACTION	1.6
3LCK	X-RAY DIFFRACTION	1.7
4C3F	X-RAY DIFFRACTION	1.72
1BHF	X-RAY DIFFRACTION	1.8
1LCJ	X-RAY DIFFRACTION	1.8
1LKL	X-RAY DIFFRACTION	1.8
6PDJ	X-RAY DIFFRACTION	1.81
1BHH	X-RAY DIFFRACTION	1.9
3MPM	X-RAY DIFFRACTION	1.95
3AC1	X-RAY DIFFRACTION	1.99
1QPD	X-RAY DIFFRACTION	2
1QPE	X-RAY DIFFRACTION	2
2OF2	X-RAY DIFFRACTION	2
2OFU	X-RAY DIFFRACTION	2
2OFV	X-RAY DIFFRACTION	2
3AD5	X-RAY DIFFRACTION	2
3BYM	X-RAY DIFFRACTION	2
3BYO	X-RAY DIFFRACTION	2
6H6A	X-RAY DIFFRACTION	2
2ZM1	X-RAY DIFFRACTION	2.1
3AC2	X-RAY DIFFRACTION	2.1
3AD6	X-RAY DIFFRACTION	2.15
1IJR	X-RAY DIFFRACTION	2.2
1QPJ	X-RAY DIFFRACTION	2.2
3ACJ	X-RAY DIFFRACTION	2.2
3AD4	X-RAY DIFFRACTION	2.2
3BRH	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06239-F1	84.12	0.62

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 364 (proton acceptor)

Ligand- & substrate-binding residues (2): 251–259; 273

Post-translational modifications (12): 102, 159, 162, 192, 194, 394, 505, 2, 3, 5, 99, 276

Mutagenesis-validated functional residues (7):

Position	Phenotype
59	allows interaction with sqstm1.
99	abolishes ubr2-mediated ’lys-63’-linked ubiquitination. abolishes ubr2-mediated ’lys-63’-linked ubiquitination and autop
154	no effect on interaction with sqstm1.
273	abolished autoinhibition; when associated with f-505.
276	abolishes ubr2-mediated ’lys-63’-linked ubiquitination. abolishes ubr2-mediated ’lys-63’-linked ubiquitination and autop
394	abolishes autophosphorylation.
505	abolished autoinhibition; when associated with r-273.

Function

Pathways and Gene Ontology

Reactome pathways

53 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1433559	Regulation of KIT signaling
R-HSA-164944	Nef and signal transduction
R-HSA-167590	Nef Mediated CD4 Down-regulation
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-210990	PECAM1 interactions
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2424491	DAP12 signaling
R-HSA-389356	Co-stimulation by CD28
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-389948	Co-inhibition by PD-1
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9020558	Interleukin-2 signaling
R-HSA-9670439	Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
R-HSA-9706374	FLT3 signaling through SRC family kinases
R-HSA-109582	Hemostasis
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease

MSigDB gene sets: 572 (showing top): PID_SHP2_PATHWAY, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, FERRANDO_TAL1_NEIGHBORS, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, REACTOME_INTERLEUKIN_2_FAMILY_SIGNALING, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BIOCARTA_TCRA_PATHWAY, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION

GO Biological Process (33): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), response to xenobiotic stimulus (GO:0009410), positive regulation of gene expression (GO:0010628), hemopoiesis (GO:0030097), platelet activation (GO:0030168), T cell differentiation (GO:0030217), T cell costimulation (GO:0031295), positive regulation of heterotypic cell-cell adhesion (GO:0034116), intracellular signal transduction (GO:0035556), Fc-gamma receptor signaling pathway (GO:0038094), T cell activation (GO:0042110), gamma-delta T cell differentiation (GO:0042492), positive regulation of gamma-delta T cell differentiation (GO:0045588), regulation of regulatory T cell differentiation (GO:0045589), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), positive regulation of T cell receptor signaling pathway (GO:0050862), positive regulation of T cell activation (GO:0050870), leukocyte migration (GO:0050900), release of sequestered calcium ion into cytosol (GO:0051209), regulation of lymphocyte activation (GO:0051249), CD27 signaling pathway (GO:0160162), positive regulation of leukocyte cell-cell adhesion (GO:1903039), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), immune response-activating cell surface receptor signaling pathway (GO:0002429), protein phosphorylation (GO:0006468), intracellular zinc ion homeostasis (GO:0006882), cell surface receptor signaling pathway (GO:0007166), peptidyl-tyrosine phosphorylation (GO:0018108), peptidyl-tyrosine autophosphorylation (GO:0038083), positive regulation of MAPK cascade (GO:0043410), regulation of T cell receptor signaling pathway (GO:0050856), positive regulation of multicellular organismal process (GO:0051240)

GO Molecular Function (23): phosphotyrosine residue binding (GO:0001784), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), protein serine/threonine phosphatase activity (GO:0004722), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), phospholipase activator activity (GO:0016004), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), SH2 domain binding (GO:0042169), T cell receptor binding (GO:0042608), CD4 receptor binding (GO:0042609), CD8 receptor binding (GO:0042610), identical protein binding (GO:0042802), phospholipase binding (GO:0043274), phosphatidylinositol 3-kinase binding (GO:0043548), ATPase binding (GO:0051117), protein antigen binding (GO:1990405), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): pericentriolar material (GO:0000242), immunological synapse (GO:0001772), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane raft (GO:0045121), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
TCR signaling	4
Regulation of T cell activation by CD28 family	3
Co-stimulation by CD28	2
Platelet activation, signaling and aggregation	1
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by SCF-KIT	1
The role of Nef in HIV-1 replication and disease pathogenesis	1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1
Cell surface interactions at the vascular wall	1
PI3K/AKT Signaling in Cancer	1
DAP12 interactions	1
Negative regulation of the PI3K/AKT network	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein binding	4
signaling receptor binding	3
T cell activation	2
intracellular anatomical structure	2
antigen receptor-mediated signaling pathway	2
enzyme binding	2
enzyme-linked receptor protein signaling pathway	1
response to chemical	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell development	1
cell activation	1
blood coagulation	1
lymphocyte differentiation	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
positive regulation of cell-cell adhesion	1
heterotypic cell-cell adhesion	1
regulation of heterotypic cell-cell adhesion	1
signal transduction	1
Fc receptor signaling pathway	1
lymphocyte activation	1
T cell differentiation	1
gamma-delta T cell activation	1
gamma-delta T cell differentiation	1
positive regulation of T cell differentiation	1
regulation of gamma-delta T cell differentiation	1
positive regulation of gamma-delta T cell activation	1
regulatory T cell differentiation	1
regulation of T cell differentiation	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
regulation of T cell activation	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
immune system process	1
cell migration	1

Protein interactions and networks

STRING

4808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LCK	CD4	P01730	998
LCK	CD8A	P01732	998
LCK	CD28	P10747	996
LCK	LCP2	Q13094	995
LCK	PTPRC	P08575	993
LCK	ZAP70	P43403	986
LCK	FYN	P06241	981
LCK	SQSTM1	Q13501	979
LCK	VAV1	P15498	967
LCK	LIME1	Q9H400	951
LCK	CD2	P06729	947
LCK	CD247	P20963	945
LCK	GRB2	P29354	939
LCK	CD48	P09326	917
LCK	DLG1	Q12959	909

IntAct

243 interactions, top by confidence:

A	B	Type	Score
LCK	PTPRC	psi-mi:“MI:0915”(physical association)	0.850
PTPRC	LCK	psi-mi:“MI:0203”(dephosphorylation reaction)	0.850
PTPRC	LCK	psi-mi:“MI:0217”(phosphorylation reaction)	0.850
PTPRC	LCK	psi-mi:“MI:0407”(direct interaction)	0.850
LCK	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.830
KHDRBS1	LCK	psi-mi:“MI:0915”(physical association)	0.830
	LCK	psi-mi:“MI:0915”(physical association)	0.820
LCK		psi-mi:“MI:0915”(physical association)	0.820
	LCK	psi-mi:“MI:0407”(direct interaction)	0.820
LCK		psi-mi:“MI:0407”(direct interaction)	0.820
PTPN22	LCK	psi-mi:“MI:0914”(association)	0.780
PTPN22	LCK	psi-mi:“MI:0407”(direct interaction)	0.780
PTPN22	LCK	psi-mi:“MI:0203”(dephosphorylation reaction)	0.780
SH2D2A	LCK	psi-mi:“MI:0915”(physical association)	0.770
LCK	SH2D2A	psi-mi:“MI:0915”(physical association)	0.770

BioGRID (505): CDKAL1 (Two-hybrid), LZTS2 (Two-hybrid), LCK (Two-hybrid), BRCA1 (Two-hybrid), LCK (Protein-peptide), LCK (Co-crystal Structure), LCK (Two-hybrid), LCK (Two-hybrid), LCK (Two-hybrid), CD55 (Co-localization), DLG1 (Co-localization), LCK (Affinity Capture-Western), LCK (Biochemical Activity), PIK3R1 (Reconstituted Complex), PTK2 (Two-hybrid)

ESM2 similar proteins: A0JNB0, A1A5H8, A1Y2K1, F1LM93, F1RDG9, P00523, P00524, P00525, P00526, P00527, P05480, P06239, P06240, P06241, P07947, P07948, P08103, P08631, P09324, P09769, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P17713, P25020, P27446, P27447, P31693, P39688, P42683, P50545, P63185, Q01621, Q02977, Q04736

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

124 interactions.

A	Effect	B	Mechanism
PTPN6	“down-regulates activity”	LCK	dephosphorylation
LCK	“up-regulates activity”	CD5	phosphorylation
LCK	up-regulates	SIGLEC10	phosphorylation
LCK	unknown	SIGLEC10	phosphorylation
LCK	up-regulates	ADAM15	phosphorylation
LCK	up-regulates	PTEN	phosphorylation
LCK	up-regulates	NOTCH1	binding
PTPN22	down-regulates	LCK	dephosphorylation
LCK	up-regulates	MED28	phosphorylation
LCK	up-regulates	LAT	phosphorylation
LCK	up-regulates	MAPK1
LCK	up-regulates	MAPK3	phosphorylation
PTCRA	“up-regulates activity”	LCK	binding
CCT239065	down-regulates	LCK	“chemical inhibition”
LCK	up-regulates	CD28	phosphorylation
LCK	down-regulates	FOXP3	phosphorylation
CSK	down-regulates	LCK	phosphorylation
SYK	“down-regulates activity”	LCK	phosphorylation
LCK	“up-regulates activity”	MUC1	phosphorylation
PTPRC	“up-regulates activity”	LCK	dephosphorylation
PTPRC	“down-regulates activity”	LCK	dephosphorylation
PTPN22	“down-regulates activity”	LCK	dephosphorylation
LCK	“up-regulates activity”	ZAP70	phosphorylation
MAPK1	“up-regulates activity”	LCK	phosphorylation
MAPK3	“up-regulates activity”	LCK	phosphorylation
LCK	“up-regulates quantity by stabilization”	CTLA4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of signaling by CBL	9	66.7×	3e-12
Phosphorylation of CD3 and TCR zeta chains	8	64.9×	4e-11
Regulation of KIT signaling	6	53.8×	8e-08
Negative regulation of FLT3	5	53.3×	1e-06
GAB1 signalosome	5	47.4×	2e-06
Translocation of ZAP-70 to Immunological synapse	5	47.4×	2e-06
Signaling by CSF1 (M-CSF) in myeloid cells	9	46.5×	4e-11
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	46.5×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
Fc-gamma receptor signaling pathway involved in phagocytosis	6	56.9×	1e-07
negative regulation of inflammatory response to antigenic stimulus	5	40.7×	1e-05
peptidyl-tyrosine phosphorylation	7	39.9×	7e-08
positive regulation of interleukin-4 production	5	38.0×	1e-05
T cell differentiation	7	36.2×	1e-07
T cell costimulation	7	35.4×	1e-07
positive regulation of calcium-mediated signaling	6	34.2×	2e-06
T cell activation	9	31.5×	4e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

328 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	9
Uncertain significance	103
Likely benign	192
Benign	7

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1038789	NM_005356.5(LCK):c.415del (p.Arg139fs)	Pathogenic
127135	NM_005356.5(LCK):c.1022T>C (p.Leu341Pro)	Pathogenic
1411689	NM_005356.5(LCK):c.477del (p.Ala160fs)	Pathogenic
2041799	NM_005356.5(LCK):c.115C>T (p.Arg39Ter)	Pathogenic
2858686	NM_005356.5(LCK):c.1126del (p.Thr375_Leu376insTer)	Pathogenic
3064211	NM_005356.5(LCK):c.188-2A>G	Pathogenic
3064212	NM_005356.5(LCK):c.1393T>C (p.Cys465Arg)	Pathogenic
3064214	NM_005356.5(LCK):c.1318C>T (p.Pro440Ser)	Pathogenic
847660	NM_005356.5(LCK):c.1201A>T (p.Lys401Ter)	Pathogenic
1804705	NM_005356.5(LCK):c.277C>T (p.Gln93Ter)	Likely pathogenic
2068900	NM_005356.5(LCK):c.481+2T>G	Likely pathogenic
3376436	NM_005356.5(LCK):c.1515C>A (p.Tyr505Ter)	Likely pathogenic
3689457	NM_005356.5(LCK):c.785-1G>A	Likely pathogenic
3779812	NM_005356.5(LCK):c.584dup (p.Arg196fs)	Likely pathogenic
4723903	NM_005356.5(LCK):c.482-1G>A	Likely pathogenic
4735122	NM_005356.5(LCK):c.1042-1G>T	Likely pathogenic
4761675	NM_005356.5(LCK):c.481+1G>A	Likely pathogenic
804376	NM_005356.5(LCK):c.1129dup (p.Ser377fs)	Likely pathogenic

SpliceAI

1666 predictions. Top by Δscore:

Variant	Effect	Δscore
1:32274321:TCAG:T	acceptor_loss	1.0000
1:32274322:CA:C	acceptor_loss	1.0000
1:32274323:A:AG	acceptor_gain	1.0000
1:32274323:AG:A	acceptor_gain	1.0000
1:32274324:G:GG	acceptor_gain	1.0000
1:32274324:GG:G	acceptor_gain	1.0000
1:32274433:CGGT:C	donor_loss	1.0000
1:32274435:G:C	donor_loss	1.0000
1:32274436:T:A	donor_loss	1.0000
1:32274736:GC:G	acceptor_gain	1.0000
1:32275079:GAGCA:G	donor_gain	1.0000
1:32275081:GCA:G	donor_gain	1.0000
1:32275084:G:GG	donor_gain	1.0000
1:32275205:C:G	donor_gain	1.0000
1:32275209:G:GG	donor_gain	1.0000
1:32275415:GAACC:G	donor_gain	1.0000
1:32275420:G:GG	donor_gain	1.0000
1:32275567:AGCT:A	acceptor_gain	1.0000
1:32275568:GCT:G	acceptor_gain	1.0000
1:32275568:GCTG:G	acceptor_gain	1.0000
1:32275897:T:G	acceptor_gain	1.0000
1:32275900:A:AG	acceptor_gain	1.0000
1:32275901:T:G	acceptor_gain	1.0000
1:32275904:A:AG	acceptor_gain	1.0000
1:32275905:T:G	acceptor_gain	1.0000
1:32275908:A:AG	acceptor_gain	1.0000
1:32275909:T:G	acceptor_gain	1.0000
1:32275912:AG:A	acceptor_gain	1.0000
1:32275913:GG:G	acceptor_gain	1.0000
1:32275913:GGATC:G	acceptor_gain	1.0000

AlphaMissense

3344 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:32275068:T:C	L88P	1.000
1:32275570:T:A	W127R	1.000
1:32275570:T:C	W127R	1.000
1:32275591:C:A	R134S	1.000
1:32275600:G:C	A137P	1.000
1:32275613:T:A	L141H	1.000
1:32275613:T:C	L141P	1.000
1:32275642:T:C	F151L	1.000
1:32275644:C:A	F151L	1.000
1:32275644:C:G	F151L	1.000
1:32275646:T:C	L152P	1.000
1:32275649:T:A	I153N	1.000
1:32275652:G:C	R154P	1.000
1:32275926:T:C	L165P	1.000
1:32275928:T:C	S166P	1.000
1:32275932:T:A	V167D	1.000
1:32275935:G:C	R168P	1.000
1:32275970:C:G	H180D	1.000
1:32275971:A:G	H180R	1.000
1:32275972:T:A	H180Q	1.000
1:32275972:T:G	H180Q	1.000
1:32275973:T:C	Y181H	1.000
1:32275973:T:G	Y181D	1.000
1:32275976:A:G	K182E	1.000
1:32275978:G:C	K182N	1.000
1:32275978:G:T	K182N	1.000
1:32275980:T:A	I183N	1.000
1:32275980:T:C	I183T	1.000
1:32275980:T:G	I183S	1.000
1:32275983:G:C	R184P	1.000

dbSNP variants (sampled 300 via entrez): RS1000065202 (1:32268578 T>C), RS1000131336 (1:32269295 G>A), RS1000167280 (1:32264438 C>T), RS1000198232 (1:32264727 C>T), RS1000356219 (1:32284129 C>T), RS1000506377 (1:32250857 G>A), RS1000543759 (1:32265939 A>C), RS1000680233 (1:32270960 C>T), RS1000685606 (1:32259369 C>T), RS1000761236 (1:32257441 G>A), RS1000812274 (1:32253137 G>A), RS1000864590 (1:32252847 G>A), RS1001065542 (1:32256363 G>A), RS1001101507 (1:32256674 A>C), RS1001149025 (1:32254466 G>A)

Disease associations

OMIM: gene MIM:153390 | disease phenotypes: MIM:615758

GenCC curated gene-disease

Disease	Classification	Inheritance
severe combined immunodeficiency due to LCK deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
severe combined immunodeficiency due to LCK deficiency	Definitive	AR

Mondo (2): severe combined immunodeficiency due to LCK deficiency (MONDO:0014334), severe combined immunodeficiency (MONDO:0015974)

Orphanet (2): Combined immunodeficiency due to LCK deficiency (Orphanet:280142), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001508	Failure to thrive
HP:0001541	Ascites
HP:0001701	Pericarditis
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004385	Protracted diarrhea
HP:0005479	Decreased circulating IgE concentration
HP:0009098	Chronic oral candidiasis
HP:0011463	Childhood onset
HP:0012490	Panniculitis
HP:0025188	Retinal vasculitis
HP:0025615	Abscess
HP:0030005	Capillary leak
HP:0032218	Decreased CD4+ T cell proportion
HP:0004430	Severe combined immunodeficiency

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009597_84	Multiple sclerosis	1.000000e-15

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL2363074 (PROTEIN FAMILY), CHEMBL258 (SINGLE PROTEIN), CHEMBL4523727 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523978 (SELECTIVITY GROUP), CHEMBL5291685 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066027 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066564 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

126 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 332,442 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1009	LEVODOPA	4	103,854
CHEMBL11359	CISPLATIN	4
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1200558	BACITRACIN	4	154
CHEMBL1200748	CARBIDOPA	4	354
CHEMBL1201469	GRAMICIDIN	4
CHEMBL1201631	INSULIN HUMAN	4
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2103743	TOFACITINIB CITRATE	4
CHEMBL2105712	AFATINIB DIMALEATE	4
CHEMBL2105717	CABOZANTINIB	4
CHEMBL2110732	DACOMITINIB ANHYDROUS	4
CHEMBL221959	TOFACITINIB	4
CHEMBL2403108	CERITINIB	4
CHEMBL24828	VANDETANIB	4
CHEMBL24944	TRIBROMSALAN	4
CHEMBL255863	NILOTINIB	4
CHEMBL288441	BOSUTINIB	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Src family

Most potent curated ligand interactions (29 total), top 25:

Ligand	Action	Affinity	Parameter
eCF506	Inhibition	9.3	pIC50
Lck inhibitor	Inhibition	9.0	pIC50
compound 2 [PMID: 15546730]	Inhibition	9.0	pIC50
WH-4-023	Inhibition	8.7	pIC50
CCT241161	Inhibition	8.52	pIC50
saracatinib	Inhibition	8.4	pIC50
PP2	Inhibition	8.4	pIC50
compound 30 [PMID: 17280833]	Inhibition	8.3	pIC50
PP1	Inhibition	8.3	pIC50
nefextinib	Inhibition	8.26	pIC50
ibrutinib	Inhibition	8.2	pIC50
compound 23 [PMID: 17600705]	Inhibition	8.07	pIC50
dorsomorphin	Inhibition	7.8	pIC50
CCT196969	Inhibition	7.7	pIC50
belizatinib	Inhibition	7.55	pKd
compound 7 [PMID: 22464456]	Inhibition	7.41	pIC50
7-hydroxystaurosporine	Inhibition	7.3	pIC50
JNJ-28312141	Inhibition	7.06	pIC50
SU6656	Inhibition	6.82	pIC50
ZAK inhibitor 6p	Inhibition	6.8	pKd
xiliertinib	Inhibition	6.75	pIC50
DDR1/2 inhibitor 5n	Inhibition	6.74	pKd
compound 19a [PMID: 21855335]	Inhibition	6.74	pIC50
compound 36 [PMID: 21958547]	Inhibition	6.11	pIC50
pexidartinib	Inhibition	6.07	pIC50

Binding affinities (BindingDB)

367 measured of 681 human assays (693 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(2-Chloro-6-methylphenyl)-2-(6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino)-1,3-thiazole-5-carboxamide	IC50	0.2 nM
N-(2,6-dimethylphenyl)-2-(pyridazin-3-ylamino)-1,3-thiazole-5-carboxamide	IC50	0.3 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
N-(2-Chloro-6-methylphenyl)-2-[(4-methyl-2-pyridinyl)amino]-1,3-thiazole-5-carboxamide	IC50	0.5 nM
N-(2-Chloro-6-methylphenyl)-2-(6-(3-morpholinopropylamino)pyridin-2-ylamino)-1,3-thiazole-5-carboxamide	IC50	0.5 nM
N-(2-chloro-6-methylphenyl)-2-{[6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1,3-thiazole-5-carboxamide	IC50	0.5 nM
N-(2-chloro-6-methylphenyl)-2-({6-[(2-hydroxyethyl)amino]pyridin-2-yl}amino)-1,3-benzothiazole-6-carboxamide	IC50	0.5 nM
N-(2-chloro-6-methylphenyl)-2-[(6-methylpyridin-2-yl)amino]-1,3-thiazole-5-carboxamide	IC50	0.6 nM
N-(2-Chloro-6-methylphenyl)-2-(2-methyl-6-(3-morpholinopropyl)-pyrimidin-4-ylamino)-1,3-thiazole-5-carboxamide	IC50	0.7 nM
N-(2-Chloro-6-methylphenyl)-2-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpyrimidin-4-ylamino)-1,3-thiazole-5-carboxamide	IC50	0.7 nM
1-[3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	IC50	0.8 nM	US-9975882: Heteroaromatic compounds as BTK inhibitors
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-(2-Chloro-6-methylphenyl)-2-[(2,6-dimethyl-4-pyrimidinyl)-amino]-1,3-thiazole-5-carboxamide	IC50	1 nM
4-Methyl-3-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)-N-(3-(trifluoromethyl)phenyl)benzamide	IC50	1 nM
3-(2-aminoquinazolin-6-yl)-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide	IC50	1 nM
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-(2-chloro-6-methylphenyl)-2-(pyridin-2-ylamino)-1,3-thiazole-5-carboxamide	IC50	1.2 nM
N-(2,6-dimethylphenyl)-2-(pyridin-2-ylamino)-1,3-thiazole-5-carboxamide	IC50	1.2 nM
N-(2-Chloro-6-methylphenyl)-2-(2-methyl-6-morpholinopyrimidin-4-ylamino)-1,3-thiazole-5-carboxamide	IC50	1.3 nM
Staurosporine	KD	1.7 nM
4-Methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzamide	IC50	1.8 nM
3-(2-(3H-Imidazo[4,5-b]pyridin-6-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide	IC50	2 nM
1-[(2S)-2-[[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]prop-2-en-1-one	IC50	2.3 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one	KD	2.8 nM
2-[(2,6-dimethylpyrimidin-4-yl)amino]-N-(2,4,6-trimethylphenyl)-1,3-thiazole-5-carboxamide	IC50	3 nM
3-(2-(2-Aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide	IC50	3 nM
3-[2-(6-aminopyridin-3-yl)ethynyl]-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide	IC50	3 nM
6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methylpyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	3 nM	US-20250197405: HETEROAROMATIC COMPOUNDS AS PKMYT1 INHIBITORS AND USE THEREOF
4-Methyl-3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide	IC50	3.6 nM
(3R,4R)-3-methoxy-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	3.93 nM	US-10189849: CDK inhibitors
N-(2-chloro-6-methylphenyl)-2-(pyridazin-3-ylamino)-1,3-thiazole-5-carboxamide	IC50	4 nM
N-(2-Chloro-6-methylphenyl)-2-[(4,6-dimethyl-2-pyridinyl)-amino]-1,3-thiazole-5-carboxamide	IC50	4 nM
2-(pyrazin-2-ylamino)-N-(2,4,6-trimethylphenyl)-1,3-thiazole-5-carboxamide	IC50	4.9 nM
2-(pyridin-2-ylamino)-N-(2,4,6-trimethylphenyl)-1,3-thiazole-5-carboxamide	IC50	5 nM
5-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-{2-[(3S)-3-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)phenyl}-2-fluorobenzamide	IC50	5 nM
3-[[2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridin-7-yl]amino]phenol	IC50	5.1 nM	US-9062066: Anti-inflammatory compound having inhibitory activity against multiple tyrosine kinases and pharmaceutical composition containing same
aminoisoquinoline, 16	IC50	5.8 nM
1-tert-butyl-3-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine	IC50	6 nM
N-(2-Chloro-6-methylphenyl)-2-[(3,5-dimethyl-2-pyrazinyl)-amino]-1,3-thiazole-5-carboxamide	IC50	6.3 nM
N-(2-Chloro-6-methylphenyl)-2-[(3-pyridinyl)amino]-1,3-thiazole-5-carboxamide	IC50	6.7 nM
6-(2,6-dichlorophenyl)-8-methyl-2-{[3-(methylsulfanyl)phenyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one	IC50	7.9 nM
5-(2-(2-Aminopyrimidin-5-yl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide	IC50	8 nM
aminoisoquinoline, 15	IC50	8.1 nM
6-N-(2-chloro-6-methylphenyl)-2-N-cyclopropane-1,3-benzothiazole-2,6-dicarboxamide	IC50	9 nM
N-(2-chloro-6-methylphenyl)-2-(pyridin-4-ylamino)-1,3-thiazole-5-carboxamide	IC50	9.4 nM
4-Methyl-3-(2-(quinolin-3-yl)ethynyl)-N-(3-(trifluoromethyl)-phenyl)benzamide	IC50	10 nM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
BIIB-057	IC50	10.5 nM
3-(2-(2-Aminopyrimidin-5-yl)ethynyl)-N-(3-(trifluoromethyl)-phenyl)benzamide	IC50	11 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM

ChEMBL bioactivities

2826 potent at pChembl≥5 of 3006 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL215969
10.40	Ki	0.04	nM	CHEMBL458333
10.22	IC50	0.06	nM	CHEMBL566813
10.15	IC50	0.07	nM	CHEMBL212181
10.15	IC50	0.07	nM	CHEMBL569496
10.15	IC50	0.07	nM	CHEMBL566284
9.92	IC50	0.12	nM	CHEMBL572197
9.70	IC50	0.2	nM	CHEMBL215943
9.70	IC50	0.2	nM	CHEMBL385937
9.70	IC50	0.2	nM	CHEMBL386118
9.70	Kd	0.2	nM	DASATINIB
9.70	IC50	0.2	nM	CHEMBL568762
9.70	IC50	0.2	nM	CHEMBL565263
9.70	Kd	0.2	nM	CHEMBL1234002
9.60	IC50	0.25	nM	CHEMBL569052
9.57	IC50	0.27	nM	CHEMBL212964
9.55	IC50	0.28	nM	PONATINIB
9.52	IC50	0.3	nM	CHEMBL212964
9.52	IC50	0.3	nM	CHEMBL212128
9.52	IC50	0.3	nM	CHEMBL427233
9.52	IC50	0.3	nM	CHEMBL405630
9.52	IC50	0.3	nM	CHEMBL407063
9.52	IC50	0.3	nM	CHEMBL607366
9.40	IC50	0.4	nM	CHEMBL214530
9.40	IC50	0.4	nM	CHEMBL212900
9.40	IC50	0.4	nM	CHEMBL213831
9.40	IC50	0.4	nM	DASATINIB
9.40	IC50	0.4	nM	CHEMBL429582
9.40	IC50	0.4	nM	CHEMBL364623
9.40	IC50	0.4	nM	CHEMBL569272
9.40	IC50	0.4	nM	CHEMBL568759
9.39	IC50	0.41	nM	CHEMBL591324
9.36	IC50	0.44	nM	CHEMBL595398
9.35	IC50	0.45	nM	CHEMBL566507
9.30	IC50	0.5	nM	CHEMBL312933
9.30	IC50	0.5	nM	CHEMBL281957
9.30	IC50	0.5	nM	CHEMBL215745
9.30	IC50	0.5	nM	CHEMBL212953
9.30	IC50	0.5	nM	CHEMBL386661
9.30	IC50	0.5	nM	CHEMBL215019
9.30	IC50	0.5	nM	CHEMBL189649
9.30	IC50	0.5	nM	CHEMBL273250
9.30	IC50	0.5	nM	CHEMBL186568
9.30	IC50	0.5	nM	CHEMBL408070
9.29	IC50	0.51	nM	CHEMBL592260
9.27	Ki	0.54	nM	CHEMBL432189
9.26	IC50	0.55	nM	CHEMBL592262
9.25	IC50	0.56	nM	CHEMBL596079
9.23	Kd	0.59	nM	BOSUTINIB
9.22	IC50	0.6	nM	CHEMBL386760

PubChem BioAssay actives

2258 with measured affinity, of 5660 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[2-(methylamino)quinazolin-6-yl]-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	<0.0001	uM
3-N-(2,6-dimethylphenyl)-1-(3-methoxy-3-methylbutyl)-6-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrazolo[3,4-d]pyrimidine-3,6-diamine	411391: Inhibition of LCK	ki	<0.0001	uM
3-[2-(cyclopropylamino)quinazolin-6-yl]-4-methyl-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0001	uM
(3S)-4-methyl-N-naphthalen-1-yl-3-[(1S)-1-[[4-(5-pyridin-4-ylbenzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]piperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0001	uM
(3S)-3-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-4-methyl-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0001	uM
(3S)-3-[(1S)-1-[[4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]pyrimidin-2-yl]amino]ethyl]-4-methyl-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0001	uM
(3S)-3-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-4-ethyl-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0001	uM
N-(2-chloro-6-methylphenyl)-2-[[6-(2-hydroxyethylamino)-2-pyridinyl]amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0002	uM
N-(2-chloro-6-methylphenyl)-2-[[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0002	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	435676: Binding constant for LCK kinase domain	kd	0.0002	uM
3-(2-aminoquinazolin-6-yl)-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide	1798673: HTRF Kinase Inhibition Assay from Article 10.1021/jm7010996: “Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.”	ic50	0.0002	uM
4-methyl-3-[2-(2-morpholin-4-ylethylamino)quinazolin-6-yl]-N-[3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0002	uM
3-(2,6-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-1-methyl-4H-pyrimido[4,5-d]pyrimidin-2-one	592304: Inhibition of LCK	kd	0.0002	uM
(3S)-3-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-4-(2-methylpropyl)-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0002	uM
(3S)-3-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-N-naphthalen-1-yl-4-pyridin-4-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0002	uM
9-(2-aminoethoxy)-2-(4-phenoxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0003	uM
4-methyl-3-[2-(methylamino)quinazolin-6-yl]-N-[3-(trifluoromethyl)phenyl]benzamide	1799308: In Vitro BRAF Kinase Assay from Article 10.1021/jm901081g: “Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline.”	ic50	0.0003	uM
N-[4-methyl-3-[2-(methylamino)quinazolin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0003	uM
N-(2,3-dihydro-1H-inden-4-yl)-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0003	uM
5-[[3-fluoro-5-(trifluoromethyl)benzoyl]amino]-2-methyl-N-[2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-5-yl]benzamide	1798673: HTRF Kinase Inhibition Assay from Article 10.1021/jm7010996: “Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.”	ic50	0.0003	uM
3-[1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-4-methyl-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0003	uM
N-(2,6-dimethylphenyl)-2-(pyridazin-3-ylamino)-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0003	uM
Ponatinib	1716392: Binding affinity to human LCK using poly[Glu:Tyr] (4:1) as substrate by radiometric hotspot kinase assay	ic50	0.0003	uM
3-(2-aminoquinazolin-6-yl)-4-chloro-N-[3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0004	uM
8-(2-aminoethoxy)-2-(4-phenoxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0004	uM
8-[2-(dimethylamino)ethoxy]-2-(4-hydroxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0004	uM
4-methyl-3-[2-(methylamino)quinazolin-6-yl]-N-[2-(2-morpholin-4-ylethylcarbamoylamino)-5-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0004	uM
4-methyl-N-[2-methyl-3-(trifluoromethyl)phenyl]-3-[2-(3-morpholin-4-ylpropylamino)quinazolin-6-yl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0004	uM
(3S)-3-[(1S)-1-[[4-[5-(3-ethyl-2-oxoimidazolidin-1-yl)benzimidazol-1-yl]pyrimidin-2-yl]amino]ethyl]-4-methyl-N-naphthalen-1-ylpiperazine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0004	uM
N-[3-(2-aminoquinazolin-6-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	1798673: HTRF Kinase Inhibition Assay from Article 10.1021/jm7010996: “Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.”	ic50	0.0004	uM
Dasatinib	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0004	uM
(3S)-3-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-N-naphthalen-1-ylpiperidine-1-carboxamide	449343: Inhibition of Lck	ic50	0.0004	uM
ethyl 2-[(2S)-2-[(1S)-1-[[4-(benzimidazol-1-yl)pyrimidin-2-yl]amino]ethyl]-4-(naphthalen-1-ylcarbamoyl)piperazin-1-yl]acetate	449343: Inhibition of Lck	ic50	0.0004	uM
N-(2-chloro-6-methylphenyl)-2-[[6-(3-morpholin-4-ylpropylamino)-2-pyridinyl]amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0005	uM
N-(2-chloro-6-methylphenyl)-2-[[6-(3-imidazol-1-ylpropylamino)-2-pyridinyl]amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0005	uM
N-(2-chloro-6-methylphenyl)-2-[(6-morpholin-4-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0005	uM
9-[3-(dimethylamino)propoxy]-2-(4-phenoxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0005	uM
N-[2-[[2-(diethylamino)acetyl]amino]-5-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0005	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)quinazolin-6-yl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0005	uM
4-methyl-3-[2-(methylamino)quinazolin-6-yl]-N-[2-(1-methylpiperidin-4-yl)oxy-5-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0005	uM
2-fluoro-4-methyl-5-[2-(methylamino)quinazolin-6-yl]-N-[3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0005	uM
N-(2-chloro-6-methylphenyl)-2-[(4-methyl-2-pyridinyl)amino]-1,3-thiazole-5-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0005	uM
4-methyl-3-N-[2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-5-yl]-1-N-[3-(trifluoromethyl)phenyl]benzene-1,3-dicarboxamide	1798673: HTRF Kinase Inhibition Assay from Article 10.1021/jm7010996: “Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.”	ic50	0.0005	uM
N-(2-chloro-6-methylphenyl)-2-[[6-methyl-2-(oxolan-2-ylmethylamino)pyrimidin-4-yl]amino]-1,3-benzothiazole-6-carboxamide	224139: Inhibition of p56 Lck tyrosine kinase	ki	0.0005	uM
2-(2,6-dichloroanilino)-7-[(E)-3-(diethylamino)prop-1-enyl]-1,6-dimethyl-8H-imidazo[4,5-h]isoquinolin-9-one	224146: Inhibition of p56 Lck tyrosine kinase	ic50	0.0005	uM
N-(2-chloro-6-methylphenyl)-2-[[6-(2-hydroxyethylamino)-2-pyridinyl]amino]-1,3-benzothiazole-6-carboxamide	1797004: Lck Kinase Inhibition Assay from Article 10.1021/jm060727j: “2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase i”	ic50	0.0005	uM
3-(2-aminoquinazolin-6-yl)-4-methyl-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide	270658: Inhibition of Lck by HTRF kinase assay	ic50	0.0006	uM
(2,6-dimethylphenyl) N-[2-[3,5-dimethoxy-4-[3-(4-methylpiperazin-1-yl)propoxy]anilino]pyrimidin-4-yl]-N-(2,4-dimethoxyphenyl)carbamate	1797647: HTRF Kinase Inhibition Assay from Article 10.1021/jm060435i: “Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.”	ic50	0.0006	uM
9-[2-(4-methylpiperazin-1-yl)ethoxy]-2-(4-phenoxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0006	uM
8-(2-morpholin-4-ylethoxy)-2-(4-phenoxyphenyl)-6,11-dihydro-5H-pyrazolo[5,1-b][1,3]benzodiazepine-1-carboxamide	452195: Inhibition of GST-tagged human LCK by scintillation counting	ic50	0.0006	uM

CTD chemical–gene interactions

83 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	4
(+)-JQ1 compound	decreases expression, increases expression	3
Estradiol	decreases expression, increases expression, affects cotreatment	3
Tetrachlorodibenzodioxin	decreases reaction, increases expression	3
sodium arsenite	decreases expression, increases expression	2
chromium hexavalent ion	affects reaction, increases expression, increases phosphorylation, increases activity	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Ascorbic Acid	affects binding, affects cotreatment, decreases expression, decreases reaction, increases phosphorylation	2
Methotrexate	affects cotreatment, decreases expression, affects response to substance	2
Potassium Dichromate	decreases reaction, increases phosphorylation, affects reaction, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
biochanin A	increases phosphorylation, decreases reaction	1
methylmercuric chloride	increases expression	1
oxybenzone	decreases expression	1
propionaldehyde	decreases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases expression	1
manganese chloride	decreases reaction, affects cotreatment, increases phosphorylation	1
4-hydroxy-2-nonenal	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, decreases expression	1
1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene	decreases expression	1
7-hydroxystaurosporine	decreases activity	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
bis(2-hydroxy-2-ethylbutanoato)oxochromate(V)	decreases reaction, increases phosphorylation	1

ChEMBL screening assays

1393 unique, capped per target: 1379 binding, 8 functional, 5 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5719121	Binding	Inhibition of Src family in human RPMI-8226 cells assessed as reduction of cell growth incubated for 72 hrs by CellTiter 96 aqueous one solution cell proliferation assay	Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma. — Oncotarget
CHEMBL1963718	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: LCK	PubChem BioAssay data set
CHEMBL4414923	ADMET	Inhibition of human LCK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. — J Med Chem

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1150	CTV-1	Cancer cell line	Male
CVCL_8150	MOLT-15	Cancer cell line	Male
CVCL_B7VA	Abcam Jurkat LCK KO	Cancer cell line	Male
CVCL_B8JM	Abcam HCT 116 LCK KO	Cancer cell line	Male
CVCL_B8YA	Abcam MCF-7 LCK KO	Cancer cell line	Female
CVCL_B9LW	Abcam A-549 LCK KO	Cancer cell line	Male
CVCL_XF42	JCaM1/Lck+	Cancer cell line	Male
CVCL_XF43	JCaM1/LckR154K	Cancer cell line	Male

Clinical trials (associated diseases)

44 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts