NTRK3

Summary

NTRK3 (neurotrophic receptor tyrosine kinase 3, HGNC:8033) is a protein-coding gene on chromosome 15q25.3, encoding NT-3 growth factor receptor (Q16288). Receptor tyrosine kinase involved in nervous system and probably heart development. In precision oncology, NTRK3 F617L is associated with resistance to Larotrectinib in Solid Tumor (CIViC Level A); 7 further curated variant–drug associations are listed below.

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Disputed, ClinGen)
• GWAS associations: 7
• Clinical variants (ClinVar): 142 total — 1 pathogenic
• Druggable target: yes — 41 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 8 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_001012338

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8033
Approved symbol	NTRK3
Name	neurotrophic receptor tyrosine kinase 3
Location	15q25.3
Locus type	gene with protein product
Status	Approved
Aliases	TRKC
Ensembl gene	ENSG00000140538
Ensembl biotype	protein_coding
OMIM	191316
Entrez	4916

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 26 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000317501, ENST00000357724, ENST00000394480, ENST00000542733, ENST00000557856, ENST00000557897, ENST00000558306, ENST00000558576, ENST00000558676, ENST00000559188, ENST00000559680, ENST00000559764, ENST00000560017, ENST00000560201, ENST00000560739, ENST00000626019, ENST00000629765, ENST00000695462, ENST00000695463, ENST00000889745, ENST00000889746, ENST00000889747, ENST00000889748, ENST00000889749, ENST00000889750, ENST00000889751, ENST00000889752, ENST00000889753, ENST00000927120, ENST00000927121, ENST00000953260, ENST00000953261

RefSeq mRNA: 11 — MANE Select: NM_001012338 NM_001007156, NM_001012338, NM_001243101, NM_001320134, NM_001320135, NM_001375810, NM_001375811, NM_001375812, NM_001375813, NM_001375814, NM_002530

CCDS: CCDS10340, CCDS32322, CCDS32323, CCDS58399, CCDS81916

Canonical transcript exons

ENST00000629765 — 20 exons

Exon	Start	End
ENSE00000943688	87885694	87885735
ENSE00001134154	87940623	87940753
ENSE00001518607	87859751	87877120
ENSE00001766468	87880270	87880428
ENSE00002504927	88137404	88137561
ENSE00002521985	88136467	88136609
ENSE00002535876	88128711	88128734
ENSE00003240255	88183418	88183489
ENSE00003279643	88147335	88147403
ENSE00003313953	88127162	88127226
ENSE00003330291	88126271	88126373
ENSE00003448289	87929191	87929434
ENSE00003541167	87933012	87933184
ENSE00003627946	88135899	88136040
ENSE00003654103	88135101	88135397
ENSE00003656026	88032857	88033045
ENSE00003664319	88184225	88184299
ENSE00003764006	88255906	88256168
ENSE00003964004	88256644	88256739
ENSE00003964005	88256284	88256486

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 97.97.

FANTOM5 (CAGE): breadth broad, TPM avg 11.0873 / max 1041.1801, expressed in 592 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151381	5.3595	453
151380	1.9739	293
151378	1.6914	293
151382	0.9957	241
151379	0.8500	171
151377	0.1901	83
151376	0.0128	3
151373	0.0085	4
207637	0.0053	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 10	UBERON:0013541	97.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.53	gold quality
popliteal artery	UBERON:0002250	96.44	gold quality
tibial artery	UBERON:0007610	96.43	gold quality
frontal pole	UBERON:0002795	96.20	gold quality
middle temporal gyrus	UBERON:0002771	96.19	gold quality
paraflocculus	UBERON:0005351	96.11	gold quality
right coronary artery	UBERON:0001625	95.72	gold quality
dorsal root ganglion	UBERON:0000044	95.47	gold quality
aorta	UBERON:0000947	95.30	gold quality
middle frontal gyrus	UBERON:0002702	95.27	gold quality
ventricular zone	UBERON:0003053	95.05	gold quality
descending thoracic aorta	UBERON:0002345	95.02	gold quality
primary visual cortex	UBERON:0002436	94.77	gold quality
cerebellar vermis	UBERON:0004720	94.66	gold quality
left coronary artery	UBERON:0001626	94.63	gold quality
trigeminal ganglion	UBERON:0001675	94.56	gold quality
occipital lobe	UBERON:0002021	94.42	gold quality
coronary artery	UBERON:0001621	94.31	gold quality
blood vessel layer	UBERON:0004797	94.21	gold quality
endothelial cell	CL:0000115	94.19	gold quality
thoracic aorta	UBERON:0001515	93.92	gold quality
cortical plate	UBERON:0005343	93.84	gold quality
ascending aorta	UBERON:0001496	93.80	gold quality
orbitofrontal cortex	UBERON:0004167	93.53	gold quality
secondary oocyte	CL:0000655	93.40	gold quality
entorhinal cortex	UBERON:0002728	93.19	gold quality
superior frontal gyrus	UBERON:0002661	93.06	gold quality
oocyte	CL:0000023	92.81	gold quality
parietal lobe	UBERON:0001872	92.61	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	2198.30
E-GEOD-180759	yes	2072.67
E-CURD-119	yes	19.31
E-HCAD-5	yes	14.23
E-GEOD-93593	yes	4.54
E-GEOD-111727	no	495.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, REST, SOX2

miRNA regulators (miRDB)

131 targeting NTRK3, 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-4500	99.99	72.72	2367
HSA-MIR-23B-5P	99.98	66.07	587
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795

Literature-anchored findings (GeneRIF, showing 40)

• Although TrkB and TrkC signals mediating survival are largely similar, TrkB and TrkC signals required for maintenance of target innervation in vivo are regulated by distinct mechanisms. (PMID:11877382)
• Expression of the ETV6-NTRK3 gene fusion is a primary event in human secretory breast carcinoma. (PMID:12450792)
• ETV6-NTRK3.IRS-1 complex formation through the NTRK3 C terminus is essential for ETV6-NTRK3 transformation (PMID:14668342)
• While survival rates were higher for patients with high TrkC expression, these differences were not statistically significant. (PMID:15198123)
• truncated trkC is prevalent in the human prefrontal cortex and that neurons and glia may be responsive to NT-3 throughout life (PMID:15932601)
• These novel data demonstrate that neurotrophins influence ASM Ca(2+) and force regulation and suggest a potential role for neurotrophins in airway diseases (PMID:16648236)
• Light and electron microscopy immunohistochemistry showed that tonsillar samples were positive for TrkC. (PMID:16786155)
• TrkC was significantly present in 100% of medulloblastoma female patients (PMID:16826429)
• Human lung adenocarcinomas express TrkA and TrkB, but not TrkC; A549 cells, express mRNA transcripts encoding nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), TrkA, TrkB, and p75, and high protein levels of TrkA and TrkB. (PMID:16862449)
• NTRK3 gene was implicated in the pathogenesis of pancreatic cancers and it may be useful targets for diagnostic and therapeutic intervention in selected patients. (PMID:16941478)
• in astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression, but not p75NTR may promote tumor growth independently of grade (PMID:17971243)
• Using a conditional knock-in mouse model, the authors showed that ETV6(mouse)-NTRK3(human) fusion protein targeted committed alveolar bipotent or CD61(+) luminal progenitors for tumorigenesis via AP1 activation. (PMID:18068631)
• NTRK3 might be involved in the molecular basis of the age-dependent changes in ADHD symptoms throughout life span. (PMID:18179783)
• A strong significant association was found between eating disorders and NTRK3 gene. (PMID:18203754)
• somatic mutations in the tyrosine kinase domain of NTRK3 gene are frequent in large cell neuroendocrine carcinomas. Such mutational events could represent an important step in the cancerogenesis of these tumors (PMID:18293376)
• A potential role of all neurotrophins, through their different receptors, in pituitary functions. (PMID:18319596)
• protein levels of translational, splicing, processing, chaperone, protein handling, and metabolism machineries were shown to depend on neurotrophin-3-induced TrkC activation in the medulloblastoma cell line DAOY (PMID:18336001)
• childhood-onset mood disorders are linked to NTRK3 gene on chromosome 15q25.3-q26.2. (PMID:18347002)
• Here we present initial linkage-disequilibrium (LD) fine mapping of this signal and sequence analysis of NTRK3 (neurotrophic receptor kinase-3), a biologically plausible candidate gene. (PMID:18367154)
• NTRK3 may contribute to the genetic susceptibility to hoarding in obsessive-compulsive disorder (PMID:18616610)
• novel sequence variant, G76R, is present in 2 different patients and absent in controls could generate a lack of mature functional NTF-3 proteins in neural crest cell precursors altering NTF-3/TrkC signaling pathway and influencing ENS development. (PMID:18639687)
• Stress conditions induced the membranous expression of p75 neurotrophin receptor and tyrosine protein kinase receptor B, maximal in mature B cells (PMID:18713973)
• Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. (PMID:19011601)
• Novel R645C mutation was detected in NTRK3 in 2 affected siblings with Hirschsprung disease. (PMID:19040714)
• A proteomic approach identified thirteen proteins from several pathways that were differentially expressed following NP-3-induced TrkC receptor activation. (PMID:19156760)
• TrkC is a new neurotrophic receptor that Trypanosoma cruzi engages to promote the survival of neuronal and glial cells. (PMID:19179422)
• Insufficient expression of NTRK3 is associated with the outflow tract defect of human tetralogy of Fallot and may contribute to the progression of this defect. (PMID:19187638)
• The present results, although not robust, suggest that the NTRK-3 gene influences hippocampal function and may modify the risk for schizophrenia. (PMID:19344762)
• miRNAs are implicated as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders. (PMID:19370765)
• Trk signaling pathways were found to be targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression. (PMID:19417027)
• Findings suggest that mutations in RET and NTRK3 acting together are necessary and sufficient for the appearance of Hirschsprung disease and the EDN3 mutation acts as a phenotype modifier. (PMID:19556619)
• Mesenchymal stem cells modified by adenovirus carrying the TrkC gene are further promoted to differentiate into neuron-like cells with the potency of forming synapses by overexpressing the NT-3 gene in Schwann cells. (PMID:19680743)
• Study identified the previously reported pathogenic mutation of NTRK3 in a KRAS/BRAF wild-type tumor and 2 somatic mutations in the Src family of kinases (YES1 and LYN) that would be expected to cause structural changes. (PMID:19893451)
• ShcD binds to TrkC in a kinase-activity-dependent manner through its PTB and SH2 domains. (PMID:20078941)
• TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. (PMID:20160348)
• This study demonistrated that Intron 12 in NTRK3 is associated with bipolar disorder. (PMID:20554328)
• Overexpression of TrkC is associated with breast tumor growth and metastasis. (PMID:20802235)
• Studies indicate that insulin, IGF-1, TrkA, and TrkC receptors as trophic and as dependence receptors. (PMID:21139137)
• These results suggest that TrkA, TrkB, TrkC may contribute to growth and metastasis of liver cancer. (PMID:21295543)
• NT3 and its receptor may be involved in early folliculogenesis, particularly in the activation of primordial follicles. (PMID:21392742)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntrk3a	ENSDARG00000077228
danio_rerio	ntrk3b	ENSDARG00000086214
mus_musculus	Ntrk3	ENSMUSG00000059146
rattus_norvegicus	Ntrk3	ENSRNOG00000018674

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), 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), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

NT-3 growth factor receptor — Q16288 (reviewed: Q16288)

Alternative names: GP145-TrkC, Neurotrophic tyrosine kinase receptor type 3, TrkC tyrosine kinase

All UniProt accessions (13): A0A087WX31, A0A0D9SFP6, A0A8Q3SHY2, B7Z7U4, Q16288, H0YM90, Q96CY4, R4GMR8, R4GN40, R4GNH5, X5D2R1, X5D7M5, X5DNW6

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.

Subunit / interactions. Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Binds SH2B2. Interacts with SQSTM1 and KIDINS220. Interacts with PTPRS. Interacts with MAPK8IP3/JIP3.

Subcellular location. Membrane.

Tissue specificity. Widely expressed but mainly in nervous tissue. Isoform 2 is expressed at higher levels in adult brain than in fetal brain.

Post-translational modifications. Ligand-mediated auto-phosphorylation.

Disease relevance. Defects in NTRK3 are associated with susceptibility to congenital heart defects (CHD). A disease characterized by congenital developmental abnormalities involving structures of the heart. CHD are the most common major birth defects and the leading cause of death from congenital malformations.

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

Isoforms (5)

UniProt ID	Names	Canonical?
Q16288-1	1, A	yes
Q16288-2	2, B
Q16288-3	3, C
Q16288-4	4, D
Q16288-5	5, E

RefSeq proteins (11): NP_001007157, NP_001012338, NP_001230030, NP_001307063, NP_001307064, NP_001362739, NP_001362740, NP_001362741, NP_001362742, NP_001362743, NP_002521 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR002011	Tyr_kinase_rcpt_2_CS	Conserved_site
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020446	NTRK3	Family
IPR020635	Tyr_kinase_cat_dom	Domain
IPR020777	NTRK	Family
IPR031635	NTRK_LRRCT	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF00047, PF01462, PF07679, PF07714, PF13855, PF16920

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 (98 total): sequence variant 19, helix 15, strand 14, glycosylation site 13, disulfide bond 6, modified residue 5, domain 4, splice variant 4, sequence conflict 3, binding site 2, site 2, topological domain 2, repeat 2, turn 2, signal peptide 1, chain 1, active site 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6KZD	X-RAY DIFFRACTION	1.71
1WWC	X-RAY DIFFRACTION	1.9
4YMJ	X-RAY DIFFRACTION	2
6KZC	X-RAY DIFFRACTION	2
3V5Q	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16288-F1	77.36	0.47

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): 679 (proton acceptor); 516 (interaction with shc1); 834 (interaction with plc-gamma-1)

Ligand- & substrate-binding residues (2): 544–552; 572

Post-translational modifications (5): 493, 516, 705, 709, 710

Disulfide bonds (6): 32–38, 36–45, 164–189, 166–207, 231–284, 320–362

Glycosylation sites (13): 72, 79, 133, 163, 203, 218, 232, 259, 267, 272, 294, 375, 388

Mutagenesis-validated functional residues (1):

Position	Phenotype
572	loss of autophosphorylation and loss of ntrk3 signaling.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9034013	NTF3 activates NTRK3 signaling
R-HSA-9034015	Signaling by NTRK3 (TRKC)
R-HSA-9034793	Activated NTRK3 signals through PLCG1
R-HSA-9034864	Activated NTRK3 signals through RAS
R-HSA-9603381	Activated NTRK3 signals through PI3K
R-HSA-9603505	NTRK3 as a dependence receptor

MSigDB gene sets: 443 (showing top): PID_SHP2_PATHWAY, GOBP_CIRCADIAN_RHYTHM, GOBP_RESPONSE_TO_ETHANOL, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, PAX4_01, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_GLIOGENESIS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, AAGTCCA_MIR422B_MIR422A, GOBP_RESPONSE_TO_CORTICOSTEROID, GCANCTGNY_MYOD_Q6

GO Biological Process (38): neuron migration (GO:0001764), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), heart development (GO:0007507), circadian rhythm (GO:0007623), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), positive regulation of neuron projection development (GO:0010976), neuronal action potential propagation (GO:0019227), myelination in peripheral nervous system (GO:0022011), positive regulation of cell migration (GO:0030335), mechanoreceptor differentiation (GO:0042490), positive regulation of apoptotic process (GO:0043065), positive regulation of MAPK cascade (GO:0043410), response to ethanol (GO:0045471), neuron fate specification (GO:0048665), axon extension involved in regeneration (GO:0048677), positive regulation of axon extension involved in regeneration (GO:0048691), negative regulation of astrocyte differentiation (GO:0048712), positive regulation of positive chemotaxis (GO:0050927), response to corticosterone (GO:0051412), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of synapse assembly (GO:0051965), lens fiber cell differentiation (GO:0070306), cellular response to retinoic acid (GO:0071300), cochlea development (GO:0090102), postsynaptic density assembly (GO:0097107), regulation of presynapse assembly (GO:1905606), cellular response to nerve growth factor stimulus (GO:1990090), regulation of neural precursor cell proliferation (GO:2000177), protein phosphorylation (GO:0006468), cell communication (GO:0007154), nervous system development (GO:0007399), cell differentiation (GO:0030154), neurotrophin signaling pathway (GO:0038179), ephrin receptor signaling pathway (GO:0048013), animal organ development (GO:0048513), response to axon injury (GO:0048678), system development (GO:0048731)

GO Molecular Function (13): p53 binding (GO:0002039), transmembrane receptor protein tyrosine kinase activity (GO:0004714), GPI-linked ephrin receptor activity (GO:0005004), neurotrophin receptor activity (GO:0005030), ATP binding (GO:0005524), neurotrophin binding (GO:0043121), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): cytoplasm (GO:0005737), plasma membrane (GO:0005886), axon (GO:0030424), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by NTRK3 (TRKC)	5
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Protein-protein interactions at synapses	1
Negative regulation of the PI3K/AKT network	1
Signaling by NTRKs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	2
response to alcohol	2
cellular anatomical structure	2
generation of neurons	1
enzyme-linked receptor protein signaling pathway	1
animal organ development	1
circulatory system development	1
rhythmic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
transmission of nerve impulse	1
nervous system process	1
action potential propagation	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
regulation of cell migration	1
positive regulation of cell motility	1
neuron differentiation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cell fate specification	1
neuron fate commitment	1
regeneration	1
axon extension	1
sprouting of injured axon	1
positive regulation of axon extension	1
axon extension involved in regeneration	1
positive regulation of sprouting of injured axon	1

Protein interactions and networks

STRING

3672 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTRK3	NTF3	P20783	999
NTRK3	BDNF	P23560	999
NTRK3	NTF4	P34130	999
NTRK3	NGF	P01138	998
NTRK3	GDNF	P39905	972
NTRK3	ETV6	P41212	972
NTRK3	PTPRS	Q13332	971
NTRK3	NGFR	P08138	956
NTRK3	NTRK2	Q16620	951
NTRK3	TAMALIN	Q7Z6J2	894
NTRK3	SORT1	Q99523	842
NTRK3	NRTN	Q99748	762
NTRK3	NTRK1	P04629	750
NTRK3	EML4	Q9HC35	734
NTRK3	TPM3	P06753	726

IntAct

49 interactions, top by confidence:

A	B	Type	Score
NTRK3	PTPRS	psi-mi:“MI:0915”(physical association)	0.670
NTRK3	PTPN1	psi-mi:“MI:0407”(direct interaction)	0.570
SFN	NTRK3	psi-mi:“MI:0915”(physical association)	0.560
DOK6	NTRK3	psi-mi:“MI:0915”(physical association)	0.550
NTRK2	NTRK3	psi-mi:“MI:0915”(physical association)	0.540
NTRK3	SORT1	psi-mi:“MI:0915”(physical association)	0.540
SORT1	NTRK3	psi-mi:“MI:0407”(direct interaction)	0.540
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
NTRK1	NTRK3	psi-mi:“MI:0915”(physical association)	0.500
DDR2	NTRK3	psi-mi:“MI:0915”(physical association)	0.500
EPHA7	NTRK3	psi-mi:“MI:0915”(physical association)	0.500
NTRK3	MET	psi-mi:“MI:0915”(physical association)	0.500
NTRK3	SEL1L	psi-mi:“MI:0915”(physical association)	0.500
NTRK3	SEC61A1	psi-mi:“MI:0915”(physical association)	0.500
NTRK3	FAM171A2	psi-mi:“MI:0914”(association)	0.480
DOK6	NTF3	psi-mi:“MI:0914”(association)	0.460
NTRK3	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
	NTRK3	psi-mi:“MI:0915”(physical association)	0.400
NTRK3	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
NTRK3	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
HTR2A	NTRK3	psi-mi:“MI:0915”(physical association)	0.370
NTRK3	IRAK3	psi-mi:“MI:0915”(physical association)	0.370
NTRK3	ERLIN1	psi-mi:“MI:0914”(association)	0.350
DDR2	PLD2	psi-mi:“MI:0914”(association)	0.350
EPHA7	MYO1B	psi-mi:“MI:0914”(association)	0.350
NTRK3	ILVBL	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (426): NTRK3 (Affinity Capture-MS), SH3BP4 (Affinity Capture-MS), PTPRS (Affinity Capture-MS), MYADM (Affinity Capture-MS), C1GALT1 (Affinity Capture-MS), GNB2 (Affinity Capture-MS), C6orf120 (Affinity Capture-MS), MTOR (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), PTCD2 (Affinity Capture-MS), TMEM11 (Affinity Capture-MS), PAG1 (Affinity Capture-MS), EFR3A (Affinity Capture-MS), TBC1D24 (Affinity Capture-MS), GNB4 (Affinity Capture-MS)

ESM2 similar proteins: A2A259, A2AIR5, H2Q5A1, O00222, O15399, O60242, O75077, O75882, O97741, P15209, P24786, P31423, P35400, P37088, P47743, P55270, P70579, Q00961, Q01098, Q03351, Q03391, Q13507, Q14833, Q14957, Q16288, Q1ZZH0, Q4R766, Q5IS37, Q5RDQ8, Q62645, Q63604, Q68ED2, Q68EF4, Q6AYT7, Q80ZF8, Q8CIW5, Q8TCU5, Q8VHN2, Q91044, Q91YD4

Diamond homologs: A0M8R7, A0M8S8, A1X150, B3MH43, B3NS99, B4GBH0, B4HNW4, B4KPU0, B4MR28, B4P5Q9, B4QC63, O15146, O73798, P00529, P04629, P06213, P08069, P08581, P08922, P08941, P09208, P14616, P14617, P15127, P15208, P15209, P16056, P23049, P24062, P24786, P35739, P42159, P42681, P97523, Q00PJ8, Q01973, Q03146, Q03351, Q04912, Q05688

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NTF3	up-regulates	NTRK3	binding
NTRK3	up-regulates	SHC1	binding
NTRK3	up-regulates	PLCG1	binding
LSM-1231	“down-regulates activity”	NTRK3	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	14.7×	2e-03
PIP3 activates AKT signaling	5	10.1×	5e-03
Diseases of signal transduction by growth factor receptors and second messengers	5	8.6×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	6	30.7×	2e-05
positive regulation of ERK1 and ERK2 cascade	6	15.0×	8e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	11.5×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — ESCC, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	60
Likely benign	21
Benign	46

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1195985	t(12;15)(p13;q25)	Pathogenic

SpliceAI

5395 predictions. Top by Δscore:

Variant	Effect	Δscore
15:87876970:T:TA	donor_gain	1.0000
15:87876971:C:A	donor_gain	1.0000
15:87880257:ACCC:A	donor_gain	1.0000
15:87880258:CCCC:C	donor_gain	1.0000
15:87880271:T:TA	donor_gain	1.0000
15:87880303:T:A	donor_gain	1.0000
15:87929189:AC:A	donor_gain	1.0000
15:87929190:CC:C	donor_gain	1.0000
15:87929430:GGGCC:G	acceptor_gain	1.0000
15:87929433:CC:C	acceptor_gain	1.0000
15:87929434:CC:C	acceptor_gain	1.0000
15:87929445:A:C	acceptor_gain	1.0000
15:87933008:TTAC:T	donor_loss	1.0000
15:87933009:TACCT:T	donor_loss	1.0000
15:87933010:A:AC	donor_gain	1.0000
15:87933010:A:T	donor_loss	1.0000
15:87933010:AC:A	donor_gain	1.0000
15:87933011:C:CA	donor_gain	1.0000
15:87933011:CC:C	donor_gain	1.0000
15:87933011:CCT:C	donor_gain	1.0000
15:87933011:CCTG:C	donor_gain	1.0000
15:87933180:AGGGC:A	acceptor_gain	1.0000
15:87933181:GGGC:G	acceptor_gain	1.0000
15:87933182:GGC:G	acceptor_gain	1.0000
15:87933183:GC:G	acceptor_gain	1.0000
15:87933184:CC:C	acceptor_gain	1.0000
15:87933185:C:CA	acceptor_loss	1.0000
15:87933185:C:CC	acceptor_gain	1.0000
15:87933186:T:C	acceptor_loss	1.0000
15:87933192:C:CT	acceptor_gain	1.0000

AlphaMissense

5568 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:87877034:C:A	W807C	1.000
15:87877034:C:G	W807C	1.000
15:87877035:C:G	W807S	1.000
15:87877036:A:G	W807R	1.000
15:87877036:A:T	W807R	1.000
15:87877037:G:C	C806W	1.000
15:87877039:A:G	C806R	1.000
15:87877072:A:G	C795R	1.000
15:87877089:A:G	L789S	1.000
15:87880293:A:G	W771R	1.000
15:87880293:A:T	W771R	1.000
15:87880295:G:C	P770R	1.000
15:87880295:G:T	P770Q	1.000
15:87880296:G:A	P770S	1.000
15:87880296:G:T	P770T	1.000
15:87880304:C:A	G767V	1.000
15:87880304:C:T	G767E	1.000
15:87880305:C:G	G767R	1.000
15:87880305:C:T	G767R	1.000
15:87880319:T:A	E762V	1.000
15:87880320:C:T	E762K	1.000
15:87880321:C:A	W761C	1.000
15:87880321:C:G	W761C	1.000
15:87880323:A:G	W761R	1.000
15:87880323:A:T	W761R	1.000
15:87880334:C:A	G757V	1.000
15:87880334:C:T	G757E	1.000
15:87880335:C:A	G757W	1.000
15:87880335:C:G	G757R	1.000
15:87880335:C:T	G757R	1.000

dbSNP variants (sampled 300 via entrez): RS1000004529 (15:88137966 G>A), RS1000018833 (15:88236779 A>C), RS1000021208 (15:88174817 C>T), RS1000023614 (15:87910027 T>C), RS1000030078 (15:87887892 G>A), RS1000030541 (15:88201074 T>C), RS1000030803 (15:88140538 A>G), RS1000042013 (15:88100837 C>T), RS1000046970 (15:87926449 A>T), RS1000055247 (15:88068836 G>A,T), RS1000056673 (15:87958829 C>A,G,T), RS1000065704 (15:87873216 TC>T), RS1000069306 (15:88071719 G>A), RS1000078041 (15:88018530 A>C,G), RS1000079957 (15:88240258 A>T)

Disease associations

OMIM: gene MIM:191316 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (3): glioma (MONDO:0021042), premature menopause (MONDO:0001119), congenital heart disease (MONDO:0005453)

Orphanet (1): Glial tumor (Orphanet:182067)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001380_3	Gaucher disease severity	7.000000e-06
GCST001877_9	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	6.000000e-06
GCST002337_157	Amyotrophic lateral sclerosis (sporadic)	3.000000e-07
GCST006585_1720	Blood protein levels	5.000000e-10
GCST007325_187	General risk tolerance (MTAG)	1.000000e-08
GCST007325_204	General risk tolerance (MTAG)	2.000000e-08
GCST008223_3	Diabetic peripheral neuropathy in type 2 diabetes	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005910	Glioma	C04.557.465.625.600.380; C04.557.470.670.380; C04.557.580.625.600.380
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3559684 (PROTEIN FAMILY), CHEMBL5608 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

41 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 292,458 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3813873	PEXIDARTINIB	4	3,586
CHEMBL3889654	LAROTRECTINIB	4	1,850
CHEMBL3989939	LAROTRECTINIB SULFATE	4	771
CHEMBL4298138	REPOTRECTINIB	4	1,038
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL483158	ALISERTIB	3	2,305
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL124660	TANDUTINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL3545365	ALTIRATINIB	2
CHEMBL3673452	GZ-389988	2
CHEMBL4297627	SELITRECTINIB	2

Clinical evidence (CIViC)

Drug × variant × indication: 8 predictive associations from 8 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
NTRK3 F617L	Larotrectinib	Solid Tumor	Resistance	CIViC A	EID11571
NTRK1 Amplification OR NTRK3 Amplification OR NTRK2 Amplification	Entrectinib	Cancer	Sensitivity/Response	CIViC B	EID2958
NTRK3 Amplification	Entrectinib	Cancer	Sensitivity/Response	CIViC B	EID2959
NTRK3 G623R AND EML4::NTRK3 Fusion	Repotrectinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID11516
ETV6::NTRK3 Fusion AND NTRK3 G623R	Entrectinib	Mammary Analogue Secretory Carcinoma	Resistance	CIViC C	EID1874
NTRK3 F617L	Larotrectinib	Gastrointestinal Stromal Tumor	Resistance	CIViC C	EID9592
NTRK3 G623R AND EML4::NTRK3 Fusion	Entrectinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID11515
ETV6::NTRK3 Fusion AND NTRK3 G623R	ALK/TRK Inhibitor TSR-011 + Entrectinib + Crizotinib + Larotrectinib	Cancer	Resistance	CIViC D	EID10093

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type VII RTKs: Neurotrophin receptor/Trk family

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
zurletrectinib	Inhibition	9.74	pIC50
repotrectinib	Inhibition	9.68	pIC50
eratrectinib	Inhibition	9.6	pIC50
GR-389988	Inhibition	9.3	pIC50
taletrectinib	Inhibition	9.01	pIC50
emzeltrectinib	Inhibition	9.0	pIC50
selitrectinib	Inhibition	8.6	pIC50
CH7057288	Inhibition	8.55	pIC50
DZX19	Inhibition	8.39	pIC50
AZD1332	Inhibition	8.3	pIC50
RIPK1 inhibitor 22b	Inhibition	8.15	pIC50
GNF-5837	Inhibition	8.15	pIC50
DDR1/2 inhibitor 5n	Inhibition	8.03	pKd
NIK inhibitor 12f	Inhibition	7.3	pIC50
GW-2580	Inhibition	6.92	pKd
pexidartinib	Inhibition	6.05	pIC50

Binding affinities (BindingDB)

32 measured of 75 human assays (75 total across all organisms); most potent 32 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.1 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxyazetidin-1-yl)ketone	IC50	1.04 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-ethylpiperazin-1-yl)ketone	IC50	1.06 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
3-methoxy-2-methyl-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	1.18 nM	US-8822500: Tyrosine kinase inhibitors
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(morpholino)ketone	IC50	1.27 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-methylpiperazin-1-yl)ketone	IC50	1.39 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
Staurosporine	KD	1.7 nM
(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone	IC50	1.77 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
6-[2-(dimethylamino)ethyl]-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	2.06 nM	US-8822500: Tyrosine kinase inhibitors
2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide	IC50	2.93 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone	IC50	3.37 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
6-(1-methylpiperidin-4-yl)-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	3.48 nM	US-8822500: Tyrosine kinase inhibitors
2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide	IC50	3.58 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone	IC50	4.16 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(pyrrolidin-1-yl)ketone	IC50	5.86 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone	IC50	6.14 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
Larotrectinib	IC50	9.7 nM	US-9676783: Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(piperidin-1-yl)ketone	IC50	30.4 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol	IC50	32.3 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide	IC50	34.2 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
6-fluoro-2-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	80 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate	IC50	98.8 nM	US-20250387388: COMPOUND AS TRK INHIBITOR AND/OR RET INHIBITOR AND USE THEREOF
PKC-412	KD	190 nM
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide	KD	370 nM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methyl-phenyl)urea	KD	450 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	KD	740 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

743 potent at pChembl≥5 of 788 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	REPOTRECTINIB
10.00	IC50	0.1	nM	REPOTRECTINIB
9.91	IC50	0.123	nM	STAUROSPORINE
9.70	IC50	0.2	nM	CHEMBL5093999
9.70	IC50	0.2	nM	CHEMBL5070835
9.70	IC50	0.2	nM	CHEMBL5080010
9.70	IC50	0.2	nM	LAROTRECTINIB
9.68	IC50	0.21	nM	CHEMBL4864729
9.68	IC50	0.211	nM	CHEMBL5400169
9.68	IC50	0.207	nM	STAUROSPORINE
9.66	IC50	0.22	nM	STAUROSPORINE
9.54	IC50	0.29	nM	LAROTRECTINIB
9.52	Kd	0.3	nM	CHEMBL6044141
9.49	IC50	0.32	nM	LAROTRECTINIB
9.39	IC50	0.41	nM	LAROTRECTINIB
9.36	IC50	0.44	nM	LAROTRECTINIB
9.35	IC50	0.45	nM	LAROTRECTINIB
9.30	IC50	0.503	nM	GZ-389988
9.30	IC50	0.5	nM	SELITRECTINIB
9.28	IC50	0.525	nM	CHEMBL1980995
9.22	IC50	0.6	nM	CHEMBL5088000
9.15	IC50	0.7	nM	CHEMBL5092943
9.15	IC50	0.7	nM	CHEMBL5176837
9.15	IC50	0.7	nM	SELITRECTINIB
9.10	Ki	0.7943	nM	CHEMBL1977148
9.08	IC50	0.83	nM	ALTIRATINIB
9.00	IC50	1	nM	CHEMBL3582439
9.00	IC50	1	nM	CHEMBL4211921
9.00	IC50	1	nM	CHEMBL4790022
9.00	IC50	1	nM	CHEMBL3666254
9.00	IC50	1	nM	CHEMBL4856292
9.00	Ki	1	nM	CHEMBL5088153
9.00	IC50	1	nM	ENTRECTINIB
9.00	IC50	1	nM	SELITRECTINIB
9.00	Ki	1	nM	CHEMBL1989708
8.96	IC50	1.1	nM	CHEMBL4210892
8.96	IC50	1.1	nM	SELITRECTINIB
8.93	IC50	1.18	nM	REPOTRECTINIB
8.90	Ki	1.259	nM	CHEMBL1988717
8.85	IC50	1.4	nM	REPOTRECTINIB
8.85	IC50	1.4	nM	SELITRECTINIB
8.80	IC50	1.585	nM	CHEMBL3671311
8.80	Ki	1.585	nM	CHEMBL2007421
8.80	Ki	1.585	nM	ENTRECTINIB
8.77	IC50	1.7	nM	LAROTRECTINIB
8.77	IC50	1.7	nM	CHEMBL5078405
8.72	IC50	1.9	nM	CHEMBL4743163
8.72	IC50	1.9	nM	CHEMBL4787950
8.71	IC50	1.94	nM	ENTRECTINIB
8.70	IC50	2	nM	CHEMBL3582442

PubChem BioAssay actives

443 with measured affinity, of 1755 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
Repotrectinib	1812768: Inhibition of TrKC (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	<0.0001	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-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	1715137: Inhibition of human TRKC using poly[Glu:Tyr] (4:1) as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
1-(3-chlorophenyl)-3-[5-[2-[[7-[3-(dimethylamino)propoxy]quinazolin-4-yl]amino]ethyl]-1,3-thiazol-2-yl]urea	1829851: Inhibition of TRKC (unknown origin)	ic50	0.0002	uM
(7S)-10-fluorospiro[14-oxa-2,5,12,17,21,22,25-heptazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812768: Inhibition of TrKC (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0002	uM
(7S)-10-fluorospiro[5,14-dioxa-2,12,17,21,22,25-hexazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812768: Inhibition of TrKC (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0002	uM
(7R)-10-fluorospiro[14-oxa-2,12,17,21,22,25-hexazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812768: Inhibition of TrKC (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0002	uM
(3R,11S)-6-fluoro-3,11-dimethyl-10-oxa-2,13,16,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	2026372: Inhibition of His-tagged human recombinant wild type TRKC	ic50	0.0002	uM
Larotrectinib	1961471: Inhibition of TRKC (unknown origin) using TK as substrate in presence of ATP incubated for 40 mins by HTRF KinEASE assay	ic50	0.0002	uM
(6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22-heptaen-17-one	1812768: Inhibition of TrKC (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0005	uM
2-[4-[5-[[(1R)-1-[2-(2,2-difluoroethoxy)-5-fluorophenyl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]pyrazol-1-yl]ethanol	1813237: Inhibition of TRKC G623R mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay	ic50	0.0006	uM
6-[7-methoxy-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-pyrrolidin-3-ylpyridin-2-amine	1894592: Inhibition of TrkC (unknown origin)	ic50	0.0007	uM
5-[(2R)-2-[2-(2,2-difluoroethoxy)-5-fluorophenyl]pyrrolidin-1-yl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	1813237: Inhibition of TRKC G623R mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay	ic50	0.0007	uM
1-N’-[4-[[2-(cyclopropanecarbonylamino)-4-pyridinyl]oxy]-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	1318753: Inhibition of TrkC (unknown origin)	ic50	0.0008	uM
(3R)-N-[5-[(2S)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide	1780793: Inhibition of N-terminal GST-tagged human TRKC (456 to 825 residues) expressed in Sf21 using TK as substrate in presence of ATP measured after 40 mins by HTRF assay	ic50	0.0010	uM
6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]-3-pyridin-2-ylimidazo[1,2-b]pyridazine	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0010	uM
2-[4-[4-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridinyl]piperazin-1-yl]acetic acid	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0010	uM
N-[5-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)-3-pyridinyl]-2-(4-chlorophenyl)acetamide	1686376: Inhibition of human TrkC expressed in human U2OS cells pre-incubated 30 mins before neurotrophin addition and measured after 2 hrs by luminescence based assay	ic50	0.0010	uM
6-(1-methylpyrazol-4-yl)-3-[(3R)-1-[2-[4-(trifluoromethoxy)phenyl]acetyl]pyrrolidin-3-yl]oxypyridine-2-carboxamide	1381369: Antagonist activity at prolink-tagged TrkC in human U2OS cells assessed as inhibition of NT3-induced receptor phosphorylation by measuring reduction in EA-tagged SH2 protein recruitment preincubated for 30 mins followed by NT3 stimulation measured after 2 hrs by PathHunter enzyme complementation assay	ic50	0.0010	uM
1-[3-tert-butyl-1-(4-chlorophenyl)pyrazol-5-yl]-3-[4-[(6,6-dimethyl-7-oxo-8H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino]-3-methylphenyl]urea	1822434: Binding affinity to TrkC (unknown origin) assessed as inhibition constant by radiometric assay	ki	0.0010	uM
Entrectinib	1878095: Inhibition of TrkC (unknown origin)	ic50	0.0010	uM
N-[5-(2-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)-3-pyridinyl]-2-(4-chlorophenyl)acetamide	1686376: Inhibition of human TrkC expressed in human U2OS cells pre-incubated 30 mins before neurotrophin addition and measured after 2 hrs by luminescence based assay	ic50	0.0010	uM
2-[(3R,4S)-3-fluoro-1-[2-[4-(trifluoromethoxy)phenyl]acetyl]piperidin-4-yl]oxy-5-(1-methylimidazol-4-yl)pyridine-3-carboxamide	1381369: Antagonist activity at prolink-tagged TrkC in human U2OS cells assessed as inhibition of NT3-induced receptor phosphorylation by measuring reduction in EA-tagged SH2 protein recruitment preincubated for 30 mins followed by NT3 stimulation measured after 2 hrs by PathHunter enzyme complementation assay	ic50	0.0011	uM
N-[(1R)-1-[2-(2,2-difluoroethoxy)-5-fluorophenyl]ethyl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine	1813237: Inhibition of TRKC G623R mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay	ic50	0.0017	uM
5-[(3,5-difluorophenyl)methyl]-3-[(E)-2-pyridin-2-ylethenyl]-2H-indazole	1741214: Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay	ic50	0.0019	uM
3-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]-methylamino]pyrazolo[1,5-a]pyrimidin-3-yl]-1,1-di(propan-2-yl)urea	1683515: Inhibition of Trk-C (unknown origin)	ic50	0.0019	uM
1-[4-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridinyl]piperidin-4-ol	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0020	uM
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-3-[(E)-2-pyridin-2-ylethenyl]-2H-indazol-5-amine	1741214: Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay	ic50	0.0020	uM
N-[[2-(2,2-difluoroethoxy)-5-fluorophenyl]methyl]-3-(1,2,4-triazol-1-yl)-1H-indazol-5-amine	2117233: Inhibition of TRKC (unknown origin) using TK as substrate incubated for 40 mins in presence of ATP by HTRF assay	ic50	0.0020	uM
1-[3-tert-butyl-1-(4-chlorophenyl)pyrazol-5-yl]-3-[4-[(2,2-dimethyl-3-oxo-4H-1,4-benzoxazin-8-yl)amino]-3-methylphenyl]urea	2139997: Inhibition of TRKC (unknown origin) by TR-FRET assay	ic50	0.0020	uM
1-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2-pyridinyl]piperidin-4-ol	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0020	uM
N-[5-[2-amino-7-(1-hydroxy-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carbonyl]-3-pyridinyl]-2-(4-chlorophenyl)acetamide	1686376: Inhibition of human TrkC expressed in human U2OS cells pre-incubated 30 mins before neurotrophin addition and measured after 2 hrs by luminescence based assay	ic50	0.0020	uM
6-amino-5-[(3S)-4,4-difluoro-1-[2-[4-(trifluoromethoxy)phenyl]acetyl]pyrrolidin-3-yl]oxy-N-methylpyridine-3-carboxamide	1381369: Antagonist activity at prolink-tagged TrkC in human U2OS cells assessed as inhibition of NT3-induced receptor phosphorylation by measuring reduction in EA-tagged SH2 protein recruitment preincubated for 30 mins followed by NT3 stimulation measured after 2 hrs by PathHunter enzyme complementation assay	ic50	0.0022	uM
5-(1-methylimidazol-4-yl)-2-[1-[2-[4-(trifluoromethoxy)phenyl]acetyl]piperidin-4-yl]oxybenzamide	1381369: Antagonist activity at prolink-tagged TrkC in human U2OS cells assessed as inhibition of NT3-induced receptor phosphorylation by measuring reduction in EA-tagged SH2 protein recruitment preincubated for 30 mins followed by NT3 stimulation measured after 2 hrs by PathHunter enzyme complementation assay	ic50	0.0023	uM
(3S)-N-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide	1683515: Inhibition of Trk-C (unknown origin)	ic50	0.0023	uM
(3S)-N-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]-methylamino]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide	1683515: Inhibition of Trk-C (unknown origin)	ic50	0.0023	uM
2-N-[(2,5-difluorophenyl)methyl]-4-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine	1883890: Inhibition of N-terminal human TRKC (456 to 825 residues) expressed in baculovirus expression system using TK as substrate measured after 40 mins in presence of ATP by HTRF assay	ic50	0.0025	uM
2-(4-methylpiperazin-1-yl)-N-[4-methyl-5-[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]-1,3-thiazol-2-yl]acetamide	1743350: Inhibition of human TRKC by Z-LYTE or ADP-Glo assay	ic50	0.0026	uM
1-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]-methylamino]pyrazolo[1,5-a]pyrimidin-3-yl]-3-(4-hydroxyphenyl)urea	1683515: Inhibition of Trk-C (unknown origin)	ic50	0.0026	uM
N-[(3,5-difluorophenyl)methyl]-3-[(E)-2-pyridin-2-ylethenyl]-2H-indazol-5-amine	1741214: Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay	ic50	0.0027	uM
N-[(3-fluorophenyl)methyl]-3-[(E)-2-pyridin-2-ylethenyl]-2H-indazol-5-amine	1741214: Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay	ic50	0.0027	uM
5-[(3,5-difluorophenyl)methoxy]-3-[(E)-2-pyridin-2-ylethenyl]-1H-indazole	1741214: Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay	ic50	0.0027	uM
N-tert-butyl-2-[2-[8-(methanesulfonamido)-6,6-dimethyl-11-oxonaphtho[2,3-b][1]benzofuran-3-yl]ethynyl]-6-methylpyridine-4-carboxamide	1864434: Inhibition of TRKC (unknown origin)	ic50	0.0028	uM
5-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-propan-2-ylphenyl]-18-oxo-9-oxa-17,23,25,26-tetrazatetracyclo[17.5.2.14,8.022,25]heptacosa-1(24),4,6,8(27),19(26),20,22-heptaen-2-yne-6-carboxamide	2014017: Inhibition of TRKC (unknown origin) using Ser/Thr 06 as peptide substrate incubated for 1 hr in presence of ATP by FRET based Z-LYTE assay	ic50	0.0028	uM
3-[2-[6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl]ethynyl]-2-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-propan-2-ylphenyl]benzamide	1556777: Inhibition of recombinant human His-tagged TrkC cytoplasmic domain (510 to 825 residues) expressed in baculovirus using tyr 01 as substrate incubated for 1 hr by Z’-Lyte assay	ic50	0.0029	uM
N-[4-[6-[(3-fluorophenyl)methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]oxane-4-carboxamide	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0030	uM
5-[[2-(2,2-difluoroethoxy)-5-fluorophenyl]methylamino]-N-methyl-1H-indazole-3-carboxamide	2117233: Inhibition of TRKC (unknown origin) using TK as substrate incubated for 40 mins in presence of ATP by HTRF assay	ic50	0.0030	uM
5-[[2-(2,2-difluoroethoxy)-5-fluorophenyl]methylamino]-1H-indazole-3-carbonitrile	2117233: Inhibition of TRKC (unknown origin) using TK as substrate incubated for 40 mins in presence of ATP by HTRF assay	ic50	0.0030	uM
4-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]benzonitrile	1229326: Inhibition of Tel-fused TRKC (unknown origin) overexpressed in mouse BA/F3 cells assessed as inhibition of cell proliferation after 48 hrs by luciferase reporter gene assay in absence of recombinant mouse IL3	ic50	0.0030	uM
4-fluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	1533334: Inhibition of TRKC (unknown origin)	ic50	0.0030	uM
N-[5-[2-amino-7-(1-hydroxy-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carbonyl]-3-pyridinyl]-2-(5-chloro-2-pyridinyl)acetamide	1686376: Inhibition of human TrkC expressed in human U2OS cells pre-incubated 30 mins before neurotrophin addition and measured after 2 hrs by luminescence based assay	ic50	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
Tretinoin	affects cotreatment, increases expression	2
Cadmium Chloride	increases expression	2
methylmercuric chloride	decreases expression	1
titanium dioxide	decreases methylation, increases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, decreases reaction, increases abundance	1
CFM 1	increases expression	1
belinostat	increases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
ponatinib	decreases activity	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Benzalkonium Compounds	affects response to substance	1
Calcitriol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	increases expression	1
Dust	decreases expression	1

ChEMBL screening assays

408 unique, capped per target: 400 binding, 4 functional, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1035905	Binding	Binding affinity to human TRKC at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem
CHEMBL1176960	Functional	Antagonist activity at human TrkC expressed in mouse NIH/3T3 cells assessed as inhibition of NT3-induced cytoprotection at 20 uM by MTT assay relative to NT3	Bivalent diketopiperazine-based tropomysin receptor kinase C (TrkC) antagonists. — J Med Chem
CHEMBL4309193	ADMET	Antagonist activity at prolink-tagged TrkC (unknown origin) expressed in cells assessed as inhibition of NT3-induced receptor phosphorylation by measuring reduction in EA-tagged SH2 protein recruitment preincubated for 30 mins followed by N	Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors. — J Med Chem

Cellosaurus cell lines

12 cell lines: 8 cancer cell line, 3 factor-dependent cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1807	AP-1060	Cancer cell line	Male
CVCL_B8LS	Abcam HCT 116 NTRK3 KO	Cancer cell line	Male
CVCL_B8ZQ	Abcam MCF-7 NTRK3 KO	Cancer cell line	Female
CVCL_B9NX	Abcam A-549 NTRK3 KO	Cancer cell line	Male
CVCL_D1TU	Abcam U-87MG NTRK3 KO	Cancer cell line	Male
CVCL_D7W6	Ubigene A-549 NTRK3 KO	Cancer cell line	Male
CVCL_KB41	CellSensor TrkC-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female
CVCL_RL93	IMS-M2	Cancer cell line	Female
CVCL_S607	SKK-1	Cancer cell line	Male
CVCL_UE77	Ba/F3 ETV6-NTRK3	Factor-dependent cell line

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT03048084	PHASE4	RECRUITING	Seizure Treatment in Glioma
NCT06625047	PHASE4	COMPLETED	Comparing Telehealth and In-person Assessments in Glioma Patients Receiving Oral Chemotherapy
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00045968	PHASE3	UNKNOWN	Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
NCT00256425	PHASE3	UNKNOWN	Cognitive Rehabilitation of Glioma Patients
NCT01479686	PHASE3	COMPLETED	iMRI Guided Resection in Cerebral Glioma Surgery
NCT01502280	PHASE3	COMPLETED	Fluorescence-guided Surgery for Low- and High-grade Gliomas
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT02363075	PHASE3	UNKNOWN	Dexamfetamine Sulphate in Patients With Glioma Suffering From Severe Asthenia
NCT03149575	PHASE3	TERMINATED	VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM
NCT03722355	PHASE3	COMPLETED	Hyperfractionated RT With BCNU Versus Conventional RT With BCNU for Supratentorial Malignant Glioma
NCT04164901	PHASE3	ACTIVE_NOT_RECRUITING	Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
NCT05303519	PHASE3	RECRUITING	SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance)