ALK

Summary

ALK (ALK receptor tyrosine kinase, HGNC:427) is a protein-coding gene on chromosome 2p23.2-p23.1, encoding ALK tyrosine kinase receptor (Q9UM73). Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. In precision oncology, ALK Mutation confers sensitivity to Lorlatinib in Lung Non-small Cell Carcinoma (CIViC Level A); 95 further curated variant–drug associations are listed below.

This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).

Source: NCBI Gene 238 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuroblastoma, susceptibility to, 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 6,456 total — 19 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes — 61 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 96 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004304

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:427
Approved symbol	ALK
Name	ALK receptor tyrosine kinase
Location	2p23.2-p23.1
Locus type	gene with protein product
Status	Approved
Aliases	CD246, ALK1
Ensembl gene	ENSG00000171094
Ensembl biotype	protein_coding
OMIM	105590
Entrez	238

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000389048, ENST00000431873, ENST00000453137, ENST00000498037, ENST00000618119, ENST00000638605, ENST00000642122

RefSeq mRNA: 2 — MANE Select: NM_004304 NM_001353765, NM_004304

CCDS: CCDS33172, CCDS86828

Canonical transcript exons

ENST00000389048 — 29 exons

Exon	Start	End
ENSE00001140354	29192774	29193922
ENSE00001154361	29196770	29196860
ENSE00001154367	29197542	29197676
ENSE00001154381	29209786	29209878
ENSE00001154390	29213984	29214081
ENSE00001154395	29220706	29220835
ENSE00001154399	29222344	29222408
ENSE00001154403	29222517	29222607
ENSE00001154407	29223342	29223528
ENSE00001154411	29225461	29225565
ENSE00001154417	29226922	29227074
ENSE00001154420	29227574	29227672
ENSE00001154426	29232304	29232448
ENSE00001154428	29233565	29233696
ENSE00001154433	29239680	29239830
ENSE00001255591	29228884	29229066
ENSE00001255625	29275099	29275227
ENSE00001255635	29275402	29275496
ENSE00001255668	29320751	29320882
ENSE00001255673	29328350	29328481
ENSE00001255693	29383732	29383859
ENSE00001290865	29694850	29695014
ENSE00001313023	29717578	29717697
ENSE00001313033	29531915	29532116
ENSE00001329399	29251105	29251267
ENSE00001682043	29207171	29207272
ENSE00001794937	29919993	29921586
ENSE00003584441	29318304	29318404
ENSE00003638382	29296888	29297057

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 85.61.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3489 / max 2521.9109, expressed in 256 samples.

FANTOM5 promoters (24 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27658	1.4789	177
27595	0.3449	50
27659	0.3409	45
27649	0.0288	5
27647	0.0156	4
27646	0.0134	2
27648	0.0122	2
27599	0.0117	3
27657	0.0115	2
27655	0.0108	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	85.61	gold quality
male germ cell	CL:0000015	85.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.22	gold quality
type B pancreatic cell	CL:0000169	83.34	gold quality
olfactory bulb	UBERON:0002264	83.23	gold quality
ventral tegmental area	UBERON:0002691	78.37	gold quality
cervix squamous epithelium	UBERON:0006922	77.67	gold quality
diaphragm	UBERON:0001103	77.39	gold quality
superior vestibular nucleus	UBERON:0007227	77.39	gold quality
medial globus pallidus	UBERON:0002477	77.03	silver quality
subthalamic nucleus	UBERON:0001906	76.80	silver quality
buccal mucosa cell	CL:0002336	76.70	silver quality
dorsal plus ventral thalamus	UBERON:0001897	76.44	silver quality
globus pallidus	UBERON:0001875	76.35	silver quality
thymus	UBERON:0002370	76.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	75.67	gold quality
inferior vagus X ganglion	UBERON:0005363	75.22	silver quality
cerebellar vermis	UBERON:0004720	74.78	silver quality
middle temporal gyrus	UBERON:0002771	74.13	gold quality
vena cava	UBERON:0004087	74.02	gold quality
trachea	UBERON:0003126	73.82	gold quality
pharyngeal mucosa	UBERON:0000355	73.76	gold quality
cardia of stomach	UBERON:0001162	73.68	gold quality
trigeminal ganglion	UBERON:0001675	73.35	silver quality
nipple	UBERON:0002030	73.25	gold quality
body of tongue	UBERON:0011876	73.15	gold quality
dorsal root ganglion	UBERON:0000044	73.10	silver quality
superior surface of tongue	UBERON:0007371	73.06	gold quality
tongue	UBERON:0001723	73.04	gold quality
pericardium	UBERON:0002407	72.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPB, ESR1, JUNB, PHOX2B, STAT5A, TCF23, TXK

miRNA regulators (miRDB)

60 targeting ALK, 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-4713-3P	100.00	65.92	505
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-378G	99.71	64.90	1106

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth (PMID:11809760)
• ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes. (PMID:11877285)
• ALK-positive anaplastic large cell lymphoma had significantly higher levels of caspase 3, while high expression of the antiapoptotic proteins Bcl-2 and PI9 was almost completely restricted to ALK-negative cases. (PMID:12036886)
• Novel fusion partners CARS and KIAA1618 (ALO17) have been detected with variant rearrangements of ALK in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor cases. (PMID:12112524)
• results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation (PMID:12115586)
• midkine binds to ALK and has a role in signal transduction for cell growth and survival (PMID:12122009)
• ALK-ShcC signal activation, possibly caused by co-amplification with the N-myc gene, might give additional effects on malignant tumor progression of neuroblastoma.ShcC is a potent substrate of the activated ALK kinase. (PMID:12185581)
• co-expression of c-Myc and ALK was seen in tumor cells of ALK-positive anaplastic large cell lymphomas; C-Myc may be a downstream target of ALK signaling (PMID:12213716)
• novel fusion created by the ALK gene on chromosome 2p23 and NPM on 5q35 or other variant translocation partners in a rare variant of diffuse large B-cell lymphoma (PMID:12763927)
• In a case of anaplastic large cell lymphoma, ALK is fused to a portion of non-muscle myosin heavy chain gene, MYH9, localized 6 bp downstream of MSN-ALK in the same exonic sequence, resulting in an in-frame fusion of the two partner proteins. (PMID:12800156)
• Src-kinases, particularly pp60(c-src), associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with large cell lymphoma (PMID:14563642)
• results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity (PMID:14656879)
• FOXO3a is a barrier to hematopoietic transformation that is overcome by phosphorylation and cytoplasmic relocalization induced by the expression of NPM-ALK (PMID:14962911)
• High dose therapy and stem cell transplantation does not produce long-term disease free survival in patients with recurrent chemotherapy-sensitive ALK-negative large cell lymphoma. (PMID:15004538)
• STAT3 directly contributes to the high level of TIMP1 expression in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. (PMID:15161657)
• ALK receptor tyrosine kinase has roles promoting cell growth and neurite outgrowth (PMID:15226403)
• ALK has roles in oncogenesis of haematopoietic and non-haematopoietic tumors [review] (PMID:15583856)
• Although 9 of 36 patients with cutaneous CD30(+) lymphoproliferative diseases had progression of their disease, neither mutations of the p53 gene nor ALK immunoreactivity were found in any of these biopsies. (PMID:15713979)
• analysis of differentiation of PC12 cells and human embryonic kidney 293 cells transfected with ALK shows absence of agonist activity of pleiotrophin (PMID:15886198)
• ALK-mediated alphaDGK activation is dependent on p60src tyrosine kinase, with which alphaDGK forms a complex; alphaDGK activation is involved in the control of ALK-mediated mitogenic properties. (PMID:15928040)
• CONCLUSIONS: ALK-ALCL arising in the skin represents a single disease with a broad spectrum of morphology; clinicians and pathologists should be aware of this neutrophil-rich (NR) variant with aggressive clinical presentation. (PMID:15933425)
• We conclude that Jak3 activation is predominantly restricted to ALK-positive ALCL tumors. (PMID:16153455)
• Genomic PCR and subsequent sequencing showed that the breakpoints were located in intron 23 of SEC31-like 1 protein-transport protein and intron 20 of ALK (PMID:16161041)
• Potent and selective ALK inhibitors may have therapeutic application for anaplastic lymphoma kinase. (PMID:16254137)
• Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract may show ALK immunopositivity but do not show consistent ALK rearrangement by fluorescent in situ hybridization. (PMID:16623783)
• can be adapted for the identification of known and unknown translocation partners of chimeric ALK fusion proteins involved in oncogenesis (PMID:16651537)
• constitutive expression of C/EBPbeta in ALK-positive anaplastic large cell lymphoma and its relationship to NPM-ALK (PMID:16709933)
• NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-beta and express FoxP3, indicating their T regulatory (Treg) cell phenotype. (PMID:16766651)
• Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. (PMID:16825495)
• AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. (PMID:16835382)
• recruitment of insulin receptor substrate-1 to activated ALK and the activation of NF-kappaB are essential for the autocrine growth and survival signaling of midkine (PMID:16878150)
• ALK has a proapoptotic activity in the absence of ligand, whereas it is antiapoptotic in the presence of its ligand and when the kinase is intrinsically activated. (PMID:16880530)
• CD26 and cell surface adenosine deaminase are selectively expressed on ALK-positive, but not on ALK-negative, anaplastic large cell lymphoma and Hodgkin’s lymphoma (PMID:17071493)
• molecular signature of ALK- anaplastic large-cell lymphoma included overexpression of CCR7, CNTFR, IL22, and IL21 genes (PMID:17077326)
• A functional role for Shc and likely FRS2 in ALK-dependant MAP-kinase activation and neuronal differentiation of PC12 cells. (PMID:17274988)
• This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway. (PMID:17490616)
• identify splicing factor as a novel nucleophosmin 1/anaplastic lymphoma kinase-binding protein and substrate (PMID:17537995)
• phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTPbeta/zeta signaling pathway (PMID:17681947)
• JunB is a critical target of mTOR and is translationally regulated in NPM-ALK-positive lymphomas. (PMID:17690253)
• Pleiotrophin failed to activate anaplastic lymphoma kinase (ALK) in neuroblastoma/glioblastoma cells expressing this receptor. ALK is still an orphan receptor in vertebrates. (PMID:17904822)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	alk	ENSDARG00000095833
mus_musculus	Alk	ENSMUSG00000055471
rattus_norvegicus	Alk	ENSRNOG00000008683

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078)

Protein

Protein identifiers

ALK tyrosine kinase receptor — Q9UM73 (reviewed: Q9UM73)

Alternative names: Anaplastic lymphoma kinase

All UniProt accessions (5): A0A087WZL3, A0A0K2YUJ3, E7EPW7, Q9UM73, H7BZ33

UniProt curated annotations — full annotation on UniProt →

Function. Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis. Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. May function as regulator of gastric epithelial differentiation.

Subunit / interactions. Homodimer; homodimerizes following heparin- and ligand-binding. Interacts with CBL, IRS1, PIK3R1 and PLCG1. Interacts with FRS2 and SHC1. Interacts with PTN and MDK.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.

Post-translational modifications. Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity. In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation. Phosphorylation at Tyr-1507 is critical for SHC1 association. N-glycosylated.

Disease relevance. A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Neuroblastoma 3 (NBLST3) [MIM:613014] A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. Disease susceptibility is associated with variants affecting the gene represented in this entry. The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion. A chromosomal aberration involving ALK has been identified in a subset of patients with non-small-cell lung carcinoma. This aberration leads to the production of a fusion protein between the N-terminus of EML4 et the C-terminus of ALK. It is unclear whether the fusion protein is caused by a simple inversion within 2p (inv(2)(p21p23)) or whether the chromosome translocation involving 2p is more complex. When tested in a heterologous system, the fusion protein EML4-ALK possesses transforming activity that is dependent on ALK catalytic activity, possibly due to spontaneous dimerization mediated by the EML4 moiety, leading to ALK kinase activation.

Activity regulation. Activated upon ALKAL2 ligand-binding. ALKAL2-driven activation is coupled with heparin-binding. Following ligand-binding, homodimerizes and autophosphorylates, activating its kinase activity. Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand. Staurosporine, crizotinib and CH5424802 act as inhibitors of ALK kinase activity.

Domain organisation. The EGF-like region drives the cytokine specificity for ALKAL2. The heparin-binding region binds heparin glycosaminoglycan. Heparin-binding is required for ALKAL2-driven activation.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

RefSeq proteins (2): NP_001340694, NP_004295* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000998	MAM_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002011	Tyr_kinase_rcpt_2_CS	Conserved_site
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR050122	RTK	Family
IPR055163	ALK/LTK-like_GRD	Domain

Pfam: PF00629, PF07714, PF12810

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (169 total): strand 45, sequence variant 38, helix 24, glycosylation site 16, modified residue 7, disulfide bond 6, mutagenesis site 6, region of interest 5, binding site 4, domain 4, turn 3, compositionally biased region 2, topological domain 2, site 2, signal peptide 1, chain 1, active site 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

79 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7MZY	X-RAY DIFFRACTION	1.5
4Z55	X-RAY DIFFRACTION	1.55
9GBE	X-RAY DIFFRACTION	1.58
5A9U	X-RAY DIFFRACTION	1.6
8ARJ	X-RAY DIFFRACTION	1.65
4CLJ	X-RAY DIFFRACTION	1.66
2YFX	X-RAY DIFFRACTION	1.7
4ANL	X-RAY DIFFRACTION	1.7
4FNX	X-RAY DIFFRACTION	1.7
4FOC	X-RAY DIFFRACTION	1.7
5AAC	X-RAY DIFFRACTION	1.7
5FTQ	X-RAY DIFFRACTION	1.7
4CMT	X-RAY DIFFRACTION	1.73
5AAA	X-RAY DIFFRACTION	1.73
3AOX	X-RAY DIFFRACTION	1.75
4FNW	X-RAY DIFFRACTION	1.75
4ANQ	X-RAY DIFFRACTION	1.76
4CTB	X-RAY DIFFRACTION	1.79
3L9P	X-RAY DIFFRACTION	1.8
4CMU	X-RAY DIFFRACTION	1.8
6CDT	X-RAY DIFFRACTION	1.8
7R7K	X-RAY DIFFRACTION	1.83
4ANS	X-RAY DIFFRACTION	1.85
5AA8	X-RAY DIFFRACTION	1.86
7BTT	X-RAY DIFFRACTION	1.86
5IUI	X-RAY DIFFRACTION	1.88
2XP2	X-RAY DIFFRACTION	1.9
2YHV	X-RAY DIFFRACTION	1.9
2YJR	X-RAY DIFFRACTION	1.9
2YJS	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UM73-F1	68.26	0.20

Antibody-complex structures (SAbDab): 1 — 7NX3

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 (3): 1249 (proton acceptor); 1057–1058 (breakpoint for translocation to form the eml4-alk fusion protein (variant 1)); 1058–1059 (breakpoint for translocation to form the eml4-alk fusion protein (variant 2))

Ligand- & substrate-binding residues (4): 1124; 1150; 1197–1199; 1270

Post-translational modifications (7): 1078, 1092, 1096, 1131, 1278, 1507, 1604

Disulfide bonds (6): 688–701, 783–794, 906–928, 987–995, 990–1006, 1008–1021

Glycosylation sites (16): 169, 244, 285, 324, 411, 424, 445, 563, 571, 627, 709, 808, 863, 864, 886, 986

Mutagenesis-validated functional residues (6):

Position	Phenotype
48–52	abolished heparin-binding, leading to decreased alk activation.
859	slightly decreased autophosphorylation. decreased autophosphorylation and subsequent activation; when associated with a-
966	slightly decreased autophosphorylation. strongly reduced autophosphorylation and subsequent activation; when associated
974	slightly decreased autophosphorylation. decreased autophosphorylation and subsequent activation; when associated with a-
994	slstrongly reduced autophosphorylation and subsequent activation; when associated with a-966.
1507	impairs interaction with shc1.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-201556	Signaling by ALK
R-HSA-9700645	ALK mutants bind TKIs
R-HSA-9717264	ASP-3026-resistant ALK mutants
R-HSA-9717301	NVP-TAE684-resistant ALK mutants
R-HSA-9717316	alectinib-resistant ALK mutants
R-HSA-9717319	brigatinib-resistant ALK mutants
R-HSA-9717323	ceritinib-resistant ALK mutants
R-HSA-9717326	crizotinib-resistant ALK mutants
R-HSA-9717329	lorlatinib-resistant ALK mutants
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-9851151	MDK and PTN in ALK signaling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9700206	Signaling by ALK in cancer
R-HSA-9700649	Drug resistance of ALK mutants

MSigDB gene sets: 361 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_DENDRITE_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, GOBP_NEUROGENESIS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, CAGCTG_AP4_Q5, GOBP_FOREBRAIN_DEVELOPMENT, GOMF_KINASE_ACTIVATOR_ACTIVITY, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS

GO Biological Process (23): response to stress (GO:0006950), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), phosphorylation (GO:0016310), hippocampus development (GO:0021766), adult behavior (GO:0030534), swimming behavior (GO:0036269), peptidyl-tyrosine autophosphorylation (GO:0038083), regulation of cell population proliferation (GO:0042127), regulation of apoptotic process (GO:0042981), regulation of neuron differentiation (GO:0045664), protein autophosphorylation (GO:0046777), neuron development (GO:0048666), negative regulation of lipid catabolic process (GO:0050995), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), regulation of dopamine receptor signaling pathway (GO:0060159), response to environmental enrichment (GO:0090648), energy homeostasis (GO:0097009), positive regulation of dendrite development (GO:1900006), protein phosphorylation (GO:0006468), nervous system development (GO:0007399), brain development (GO:0007420), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (11): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), ATP binding (GO:0005524), heparin binding (GO:0008201), receptor signaling protein tyrosine kinase activator activity (GO:0030298), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): plasma membrane (GO:0005886), protein-containing complex (GO:0032991), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Drug resistance of ALK mutants	7
Signaling by ALK in cancer	3
Signaling by Receptor Tyrosine Kinases	1
Signaling by ALK	1
Disease	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cellular process	2
neuron differentiation	2
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
phosphate-containing compound metabolic process	1
pallium development	1
limbic system development	1
anatomical structure development	1
behavior	1
locomotory behavior	1
peptidyl-tyrosine phosphorylation	1
protein autophosphorylation	1
cell population proliferation	1
apoptotic process	1
regulation of programmed cell death	1
regulation of cell differentiation	1
protein phosphorylation	1
cell development	1
negative regulation of catabolic process	1
lipid catabolic process	1
negative regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
G protein-coupled dopamine receptor signaling pathway	1
regulation of G protein-coupled receptor signaling pathway	1
response to external stimulus	1
multicellular organismal-level homeostasis	1
positive regulation of neuron projection development	1
dendrite development	1
regulation of dendrite development	1
positive regulation of developmental process	1
phosphorylation	1
protein modification process	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

3930 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALK	EML4	Q9HC35	997
ALK	PTN	P21246	991
ALK	NPM1	P06748	990
ALK	MDK	P21741	971
ALK	TGFBR2	P37173	947
ALK	ACVR1B	P36896	929
ALK	KRAS	P01116	887
ALK	TGFBR1	P36897	876
ALK	ATIC	P31939	867
ALK	NRAS	P01111	854
ALK	ACVR2A	P27037	840
ALK	SHC1	P29353	824
ALK	TNFRSF8	P28908	823
ALK	KIF5B	P33176	822
ALK	CD274	Q9NZQ7	818

IntAct

120 interactions, top by confidence:

A	B	Type	Score
ALK	SHC1	psi-mi:“MI:0915”(physical association)	0.690
ALKAL1	ALK	psi-mi:“MI:0407”(direct interaction)	0.660
ALKAL1	ALK	psi-mi:“MI:0915”(physical association)	0.660
ALKAL1	ALK	psi-mi:“MI:0403”(colocalization)	0.660
LTK	ALKAL1	psi-mi:“MI:0914”(association)	0.590
PIK3R1	ALK	psi-mi:“MI:0915”(physical association)	0.590
ALK	ALKAL2	psi-mi:“MI:0915”(physical association)	0.560
ALK	ALKAL2	psi-mi:“MI:0403”(colocalization)	0.560
	ALK	psi-mi:“MI:0407”(direct interaction)	0.560
ALK	PTPRZ1	psi-mi:“MI:0915”(physical association)	0.540
PTPRZ1	ALK	psi-mi:“MI:0203”(dephosphorylation reaction)	0.540
CRKL	ALK	psi-mi:“MI:0915”(physical association)	0.520
ALK	RACK1	psi-mi:“MI:0915”(physical association)	0.520
HSP90AB1	ALK	psi-mi:“MI:0915”(physical association)	0.520
ALK	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.520
NCK2	ALK	psi-mi:“MI:0915”(physical association)	0.510
ALK	NCK2	psi-mi:“MI:0915”(physical association)	0.510
RET	ALK	psi-mi:“MI:0915”(physical association)	0.500
ALK	ALK	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (742): BCAR1 (Affinity Capture-MS), ACTB (Affinity Capture-MS), PDLIM3 (Affinity Capture-MS), VIM (Affinity Capture-MS), TUBB4B (Affinity Capture-MS), MYO6 (Affinity Capture-MS), MYH10 (Affinity Capture-MS), MYH9 (Affinity Capture-MS), TUBGCP2 (Affinity Capture-MS), ACTN4 (Affinity Capture-MS), CORO1C (Affinity Capture-MS), FLII (Affinity Capture-MS), BICD2 (Affinity Capture-MS), GNB2L1 (Affinity Capture-MS), BCAR1 (Affinity Capture-Western)

ESM2 similar proteins: A0EQL2, A2AJ76, A2AJA7, A6H8M9, A8T650, A8T682, A8T688, A8T6A6, D3ZLH5, F1QVU0, O08628, O75173, O88839, P04278, P08514, P08689, P0DV84, P15196, P20701, P29376, P32970, P38570, P60882, P80012, P97497, P97793, Q13444, Q15113, Q5RFQ8, Q5TM20, Q61398, Q63191, Q6UXC1, Q7Z304, Q7Z442, Q7Z7M0, Q8BNJ2, Q8CG85, Q8K1S7, Q8NBP7

Diamond homologs: A0JM20, A0M8R7, A0M8S8, A1X150, F1QVU0, G3V9H8, O02466, O35346, P00519, P00520, P00521, P00522, P00529, P06213, P07949, P08069, P08581, P08941, P09760, P0DV84, P10447, P13368, P14617, P16056, P20806, P22182, P23049, P30530, P33497, P34152, P34925, P35546, P35590, P42684, P55144, P55146, P57097, P70451, P97523, P97793

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
PTN	up-regulates	ALK	binding
ALK	up-regulates	PLCG1	binding
ALK	up-regulates	STAT3	binding
ALK	down-regulates	SFPQ	phosphorylation
PTPRB	down-regulates	ALK	dephosphorylation
PTPRZ1	down-regulates	ALK	dephosphorylation
alectinib	down-regulates	ALK	“chemical inhibition”
crizotinib	down-regulates	ALK	“chemical inhibition”
5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	down-regulates	ALK	“chemical inhibition”
ALK	unknown	GRB2	phosphorylation
ALK	“up-regulates activity”	PIK3R3	phosphorylation
ceritinib	“down-regulates activity”	ALK	“chemical inhibition”
ALK	“up-regulates activity”	ATIC	phosphorylation
ALK	“up-regulates quantity”	MAPT	phosphorylation
ALK	“up-regulates activity”	STAT3	phosphorylation
ALK	“up-regulates activity”	GSK3B	phosphorylation
ALK	“up-regulates activity”	HES1	phosphorylation
ALK	up-regulates	SHC1	phosphorylation
ALK	up-regulates	SHC3	phosphorylation
ALK	“up-regulates activity”	ALK	phosphorylation
crizotinib	“down-regulates activity”	ALK	“chemical inhibition”
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	“down-regulates activity”	ALK	“chemical inhibition”
5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	“down-regulates activity”	ALK	“chemical inhibition”
ALK	“up-regulates activity”	CDK9	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 76 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
Signaling by ALK	6	54.4×	8e-08
Signaling by CSF3 (G-CSF)	6	54.4×	8e-08
Downstream signal transduction	8	48.3×	2e-09
Tie2 Signaling	5	47.7×	2e-06
Regulation of signaling by CBL	6	47.3×	2e-07
FLT3 Signaling	8	43.9×	2e-09
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	41.2×	4e-06
Signaling by CSF1 (M-CSF) in myeloid cells	7	38.5×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
Fc-gamma receptor signaling pathway involved in phagocytosis	6	57.7×	2e-07
peptidyl-tyrosine phosphorylation	8	46.2×	3e-09
cell surface receptor protein tyrosine kinase signaling pathway	14	33.3×	5e-15
ephrin receptor signaling pathway	6	28.3×	9e-06
epidermal growth factor receptor signaling pathway	8	27.2×	2e-07
ERK1 and ERK2 cascade	5	21.8×	3e-04
cellular response to transforming growth factor beta stimulus	5	18.9×	4e-04
T cell receptor signaling pathway	9	18.7×	3e-07

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ALK amplifications, fusions and mutations have been shown to be driving events in non-small cell lung cancer. While crizontinib has demonstrated efficacy in treating the amplification, mutations in ALK have been shown to confer resistance to current tyrosine kinase inhibitors. Second-generation TKI’s have seen varied success in treating these resistant cases, and the HSP90 inhibitor 17-AAG has been shown to be cytostatic in ALK-altered cell lines.

From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — BRCA, HCC, NBL, NSCLC, PROSTATE, SCLC.

Clinical variants and AI predictions

ClinVar

6456 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	7
Uncertain significance	3632
Likely benign	2154
Benign	145

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1527803	GRCh37/hg19 2p23.2-21(chr2:29899368-42441440)	Pathogenic
18083	NM_004304.5(ALK):c.3824G>A (p.Arg1275Gln)	Pathogenic
18085	NM_004304.5(ALK):c.3575G>C (p.Arg1192Pro)	Pathogenic
217849	NM_004304.5(ALK):c.3520T>C (p.Phe1174Leu)	Pathogenic
217850	NM_004304.5(ALK):c.3520T>A (p.Phe1174Ile)	Pathogenic
217851	NM_004304.5(ALK):c.3522C>A (p.Phe1174Leu)	Pathogenic
217852	NM_004304.5(ALK):c.3522C>G (p.Phe1174Leu)	Pathogenic
217855	NM_004304.5(ALK):c.3733T>A (p.Phe1245Ile)	Pathogenic
217856	NM_004304.5(ALK):c.3734T>G (p.Phe1245Cys)	Pathogenic
217857	NM_004304.5(ALK):c.3735C>A (p.Phe1245Leu)	Pathogenic
217858	NM_004304.5(ALK):c.3833A>C (p.Tyr1278Ser)	Pathogenic
3247472	NC_000002.11:g.(?29287735)(29430158_?)del	Pathogenic
394466	GRCh37/hg19 2p23.2-21(chr2:28069882-43543420)x3	Pathogenic
487484	t(2;2)(p23;p21)(hg19 chr2:g.42552694::ochr2:g.29446394)	Pathogenic
545115	NM_004304.5(ALK):c.3512T>C (p.Ile1171Thr)	Pathogenic
562660	GRCh37/hg19 2p23.2-22.3(chr2:29240004-32380876)x1	Pathogenic
627530	t(2;3)(p12;p14.3)	Pathogenic
65670	NM_004304.5(ALK):c.3520T>G (p.Phe1174Val)	Pathogenic
687302	GRCh37/hg19 2p23.2-22.2(chr2:29940473-36813297)x1	Pathogenic
1705031	NM_004304.5(ALK):c.3538G>C (p.Val1180Leu)	Likely pathogenic
217854	NM_004304.5(ALK):c.3718T>G (p.Leu1240Val)	Likely pathogenic
2445401	NM_004304.5(ALK):c.402G>C (p.Lys134Asn)	Likely pathogenic
375887	NM_004304.5(ALK):c.3521T>G (p.Phe1174Cys)	Likely pathogenic
376135	NM_004304.5(ALK):c.3586C>A (p.Leu1196Met)	Likely pathogenic
547174	inv(2)(p21p23.2)	Likely pathogenic
978809	NM_004304.5(ALK):c.4298_4299del (p.Glu1433fs)	Likely pathogenic

SpliceAI

6693 predictions. Top by Δscore:

Variant	Effect	Δscore
2:29193928:G:C	acceptor_gain	1.0000
2:29196764:TTTTA:T	donor_loss	1.0000
2:29196765:TTTA:T	donor_loss	1.0000
2:29196766:TTAC:T	donor_loss	1.0000
2:29196767:TACCT:T	donor_loss	1.0000
2:29196768:A:AT	donor_loss	1.0000
2:29196769:C:A	donor_loss	1.0000
2:29196858:TAT:T	acceptor_gain	1.0000
2:29196859:AT:A	acceptor_gain	1.0000
2:29196859:ATCTA:A	acceptor_loss	1.0000
2:29196861:C:CC	acceptor_gain	1.0000
2:29196861:CTAA:C	acceptor_loss	1.0000
2:29209874:TGTCT:T	acceptor_gain	1.0000
2:29209877:CT:C	acceptor_gain	1.0000
2:29220702:TCA:T	donor_loss	1.0000
2:29220703:CAC:C	donor_loss	1.0000
2:29220704:A:AT	donor_loss	1.0000
2:29220705:C:A	donor_loss	1.0000
2:29220705:CCGGG:C	donor_gain	1.0000
2:29220831:ATTTG:A	acceptor_gain	1.0000
2:29220832:TTTG:T	acceptor_gain	1.0000
2:29220833:TTG:T	acceptor_gain	1.0000
2:29220834:TG:T	acceptor_gain	1.0000
2:29220836:C:CC	acceptor_gain	1.0000
2:29222338:CTTTA:C	donor_loss	1.0000
2:29222339:TTTAC:T	donor_loss	1.0000
2:29222340:TTAC:T	donor_loss	1.0000
2:29222341:TACC:T	donor_loss	1.0000
2:29222342:A:C	donor_loss	1.0000
2:29222343:C:CA	donor_loss	1.0000

AlphaMissense

10546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:29193580:A:G	W1503R	1.000
2:29193580:A:T	W1503R	1.000
2:29196815:C:A	R1373S	1.000
2:29196815:C:G	R1373S	1.000
2:29196816:C:A	R1373M	1.000
2:29196816:C:G	R1373T	1.000
2:29196836:C:A	W1366C	1.000
2:29196836:C:G	W1366C	1.000
2:29196838:A:G	W1366R	1.000
2:29196838:A:T	W1366R	1.000
2:29197553:G:C	C1354W	1.000
2:29197563:G:T	P1351H	1.000
2:29197590:A:T	V1342D	1.000
2:29197599:A:G	L1339P	1.000
2:29197610:G:C	N1335K	1.000
2:29197610:G:T	N1335K	1.000
2:29197627:A:C	Y1330D	1.000
2:29197629:G:C	P1329R	1.000
2:29197629:G:T	P1329Q	1.000
2:29197638:C:T	G1326E	1.000
2:29197639:C:G	G1326R	1.000
2:29197639:C:T	G1326R	1.000
2:29197653:T:A	E1321V	1.000
2:29197654:C:T	E1321K	1.000
2:29197655:C:A	W1320C	1.000
2:29197655:C:G	W1320C	1.000
2:29197657:A:G	W1320R	1.000
2:29197657:A:T	W1320R	1.000
2:29197659:A:G	L1319P	1.000
2:29197662:A:G	L1318P	1.000

dbSNP variants (sampled 300 via entrez): RS1000003712 (2:29759077 T>C), RS1000004073 (2:29453529 C>T), RS1000009257 (2:29381460 G>C), RS1000009359 (2:29838718 A>G,T), RS1000010170 (2:29503653 G>A), RS1000012477 (2:29834714 G>A,T), RS1000032784 (2:29540000 G>C), RS1000039053 (2:29909812 T>A,C), RS1000040700 (2:29397255 A>G), RS1000049396 (2:29222835 T>C), RS1000050716 (2:29872586 G>A), RS1000054832 (2:29881052 A>G), RS1000056509 (2:29453749 T>C), RS1000061822 (2:29412575 C>T), RS1000066941 (2:29289839 A>G)

Disease associations

OMIM: gene MIM:105590 | disease phenotypes: MIM:613014, MIM:167000, MIM:211980, MIM:102200, MIM:182280, MIM:171400

GenCC curated gene-disease

Disease	Classification	Inheritance
neuroblastoma, susceptibility to, 3	Definitive	Autosomal dominant
spastic diplegia	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuroblastoma, susceptibility to, 3	Definitive	AD

Mondo (17): neuroblastoma, susceptibility to, 3 (MONDO:0013083), hereditary neoplastic syndrome (MONDO:0015356), ovarian cancer (MONDO:0008170), glioblastoma (MONDO:0018177), squamous cell lung carcinoma (MONDO:0005097), lung cancer (MONDO:0008903), familial isolated pituitary adenoma (MONDO:0017824), lung adenocarcinoma (MONDO:0005061), diffuse midline glioma, H3 K27-altered (MONDO:1060171), small cell lung carcinoma (MONDO:0008433), neuroblastoma (MONDO:0005072), endometrial carcinoma (MONDO:0002447), lung carcinoma (MONDO:0005138), multiple endocrine neoplasia type 2A (MONDO:0008234), diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (MONDO:0858939)

Orphanet (10): Neuroblastoma (Orphanet:635), Inherited cancer-predisposing syndrome (Orphanet:140162), Rare ovarian cancer (Orphanet:213500), Glioblastoma (Orphanet:360), Familial isolated pituitary adenoma (Orphanet:314777), Small cell lung cancer (Orphanet:70573), Multiple endocrine neoplasia type 2A (Orphanet:247698), Multiple endocrine neoplasia type 2 (Orphanet:653), Rhabdomyosarcoma (Orphanet:780), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000238	Hydrocephalus
HP:0000315	Abnormality of the orbital region
HP:0000520	Proptosis
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0000822	Hypertension
HP:0000834	Abnormality of the adrenal glands
HP:0000958	Dry skin
HP:0000970	Anhidrosis
HP:0000989	Pruritus
HP:0000998	Hypertrichosis
HP:0001000	Abnormality of skin pigmentation
HP:0001017	Anemic pallor
HP:0001053	Hypopigmented skin patches
HP:0001058	Poor wound healing
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001336	Myoclonus
HP:0001482	Subcutaneous nodule
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001928	Abnormality of coagulation
HP:0001945	Fever
HP:0002028	Chronic diarrhea
HP:0002034	Abnormal rectum morphology
HP:0002098	Respiratory distress
HP:0002176	Spinal cord compression

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002726_74	Glucose homeostasis traits	3.000000e-06
GCST002783_568	Body mass index	8.000000e-06
GCST003095_3	Adiponectin levels (BMI-adjusted)	7.000000e-06
GCST003670_7	Systolic blood pressure	1.000000e-06
GCST008176_8	Gestational age at birth (child effect)	4.000000e-06
GCST008295_44	Number of decayed, missing and filled tooth surfaces or use of dentures	2.000000e-09
GCST008306_30	Dentures	6.000000e-08
GCST008384_3	Carbamazepine-induced reaction with eosinophilia and systemic symptoms	1.000000e-06
GCST008386_3	Carbamazepine-induced serious cutaneous adverse reaction	5.000000e-08
GCST008551_19	Simvastatin-induced myopathy	5.000000e-06
GCST008758_56	Pre-treatment viral load in HIV-1 infection	7.000000e-18
GCST010989_197	Body size at age 10	3.000000e-08
GCST011346_12	Total cholesterol levels	4.000000e-09
GCST011347_14	Low density lipoprotein cholesterol levels	4.000000e-08
GCST90000582_8	Spontaneous coronary artery dissection	8.000000e-06

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0004340	body mass index
EFO:0007737	BMI-adjusted adiponectin measurement
EFO:0006335	systolic blood pressure
EFO:0005112	gestational age
EFO:0010078	dentures
EFO:1002004	drug hypersensitivity syndrome
EFO:0010125	viral load
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D005909	Glioblastoma	C04.557.465.625.600.380.080.335; C04.557.470.670.380.080.335; C04.557.580.625.600.380.080.335
D018813	Multiple Endocrine Neoplasia Type 2a	C04.588.322.400.505; C04.651.600.505; C04.700.630.505; C16.320.700.630.505; C19.344.400.505
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D055752	Small Cell Lung Carcinoma	C04.588.894.797.520.109.220.624; C08.381.540.140.750; C08.785.520.100.220.750
C537945	Cerebral palsy, spastic, diplegic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (19): CHEMBL2111387 (CHIMERIC PROTEIN), CHEMBL3883330 (CHIMERIC PROTEIN), CHEMBL4247 (SINGLE PROTEIN), CHEMBL4296165 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296166 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523743 (PROTEIN-PROTEIN INTERACTION), CHEMBL4748220 (PROTEIN-PROTEIN INTERACTION), CHEMBL4748232 (PROTEIN-PROTEIN INTERACTION), CHEMBL4879537 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465388 (CHIMERIC PROTEIN)

Molecules with ChEMBL bioactivity

61 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 245,771 (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
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL4298138	REPOTRECTINIB	4	1,038
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4
CHEMBL608533	MIDOSTAURIN	4
CHEMBL1879463	DACTOLISIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL276711	SEMAXANIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3545308	ROCILETINIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL50	QUERCETIN	3

Clinical evidence (CIViC)

Drug × variant × indication: 96 predictive associations from 127 curated evidence items; also 1 diagnostic, 1 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
ALK Mutation	Lorlatinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID11286
ALK R1275Q	Crizotinib	Neuroblastoma	Sensitivity/Response	CIViC B	EID2342 +3
ALK G1269A AND v::ALK Fusion	Ensartinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID8861
ALK Mutation	Ceritinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1237
EML4::ALK Fusion AND ALK C1156Y	Ensartinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID8860
EML4::ALK Fusion AND ALK L1196M	Ensartinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID7865
ALK F1174L	Crizotinib	Neuroblastoma	Resistance	CIViC B	EID2345 +1
ALK I1171	Ceritinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID1284 +2
ALK F1174L	Crizotinib	Neuroblastoma	Sensitivity/Response	CIViC C	EID1271 +1
ALK Alternative Transcript (ATI)	Crizotinib	Skin Melanoma	Sensitivity/Response	CIViC C	EID1936
ALK Alternative Transcript (ATI)	Entrectinib	Mucosal Melanoma	Sensitivity/Response	CIViC C	EID7421
ALK F1245V	Entrectinib	Neuroblastoma	Sensitivity/Response	CIViC C	EID2987
ALK I1171T	Ceritinib	Neuroblastoma	Sensitivity/Response	CIViC C	EID9404
EML4::ALK Fusion AND ALK C1156Y	Lorlatinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID842
EML4::ALK Fusion AND ALK F1245C	Ceritinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID1338
EML4::ALK Fusion AND ALK I1171N AND ALK L1196M	Lorlatinib	Malignant Pleural Mesothelioma	Sensitivity/Response	CIViC C	EID11113
EML4::ALK Fusion AND ALK L1198F AND ALK C1156Y	Crizotinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID844
FUS::TFCP2 Fusion AND ALK Exon 2-18 Deletion	Alectinib	Spindle Cell Rhabdomyosarcoma	Sensitivity/Response	CIViC C	EID12406
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID4034 +4
EML4::ALK Fusion AND ALK C1156Y	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID4042 +3
ALK I1171	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID4610 +2
EML4::ALK Fusion AND ALK Amplification	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID766 +2
EML4::ALK Fusion AND ALK G1269A	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID4619 +2
EML4::ALK Fusion AND ALK L1196M	Crizotinib	Lung Adenocarcinoma	Resistance	CIViC C	EID237 +2
ALK G1269A AND v::ALK Fusion	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID4617 +1
ALK I1171	Alectinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID1283 +1
EML4::ALK Fusion AND ALK C1156Y	Crizotinib	Lung Adenocarcinoma	Resistance	CIViC C	EID236 +1
EML4::ALK Fusion AND ALK T1151dup	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID444 +1
ALK F1245C	Crizotinib	Neuroblastoma	Resistance	CIViC C	EID1333
ALK G1202R AND v::ALK Fusion	Crizotinib	Lung Adenocarcinoma	Resistance	CIViC C	EID1357

+66 more predictive associations (showing top 30 by evidence level).

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs187926838	ALK		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

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

Ligand	Action	Affinity	Parameter
brigatinib	Inhibition	10.05	pKi
ceritinib	Inhibition	9.7	pIC50
belizatinib	Inhibition	9.44	pKd
ensartinib	Inhibition	9.4	pIC50
GSK-1838705A	Inhibition	9.3	pIC50
gilteritinib	Inhibition	9.3	pIC50
TL13-112	Inhibition	9.22	pIC50
lorlatinib	Inhibition	9.15	pKi
compound 8e [PMID: 24432909]	Inhibition	9.1	pIC50
iruplinalkib	Inhibition	9.0	pIC50
ficonalkib	Inhibition	9.0	pIC50
neladalkib	Inhibition	9.0	pIC50
crizotinib	Inhibition	9.0	pIC50
repotrectinib	Inhibition	8.98	pIC50
NVP-TAE684	Inhibition	8.96	pKd
zotizalkib	Inhibition	8.85	pIC50
dirozalkib	Inhibition	8.77	pIC50
alectinib	Inhibition	8.72	pIC50
compound 25b [PMID: 22564207]	Inhibition	8.72	pIC50
envonalkib	Inhibition	8.71	pIC50
CEP-37440	Inhibition	8.51	pIC50
AZD3463	Inhibition	8.0	pIC50
compound 5m [PMID: 20483621]	Inhibition	8.0	pIC50
compound 5n [PMID: 20483621]	Inhibition	8.0	pIC50
compound 5g [PMID: 20483621]	Inhibition	7.96	pIC50

Binding affinities (BindingDB)

810 measured of 946 human assays (980 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
8-(4-aminopiperidin-1-yl)-9-bromo-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.168 nM	US-9126931: Tetracyclic compound
9-bromo-8-[(3S,5R)-4-cyclobutyl-3,5-dimethylpiperazin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.3 nM	US-9126931: Tetracyclic compound
8-[4-(azetidin-1-yl)piperidin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.3 nM	US-9126931: Tetracyclic compound
9-ethyl-8-[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.3 nM	US-9126931: Tetracyclic compound
5-chloro-N4-2-(isopropylsulfonyl)phenyl)-N2-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine	IC50	0.3 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
8-(4-cyclobutylpiperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.32 nM	US-9126931: Tetracyclic compound
9-bromo-8-(4-tert-butylpiperazin-1-yl)-11-oxospiro[5H-benzo[b]carbazole-6,4’-oxane]-3-carbonitrile	IC50	0.32 nM	US-9126931: Tetracyclic compound
9-chloro-6,6-dimethyl-8-(4-morpholin-4-ylpiperidin-1-yl)-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.391 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-8-[4-(oxetan-3-yl)piperazin-1-yl]-11-oxo-9-(3-propan-2-yloxyprop-1-ynyl)-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.4 nM	US-9126931: Tetracyclic compound
8-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.4 nM	US-9126931: Tetracyclic compound
US9126931, 601	IC50	0.456 nM	US-9126931: Tetracyclic compound
5,5-dimethyl-11-oxo-3-(4-piperidin-1-ylpiperidin-1-yl)-6H-pyrido[4,3-b]carbazole-8-carbonitrile	IC50	0.494 nM	US-9126931: Tetracyclic compound
2-[4-(1-methylpiperidin-4-yl)-2-propan-2-yloxyanilino]-7-[2-(trifluoromethoxy)phenyl]thieno[3,2-d]pyrimidine-6-carboxamide	IC50	0.5 nM	US-9115140: Thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof
9-acetyl-8-[2-(diethylamino)ethoxy]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.53 nM	US-9126931: Tetracyclic compound
9-(2-cyclobutylethynyl)-8-(4-cyclobutylpiperazin-1-yl)-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.58 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-8-morpholin-4-yl-11-oxo-9-(oxolan-3-yloxy)-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.59 nM	US-9126931: Tetracyclic compound
9-ethyl-8-[4-(3-hydroxypropylamino)piperidin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.6 nM	US-9126931: Tetracyclic compound
9-ethyl-6,6-dimethyl-8-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.7 nM	US-9126931: Tetracyclic compound
2-[7-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-8-methoxy-1,3,4,5-tetrahydro-2-benzazepin-2-yl]ethanol	IC50	0.7 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
4-fluoro-6,6-dimethyl-11-oxo-8-(4-propan-2-ylpiperazin-1-yl)-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.77 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-9-(1-methylpyrazol-4-yl)-8-morpholin-4-yl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.81 nM	US-9126931: Tetracyclic compound
8-[4-(cyclopropylmethylamino)piperidin-1-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.813 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydropyridin-4-yl)-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.83 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-11-oxo-8-(1-propan-2-ylpiperidin-4-yl)-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.84 nM	US-9126931: Tetracyclic compound
2-N-[5-(2-aminoethyl)-2-methoxyphenyl]-5-chloro-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	IC50	0.85 nM	US-10100019: N2-(2-methoxyphenyl)pyrimidine derivative, method for preparing same, and pharmaceutical composition for cancer prevention or treatment containing same as active ingredient
11-oxo-8-(4-pyrrolidin-1-ylpiperidin-1-yl)spiro[5H-benzo[b]carbazole-6,4’-oxane]-3,9-dicarbonitrile	IC50	0.86 nM	US-9126931: Tetracyclic compound
9-(2-cyclopropylethynyl)-6,6-dimethyl-8-[4-(oxetan-3-yl)piperazin-1-yl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.881 nM	US-9126931: Tetracyclic compound
8-(4-morpholin-4-ylpiperidin-1-yl)-11-oxo-9-prop-1-ynylspiro[5H-benzo[b]carbazole-6,4’-oxane]-3-carbonitrile	IC50	0.9 nM	US-9126931: Tetracyclic compound
9-bromo-6,6-dimethyl-8-[4-(oxetan-3-yl)piperazin-1-yl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.952 nM	US-9126931: Tetracyclic compound
8-[(2S)-4-cyclobutyl-2-methylpiperazin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.981 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-8-(1-methylpiperidin-4-yl)oxy-9-nitro-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.991 nM	US-9126931: Tetracyclic compound
6,6-dimethyl-8-[4-(oxetan-3-yl)piperazin-1-yl]-9-[3-[4-(oxetan-3-yl)piperazin-1-yl]prop-1-ynyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	0.996 nM	US-9126931: Tetracyclic compound
2-[5-fluoro-4-(1-methylpiperidin-4-yl)-2-propan-2-yloxyanilino]-7-(2-methoxy-3-pyridinyl)thieno[3,2-d]pyrimidine-6-carboxamide	IC50	1 nM	US-9115140: Thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof
5-[(2,6-dichlorophenyl)methyl]-7-[4-[2-(dimethylamino)ethylcarbamoyl]-2-methoxyanilino]imidazo[1,2-c]pyrimidine-8-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
4-[(2,6-dichlorophenyl)methyl]-6-[4-[2-(dimethylamino)ethylcarbamoyl]-2-methoxyanilino]-3H-imidazo[4,5-c]pyridine-7-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
5-[(2,6-dichlorophenyl)methyl]-7-[2-methoxy-4-(2-pyrrolidin-1-ylethylcarbamoyl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
5-[(2,6-dichlorophenyl)methyl]-7-[2-methoxy-4-(2-piperidin-1-ylethylcarbamoyl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
5-[(2,6-dichlorophenyl)methyl]-7-[2-methoxy-4-(piperazine-1-carbonyl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
4-[(2,6-dichlorophenyl)methyl]-6-[2-methoxy-4-(pyrrolidin-1-ylmethyl)anilino]-3H-imidazo[4,5-c]pyridine-7-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
4-[(2,6-dichlorophenyl)methyl]-6-[(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]-3H-imidazo[4,5-c]pyridine-7-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
5-[(2-chlorophenyl)methyl]-7-(2-chloro-4-piperidin-4-ylanilino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
ethyl 8-carbamoyl-5-[(2,6-dichlorophenyl)methyl]-7-(2-methoxy-4-piperazin-1-ylanilino)imidazo[1,2-c]pyrimidine-2-carboxylate	KI	1 nM	US-9212192: Bicyclic carboxamide inhibitors of kinases
5-chloro-2-N-[2-methoxy-5-(2-piperazin-1-ylethyl)phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	IC50	1 nM	US-10100019: N2-(2-methoxyphenyl)pyrimidine derivative, method for preparing same, and pharmaceutical composition for cancer prevention or treatment containing same as active ingredient
5-chloro-2-N-(7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	IC50	1 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
5-chloro-2-N-(8-methoxy-2-piperidin-4-yl-1,3,4,5-tetrahydro-2-benzazepin-7-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	IC50	1 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
(2S)-1-{(10S,17E)-12-ethyl-8,10- dimethyl-16-[(propan-2-yl)oxy]- 2,8,10,11,12,13-hexahydro-14H-3,5- ethenotripyrazolo[3,4-f:3’,4’-j:4″,3″- n][1,4]oxazacyclopentadecin-14- yl}propan-2-ol	IC50	1.08 nM	US-20250353864: INDAZOLE CONTAINING MACROCYCLES AND THEIR USE
8-[4-(4-hydroxybutyl)piperazin-1-yl]-6,6-dimethyl-11-oxo-9-propyl-5H-benzo[b]carbazole-3-carbonitrile	IC50	1.09 nM	US-9126931: Tetracyclic compound
9-bromo-8-[4-(1,1-dioxothian-4-yl)piperazin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	1.13 nM	US-9126931: Tetracyclic compound
9-(3-hydroxy-3-methylbut-1-ynyl)-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	IC50	1.17 nM	US-9126931: Tetracyclic compound
5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(7-isobutoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine	IC50	1.2 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient

ChEMBL bioactivities

4638 potent at pChembl≥5 of 4762 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.15	IC50	0.07	nM	CHEMBL3397300
10.00	Ki	0.1	nM	CHEMBL3286823
10.00	Ki	0.1	nM	CHEMBL3286825
10.00	IC50	0.1	nM	CHEMBL5593687
9.96	IC50	0.11	nM	CHEMBL3286826
9.92	Ki	0.12	nM	CHEMBL3286828
9.92	IC50	0.12	nM	CHEMBL3824308
9.82	IC50	0.15	nM	TAE-684
9.78	IC50	0.168	nM	CHEMBL3892880
9.77	IC50	0.17	nM	CHEMBL3687205
9.74	IC50	0.18	nM	CHEMBL3286825
9.74	IC50	0.18	nM	CHEMBL3823235
9.74	IC50	0.18	nM	CHEMBL3822611
9.70	IC50	0.2	nM	CERITINIB
9.70	IC50	0.2	nM	CHEMBL3128069
9.70	Ki	0.2	nM	CHEMBL3128069
9.70	IC50	0.2	nM	LORLATINIB
9.68	IC50	0.21	nM	CHEMBL3286823
9.68	IC50	0.21	nM	CHEMBL3687207
9.68	IC50	0.21	nM	CHEMBL4758611
9.66	Ki	0.22	nM	CHEMBL3286815
9.66	IC50	0.22	nM	CHEMBL3823549
9.66	IC50	0.22	nM	CHEMBL3687206
9.64	IC50	0.23	nM	CHEMBL3889838
9.62	Kd	0.24	nM	CHEMBL2172315
9.62	IC50	0.24	nM	CHEMBL3823416
9.62	IC50	0.24	nM	CHEMBL3687201
9.62	IC50	0.24	nM	CHEMBL4743579
9.62	IC50	0.24	nM	CHEMBL5598386
9.62	IC50	0.24	nM	CHEMBL5844539
9.60	IC50	0.25	nM	CERITINIB
9.59	IC50	0.26	nM	CHEMBL3687202
9.59	IC50	0.26	nM	CHEMBL3687204
9.59	IC50	0.26	nM	CHEMBL3687211
9.57	IC50	0.27	nM	CHEMBL4522012
9.55	IC50	0.28	nM	CHEMBL3824327
9.54	Ki	0.29	nM	CHEMBL3286820
9.54	Ki	0.29	nM	CHEMBL4286522
9.52	Ki	0.3	nM	CHEMBL3128066
9.52	IC50	0.3	nM	CHEMBL3917178
9.52	IC50	0.3	nM	CHEMBL3953815
9.52	IC50	0.3	nM	CHEMBL3929615
9.52	IC50	0.3	nM	CHEMBL5928907
9.51	IC50	0.31	nM	CHEMBL3218856
9.51	IC50	0.31	nM	CHEMBL3824304
9.49	IC50	0.32	nM	CHEMBL3946496
9.49	IC50	0.32	nM	CHEMBL3915577
9.48	IC50	0.33	nM	CHEMBL3823107
9.48	IC50	0.33	nM	CHEMBL3823603
9.48	IC50	0.33	nM	CHEMBL3823256

PubChem BioAssay actives

2731 with measured affinity, of 6100 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
(17R)-20-amino-14-fluoro-5,9,17-trimethyl-10-oxo-18-oxa-5,6,9,21-tetrazatetracyclo[17.3.1.03,7.011,16]tricosa-1(23),3,6,11(16),12,14,19,21-octaene-4-carbonitrile	1579876: Inhibition of ALK (unknown origin)	ki	<0.0001	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0001	uM
(17S)-20-amino-14-fluoro-5,17-dimethyl-10,18-dioxa-4,5,21-triazatetracyclo[17.3.1.02,6.011,16]tricosa-1(23),2(6),3,11(16),12,14,19,21-octaene-3-carbonitrile	2026363: Binding affinity to ALK (unknown origin) assessed as inhibition of constant	ki	0.0001	uM
(16R)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,11,13,18,20-heptaene-3-carbonitrile	2187695: Binding affinity to recombinant ALK (unknown origin) assessed as inhibition constant in presence of ATP by microfluidic mobility shift assay	ki	0.0001	uM
8-[1-[3-(dimethylamino)propyl]pyrazol-3-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	2091128: Inhibition of wild type ALK (unknown origin) by enzymatic assay	ic50	0.0001	uM
5-chloro-2-N-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl]-4-N-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0001	uM
5-chloro-4-N-(2-diethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0001	uM
Lorlatinib	1153093: Inhibition of wild type human recombinant ALK kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0001	uM
20-amino-14-fluoro-10,18-dioxa-4,5,21-triazatetracyclo[17.3.1.02,6.011,16]tricosa-1(23),2(6),3,11(16),12,14,19,21-octaene-3-carbonitrile	1153094: Inhibition of human recombinant ALK L1196M mutant kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0001	uM
5-chloro-2-N-(6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1710806: Inhibition of crizotinib-resistant ALK G1269A mutant (unknown origin) using peptide substrate incubated for 30 mins in presence of ATP by fluorescence assay	ic50	0.0002	uM
(16R)-19-amino-13-fluoro-3,5,8,16-tetramethyl-17-oxa-4,8,20-triaza-5-azoniatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,10(15),11,13,18,20-octaen-9-one	1419634: Inhibition of ALK (unknown origin)	ki	0.0002	uM
4-[(2,6-dichloro-3-fluorophenyl)methoxymethyl]-12-(1-piperidin-4-ylpyrazol-4-yl)-8,9,11-triazatricyclo[6.4.0.02,6]dodeca-1,6,9,11-tetraene	2119175: Inhibition of ALK (unknown origin)	ic50	0.0002	uM
2-[4-[4-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]ethanol	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0002	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0002	uM
3,5-difluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	702988: Binding affinity to human ALK by Ambit titration assay	kd	0.0002	uM
Ceritinib	1882662: Inhibition of ALK (unknown origin)	ic50	0.0002	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-(2-methoxy-4-morpholin-4-ylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0002	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0002	uM
19-amino-13-fluoro-3,5,8-trimethyl-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2(6),3,10(15),11,13,18,20-octaen-9-one	1153093: Inhibition of wild type human recombinant ALK kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0002	uM
5-chloro-2-N-(9-methoxy-2,3,5,6-tetrahydro-1H-[1,2,4]triazino[4,3-a]quinolin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1449869: Inhibition of wild type ALK (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0003	uM
4-(furan-2-ylmethoxymethyl)-12-(1-piperidin-4-ylpyrazol-4-yl)-8,9,11-triazatricyclo[6.4.0.02,6]dodeca-1,6,9,11-tetraene	2119175: Inhibition of ALK (unknown origin)	ic50	0.0003	uM
(3S)-1-[6-[2-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N-[[4-(trifluoromethoxy)phenyl]methyl]piperidine-3-carboxamide	1579904: Inhibition of ALK (unknown origin) by TR-FRET assay	ic50	0.0003	uM
5-chloro-2-N-(4-dimethylphosphoryl-2-methoxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0003	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0003	uM
5-chloro-2-N-[4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-methoxyphenyl]-4-N-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0003	uM
5-chloro-2-N-(4-dimethylphosphoryl-2-methoxyphenyl)-4-N-(2-methylsulfonylphenyl)pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0003	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-(1-methylpyrrolidin-3-yl)oxyphenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0003	uM
5-chloro-2-N-[4-[2-(dimethylamino)ethyl]-2-methoxy-5-methylphenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1426181: Inhibition of ALK G1269A mutant (unknown origin) using peptide as substrate measured after 30 mins by fluorescence assay	ic50	0.0004	uM
N-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]phenyl]-N’-hydroxyoctanediamide	1769653: Inhibition of ALK G1202R mutant (unknown origin)	ic50	0.0004	uM
3-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]thiophene-2-carboxamide	392353: Inhibition of ALK	ic50	0.0004	uM
2-[5-[6-amino-5-[(1R)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridinyl]-4-methyl-1,3-thiazol-2-yl]propan-2-ol	1074745: Inhibition of human recombinant ALK L1196M mutant kinase domain (amino acids 1093 to 1141) expressed in baculovirus using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to Km levels of ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0004	uM
6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide	1579874: Inhibition of ALK (unknown origin) by kinome scan-based assay	ic50	0.0004	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-(1-methylpiperidin-4-yl)phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0004	uM
4-fluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	702988: Binding affinity to human ALK by Ambit titration assay	kd	0.0004	uM
Brigatinib	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0004	uM
4-N-(2-dimethylphosphorylphenyl)-5-fluoro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0004	uM
1-[4-[[5-chloro-4-(2-dimethylphosphorylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidin-4-ol	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0004	uM
4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-5-methylpyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0004	uM
14-fluoro-3-methyl-10,18-dioxa-3,4,21-triazatetracyclo[17.3.1.02,6.011,16]tricosa-1(23),2(6),4,11(16),12,14,19,21-octaen-20-amine	1153093: Inhibition of wild type human recombinant ALK kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0004	uM
19-amino-13-fluoro-9,17-dioxa-4,5,20-triazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2(6),3,10(15),11,13,18,20-octaene-3-carbonitrile	1153093: Inhibition of wild type human recombinant ALK kinase domain (amino acids 1093 to 1141) expressed in baculovirus system using 5’FAM-KKSRGDYMTMQIG-CONH2 as substrate incubated for 15 mins prior to ATP addition measured after 1 hr by microfluidic mobility shift assay	ki	0.0004	uM
5-chloro-2-N-(7-propan-2-yloxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1710803: Inhibition of ALK (unknown origin) using peptide substrate incubated for 30 mins in presence of ATP by fluorescence assay	ic50	0.0005	uM
Crizotinib	1416643: Inhibition of recombinant ALK (unknown origin) after 1 hr by fluorescence assay	ec50	0.0005	uM
4-fluoro-2-methoxy-3-(1-methylpiperidin-4-yl)-11-oxo-5-propan-2-yl-6H-indolo[2,3-b]quinoline-8-carbonitrile	1700647: Inhibition of N-terminal GST tagged wild-type human ALK cytoplasmic domain (1058-1620 amino acids) expressed Sf9 cells pre-incubated for 30 mins before addition of Ulight-CKKSRGDYMTMQIG substrate and measured after 90 mins by fluorescence based assay	ic50	0.0005	uM
5-chloro-2-N-[(6E)-3-methoxy-5,5-dimethyl-6-(4-methylpiperazin-1-yl)imino-7,8-dihydronaphthalen-2-yl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1290623: Inhibition of wild type ALK (unknown origin) after 30 mins by HTRF assay	ic50	0.0005	uM
3-[4-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-methyl-5-propan-2-yloxyphenyl]piperidin-1-yl]-N-[2-[2-(prop-2-enoylamino)ethoxy]ethyl]propanamide	1708461: Inhibition of N-terminal GST tagged human ALK cytoplasmic domain (1058 to 1620 residues) expressed in Sf21 cells by mobility shift assay	ic50	0.0005	uM
2-fluoro-6-[[2-[2-methoxy-4-(4-propan-2-ylpiperazin-1-yl)anilino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzamide	392239: Inhibition of ALK	ic50	0.0005	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	1579876: Inhibition of ALK (unknown origin)	ic50	0.0005	uM
6-[6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]-1’-methylspiro[1H-indole-3,4’-piperidine]-2-one	1056226: Inhibition of human ALK (unknown origin) using poly[Glu:Tyr] as substrate by nanoliter kinase assay	ic50	0.0005	uM
N-[6-chloro-19-methoxy-17-(4-methylpiperazin-1-yl)-2,4,8,22-tetrazatetracyclo[14.3.1.13,7.19,13]docosa-1(19),3,5,7(22),9,11,13(21),16(20),17-nonaen-10-yl]-N-methylmethanesulfonamide	643167: Inhibition of baculovirus expressed GST-tagged human ALK cytoplasmic domain using PLCgamma as substrate after 15 mins by time-resolved fluorescence analysis	ic50	0.0005	uM
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine	1310801: Inhibition of human ALK using poly[Glu:Tyr] (4:1) as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0005	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Crizotinib	decreases response to substance, decreases phosphorylation, decreases reaction, affects response to substance, affects binding (+7 more)	21
NVP-TAE684	increases response to substance, decreases phosphorylation, decreases reaction, decreases response to substance, increases mutagenesis (+2 more)	11
ceritinib	affects response to substance, decreases phosphorylation, decreases activity	3
tanespimycin	decreases activity, decreases expression	2
alectinib	decreases activity, affects response to substance	2
Aldrin	affects cotreatment, increases expression, decreases expression	2
Dichlorodiphenyldichloroethane	affects cotreatment, increases expression, decreases expression	2
Dichlorodiphenyl Dichloroethylene	affects cotreatment, increases expression, decreases expression	2
Dieldrin	affects cotreatment, increases expression, decreases expression	2
Ethylnitrosourea	decreases reaction, decreases response to substance, increases mutagenesis, decreases phosphorylation	2
Tretinoin	decreases expression, increases expression, affects cotreatment, increases cleavage	2
lorlatinib	decreases activity, decreases phosphorylation	1
WY-135	decreases expression, decreases phosphorylation	1
bisphenol A	affects cotreatment, affects methylation	1
terbufos	increases methylation	1
2,4-diaminopyrimidine	decreases phosphorylation, decreases reaction, decreases response to substance	1
benzo(e)pyrene	decreases methylation	1
2,4-diaminopyridine	affects binding, decreases activity	1
aflatoxin B2	decreases methylation	1
2,2-(2-chlorophenyl-4’-chlorophenyl)-1,1-dichloroethene	affects cotreatment, increases expression	1
N-(3-phenoxycinnamyl)acetohydroxamic acid	decreases activity	1
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin	decreases stability	1
9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one	decreases response to substance	1
N-(2-(2-(4-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methoxyphenylamino)pyrrolo(2,1-f)(1,2,4)triazin-7-yl)phenyl)-N-methylmethanesulfonamide	increases response to substance, increases activity	1
Pemetrexed	affects response to substance	1
Fulvestrant	affects cotreatment, affects methylation	1
Acetylcysteine	affects activity, affects phosphorylation	1
Adenosine Triphosphate	affects binding, increases reaction, decreases response to substance	1
Amiodarone	increases expression	1
Amphotericin B	increases expression	1

ChEMBL screening assays

1815 unique, capped per target: 1801 binding, 13 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005525	Binding	Inhibition of NPM-ALK in human Karpas299 cells at 50 nM	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — Proc Natl Acad Sci U S A
CHEMBL861020	Functional	Antiproliferative activity against SUDHL1 expressing NPM-ALK by MTT assay	Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. — J Med Chem
CHEMBL4313077	ADMET	Inhibition of human ALK using poly (Glu, Tyr)4:1 as substrate measured after 60 mins by ELISA relative to control	Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design. — J Med Chem

Cellosaurus cell lines

177 cell lines: 166 cancer cell line, 9 factor-dependent cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0019	SH-SY5Y	Cancer cell line	Female
CVCL_0389	LA-N-5	Cancer cell line	Male
CVCL_0522	SH-EP007	Cancer cell line	Female
CVCL_0523	SH-SY5Y-SPA4CT	Cancer cell line	Female
CVCL_0524	SH-EP	Cancer cell line	Female
CVCL_0531	SK-N-SH	Cancer cell line	Female
CVCL_0538	SU-DHL-1	Cancer cell line	Male
CVCL_0575	WAC2	Cancer cell line	Female
CVCL_0F47	SH-EP1	Cancer cell line	Female
CVCL_1170	DEL	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	PHASE3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	PHASE3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	PHASE3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	PHASE3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer