NTRK1

Summary

NTRK1 (neurotrophic receptor tyrosine kinase 1, HGNC:8031) is a protein-coding gene on chromosome 1q23.1, encoding High affinity nerve growth factor receptor (P04629). Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. In precision oncology, NTRK1 Amplification OR NTRK3 Amplification OR NTRK2 Amplification confers sensitivity to Entrectinib in Cancer (CIViC Level B); 14 further curated variant–drug associations are listed below.

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date.

Source: NCBI Gene 4914 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary sensory and autonomic neuropathy type 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,563 total — 105 pathogenic, 74 likely-pathogenic
• Phenotypes (HPO): 80
• Druggable target: yes — 66 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 15 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_002529

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8031
Approved symbol	NTRK1
Name	neurotrophic receptor tyrosine kinase 1
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	TRK, TRKA, MTC
Ensembl gene	ENSG00000198400
Ensembl biotype	protein_coding
OMIM	191315
Entrez	4914

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000358660, ENST00000368196, ENST00000392302, ENST00000489021, ENST00000497019, ENST00000524377, ENST00000530298, ENST00000531606, ENST00000533630, ENST00000534682, ENST00000674537, ENST00000675461, ENST00000956587

RefSeq mRNA: 3 — MANE Select: NM_002529 NM_001007792, NM_001012331, NM_002529

CCDS: CCDS1161, CCDS30891

Canonical transcript exons

ENST00000524377 — 17 exons

Exon	Start	End
ENSE00002187747	156881457	156881850
ENSE00002402062	156874383	156874400
ENSE00003491788	156868505	156868647
ENSE00003538368	156874906	156875008
ENSE00003547826	156876080	156876210
ENSE00003559053	156874571	156874626
ENSE00003567933	156864354	156864428
ENSE00003572575	156879999	156880157
ENSE00003593627	156871623	156871755
ENSE00003610371	156876400	156876572
ENSE00003620536	156866910	156866978
ENSE00003623421	156864728	156864799
ENSE00003626699	156875520	156875666
ENSE00003644412	156879122	156879362
ENSE00003653319	156873633	156873959
ENSE00003654983	156868104	156868249
ENSE00003913306	156860865	156861146

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 82.00.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4352 / max 490.8770, expressed in 302 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5785	1.4240	202
5786	0.8072	208
5784	0.1708	79
5782	0.0332	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	82.00	gold quality
apex of heart	UBERON:0002098	81.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.45	gold quality
right atrium auricular region	UBERON:0006631	72.46	gold quality
left uterine tube	UBERON:0001303	72.45	gold quality
pons	UBERON:0000988	72.09	silver quality
omental fat pad	UBERON:0010414	71.46	gold quality
peritoneum	UBERON:0002358	71.38	gold quality
cardiac atrium	UBERON:0002081	70.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	70.18	gold quality
heart left ventricle	UBERON:0002084	70.05	gold quality
adipose tissue of abdominal region	UBERON:0007808	69.78	gold quality
body of uterus	UBERON:0009853	69.75	gold quality
cardiac ventricle	UBERON:0002082	69.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	69.00	gold quality
lower esophagus	UBERON:0013473	68.90	gold quality
trigeminal ganglion	UBERON:0001675	67.94	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	67.85	gold quality
Brodmann (1909) area 10	UBERON:0013541	67.15	gold quality
putamen	UBERON:0001874	67.11	gold quality
endocervix	UBERON:0000458	67.02	gold quality
heart	UBERON:0000948	66.61	gold quality
right adrenal gland	UBERON:0001233	66.40	gold quality
right testis	UBERON:0004534	66.02	gold quality
caudate nucleus	UBERON:0001873	65.39	gold quality
adenohypophysis	UBERON:0002196	65.22	gold quality
left adrenal gland cortex	UBERON:0035825	64.73	gold quality
sigmoid colon	UBERON:0001159	64.66	gold quality
left testis	UBERON:0004533	64.33	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	792.32
E-MTAB-9067	yes	12.36
E-MTAB-9801	yes	4.39
E-ANND-3	yes	4.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREBZF, CUX1, EGR3, HAND1, HIF1A, HMX1, ING4, JUN, KLF7, LRRFIP1, MYCN, POU4F1, RUNX1, SP1, SSRP1, STAT5A, TBP, TCF3, TLX3, TP53, TXK, ZBTB17, ZNF354C, ZNF91

miRNA regulators (miRDB)

14 targeting NTRK1, 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-185-3P	99.95	67.01	1743
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-8077	99.17	66.67	862
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-1915-5P	95.25	65.78	571

Literature-anchored findings (GeneRIF, showing 40)

• congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency (PMID:11668614)
• TrkA is expressed in pleural and peritoneal effusions and in advanced-stage ovarian carcinoma. (PMID:11705863)
• biologic effects of trkA neurotrophin receptor activation by nerve growth factor in a newly established Askin tumor cell line (PMID:11850535)
• Cys436 of the trkA is responsible for the rapid transfer of the transmembrane occupancy signal to the SHC adaptor protein for activation of the Ras-Erk pathway and DNA synthesis. (PMID:11859925)
• genetics of hereditary sensory and autonomic neuropathy type IV: clinical, biological and molecular aspects of mutations (REVIEW) (PMID:12102460)
• role in tyrosine phosphorylation and processing of beta-APP (PMID:12150951)
• TrkA as a life and death receptor: receptor dose as a mediator of function. (PMID:12208732)
• No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V. (PMID:12210794)
• These results suggest that Grit, a novel TrkA-interacting protein, regulates neurite outgrowth by modulating the Rho family of small GTPases. (PMID:12446789)
• Most of the GFAP-positive cells express TrkA, whereas a rare, novel subpopulation of astrocytes was found to be devoid of TrkA. Those results support the idea that astrocytes play an important neurotrophic role in the retina. (PMID:12536040)
• Nerve growth factor decreases N-myc levels in TRKA-infected neuroblastoma cells and decreases cell proliferation via a MAPK path. (PMID:14691455)
• Constitutively activated Scr facilitates NGF-induced phosphorylation of TRKA. (PMID:14988025)
• CIPA patients had a branch site mutation in intron 7 (IVS7-33 T–>A) of the NTRK1 gene and a marked reduction of small myelinated and unmyelinated fibers and a relatively increased axon size. This is the first CIPA family encountered in Taiwan (PMID:15159601)
• genes are rearranged in papillary thyroid cancer. (PMID:15273715)
• a role for TrkA activation in a subset of melanomas as a predictor of an aggressive phenotype and poor outcome (PMID:15362372)
• a novel alternative TrkA splice variant, TrkAIII, that exhibits expression restricted to undifferentiated early neural progenitors, human neuroblastomas, and a subset of other neural crest-derived tumors (PMID:15488758)
• expression of NGF and its receptors, TrkA and p75NTR, in hepatocellular carcinomas (HCC); NGF and its receptors are thought to have a role in cellular interactions involving HCC cells, hepatic stellate cells, arterial cells and nerve cells in HCC tissues (PMID:15523689)
• upregulation of proapoptotic genes and angiogenesis inhibitors (PMID:15637590)
• mechanism that regulates aberrant or increased TrkA expression in various cancer cell lines and in the course of pancreatic cancer progression. (PMID:15870692)
• These results strongly indicate that the expression level of PS1 protein has a cross talk with the Trk-dependent neuroprotective intracellular signaling pathway. (PMID:15950763)
• TrkA induces apoptosis of neuroblastoma cells through a p53-dependent mechanism (PMID:15961390)
• Data show that nerve growth factor activation of the TrkA receptor involves two distinct signalling pathways, and that both are necessary to induce airway smooth muscle cell proliferation. (PMID:16091303)
• Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene which encodes the receptor for nerve growth factor (NGF). (PMID:16138253)
• Phosphorylated TrkA is localized at the mitotic apparatus in a human glioma cell line. (PMID:16181609)
• Trk receptor signaling involves an inducible switch mechanism through an unconventional substrate that distinguishes neurotrophin action from other growth factor receptors (PMID:16284401)
• Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV. (PMID:16373086)
• frequency of NTRK1 rearrangements in papillary thyroid carcinoma for the Polish population (PMID:16483615)
• Overexpression in salivary adenoid cystic carcinoma may constitute a reason for perineural invasion (PMID:16546643)
• Some trkA immunoreactivity was observed in the outer membrane of cells in the basal and spinal layers of the epidermis in atopic dermatitis (AD). In the papillary dermis, a larger number of cells demonstrated strong trkA immunoreactivity. (PMID:16586073)
• Expression of TrkA in pancreatic cancer is a marker of tumor aggressiveness. (PMID:16704535)
• Light and electron microscopy immunohistochemistry showed that human tonsillar samples were positive for TrkA. (PMID:16786155)
• These results indicate that Fyn is activated by G-protein-coupled receptor stimulation and is responsible for transactivation of TrkA receptors on intracellular membranes. (PMID:16860569)
• 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)
• Findings report, for the first time, the expression pattern of NGF and TrkA proteins in human scalp skin and hair follicle. (PMID:16919030)
• These data strongly indicate that these anti-neutral glycosphingolipids antibodies have a functional impact on nerve growth factor (NGF)-Trk-mediated intracellular signal transduction pathway. (PMID:16935282)
• Data provide further evidence regarding the clinical role of p-TrkA in ovarian carcinoma. (PMID:16996570)
• CEP-701 could be used to reduce the metastasis formation in advanced prostatic cncer by inhibiting NTRK1. (PMID:17143529)
• We propose that TrkA and p75 likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules, rather than through direct extracellular interactions. (PMID:17196528)
• TrkA is located in carrier vesicles, including ring-like vesicles near the plasma membrane, and dense core vesicles around the nucleius in a glioma cell line. (PMID:17447019)
• trkA(NGFR) and p75(NTR) have roles with nerve growth factor in the healing process as a result of injury [review] (PMID:17531524)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ntrk1	ENSDARG00000004586
mus_musculus	Ntrk1	ENSMUSG00000028072
rattus_norvegicus	Ntrk1	ENSRNOG00000013953

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

High affinity nerve growth factor receptor — P04629 (reviewed: P04629)

Alternative names: Neurotrophic tyrosine kinase receptor type 1, TRK1-transforming tyrosine kinase protein, Tropomyosin-related kinase A, Tyrosine kinase receptor, Tyrosine kinase receptor A, gp140trk, p140-TrkA

All UniProt accessions (7): A0A6Q8PF65, A0A6Q8PGU5, A0A6Q8PHG5, E9PQG0, P04629, J3KP20, X5DR71

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.

Subunit / interactions. Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer. Interacts with SQSTM1; bridges NTRK1 to NGFR. Forms a ternary complex with NGFR and KIDINS220; this complex is affected by the expression levels of KIDINS220 and an increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1. Interacts with SH2D1A; regulates NTRK1. Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation. Interacts (phosphorylated) with SH2B1 and SH2B2. Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. Interacts with SORT1; may regulate NTRK1 anterograde axonal transport. Interacts with RAB7A. Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner. Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation. Interacts with PTPRS. Interacts with USP36; USP36 does not deubiquitinate NTRK1. Interacts with GGA3. Interacts with TSPAN1; this interaction promotes NTRK1 stability.

Subcellular location. Cell membrane. Early endosome membrane. Late endosome membrane. Recycling endosome membrane.

Tissue specificity. Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors.

Post-translational modifications. Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 mediates interaction and phosphorylation of SHC1. N-glycosylated. Isoform TrkA-I and isoform TrkA-II are N-glycosylated. Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination by NEDD4L leads to degradation. Ubiquitination regulates the internalization of the receptor.

Disease relevance. Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800] Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and intellectual disability. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. The disease is caused by variants affecting the gene represented in this entry. Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3’-end of NTRK1. A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3’-end of NTRK1. An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5’-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.

Activity regulation. The pro-survival signaling effect of NTRK1 in neurons requires its endocytosis into signaling early endosomes and its retrograde axonal transport. This is regulated by different proteins including CFL1, RAC1 and SORT1. NTF3 is unable to induce this signaling probably due to the lability of the NTF3-NTRK1 complex in endosomes. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. Regulated by NGFR.

Domain organisation. The transmembrane domain mediates interaction with KIDINS220. The extracellular domain mediates interaction with NGFR.

Induction. Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it.

Miscellaneous. Trk also stands for tropomyosin-related kinase since it was first isolated as an oncogenic protein which was the result of a fusion between the tropomyosin gene TPM3 and NTRK1. Major isoform. Has enhanced responsiveness to NTF3 neurotrophin. Constitutively active. Does not bind NGF and does not interact with GRB2 and FRS2.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P04629-1	TrkA-II, TrkAII	yes
P04629-2	TrkA-I, TrkAI
P04629-3	3
P04629-4	TrkA-III, TrkAIII

RefSeq proteins (3): NP_001007793, NP_001012331, NP_002520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
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
IPR007110	Ig-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020461	NTRK1	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
IPR040665	TrkA_TMD	Domain
IPR050122	RTK	Family

Pfam: PF07714, PF13855, PF16920, PF18613

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 (178 total): sequence variant 45, strand 39, helix 30, glycosylation site 13, turn 8, mutagenesis site 6, modified residue 5, disulfide bond 5, domain 4, site 4, sequence conflict 3, splice variant 3, short sequence motif 2, binding site 2, topological domain 2, repeat 2, signal peptide 1, chain 1, region of interest 1, active site 1, transmembrane region 1

Structure

Experimental structures (PDB)

65 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5JFW	X-RAY DIFFRACTION	1.52
5JFV	X-RAY DIFFRACTION	1.59
5JFX	X-RAY DIFFRACTION	1.63
4PMP	X-RAY DIFFRACTION	1.8
7N3T	X-RAY DIFFRACTION	1.84
5KMI	X-RAY DIFFRACTION	1.87
6D1Z	X-RAY DIFFRACTION	1.87
6D1Y	X-RAY DIFFRACTION	1.93
6D20	X-RAY DIFFRACTION	1.94
6NSS	X-RAY DIFFRACTION	1.97
1HE7	X-RAY DIFFRACTION	2
4PMM	X-RAY DIFFRACTION	2
5KML	X-RAY DIFFRACTION	2.01
4YNE	X-RAY DIFFRACTION	2.02
6PL1	X-RAY DIFFRACTION	2.03
5KMJ	X-RAY DIFFRACTION	2.04
6PL4	X-RAY DIFFRACTION	2.06
5JFS	X-RAY DIFFRACTION	2.07
8J5X	X-RAY DIFFRACTION	2.09
4PMT	X-RAY DIFFRACTION	2.1
5H3Q	X-RAY DIFFRACTION	2.1
4YPS	X-RAY DIFFRACTION	2.1
6DKI	X-RAY DIFFRACTION	2.11
5KMM	X-RAY DIFFRACTION	2.12
5KMN	X-RAY DIFFRACTION	2.14
7XBI	X-RAY DIFFRACTION	2.16
6NPT	X-RAY DIFFRACTION	2.19
6PMC	X-RAY DIFFRACTION	2.19
1WWW	X-RAY DIFFRACTION	2.2
5KMK	X-RAY DIFFRACTION	2.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04629-F1	78.92	0.38

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 (5): 650 (proton acceptor); 398–399 (breakpoint for translocation to form trk and trk-t3); 486 (breakpoint for translocation to form trk-t1); 496 (interaction with shc1); 791 (interaction with plcg1)

Ligand- & substrate-binding residues (2): 516–524; 544

Post-translational modifications (5): 496, 676, 680, 681, 791

Disulfide bonds (5): 36–41, 40–50, 154–191, 215–265, 300–345

Glycosylation sites (13): 67, 95, 121, 188, 202, 253, 262, 281, 318, 323, 338, 358, 401

Mutagenesis-validated functional residues (6):

Position	Phenotype
496	loss of interaction with shc1 and altered phosphorylation of shc1. altered neurite outgrowth and altered activation of t
540–541	abolishes interaction with gga3.
544	no effect on interaction with gga3.
544	loss of kinase activity.
610–611	no effect on interaction with gga3.
791	loss of interaction with plcg1 and altered phosphorylation of plcg1. altered neurite outgrowth and altered activation of

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-167021	PLC-gamma1 signalling
R-HSA-167044	Signalling to RAS
R-HSA-170984	ARMS-mediated activation
R-HSA-177504	Retrograde neurotrophin signalling
R-HSA-187024	NGF-independant TRKA activation
R-HSA-187042	TRKA activation by NGF
R-HSA-187706	Signalling to p38 via RIT and RIN
R-HSA-198203	PI3K/AKT activation
R-HSA-198745	Signalling to STAT3
R-HSA-170968	Frs2-mediated activation

MSigDB gene sets: 518 (showing top): PID_SHP2_PATHWAY, GOBP_CIRCADIAN_RHYTHM, REACTOME_RETROGRADE_NEUROTROPHIN_SIGNALLING, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_SYNAPSE_ASSEMBLY

GO Biological Process (50): protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), spermatogenesis (GO:0007283), axon guidance (GO:0007411), learning or memory (GO:0007611), circadian rhythm (GO:0007623), negative regulation of cell population proliferation (GO:0008285), response to xenobiotic stimulus (GO:0009410), programmed cell death involved in cell development (GO:0010623), positive regulation of neuron projection development (GO:0010976), peptidyl-tyrosine phosphorylation (GO:0018108), olfactory nerve development (GO:0021553), B cell differentiation (GO:0030183), neuron projection development (GO:0031175), response to nutrient levels (GO:0031667), peptidyl-tyrosine autophosphorylation (GO:0038083), nerve growth factor signaling pathway (GO:0038180), mechanoreceptor differentiation (GO:0042490), negative regulation of apoptotic process (GO:0043066), positive regulation of programmed cell death (GO:0043068), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of GTPase activity (GO:0043547), positive regulation of angiogenesis (GO:0045766), positive regulation of Ras protein signal transduction (GO:0046579), protein autophosphorylation (GO:0046777), neurotrophin TRK receptor signaling pathway (GO:0048011), sympathetic nervous system development (GO:0048485), neuron development (GO:0048666), response to axon injury (GO:0048678), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), detection of mechanical stimulus involved in sensory perception of pain (GO:0050966), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), neuron apoptotic process (GO:0051402), response to hydrostatic pressure (GO:0051599), response to electrical stimulus (GO:0051602), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of synapse assembly (GO:0051965), positive regulation of synaptic transmission, glutamatergic (GO:0051968), Sertoli cell development (GO:0060009), axonogenesis involved in innervation (GO:0060385)

GO Molecular Function (17): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), GPI-linked ephrin receptor activity (GO:0005004), neurotrophin receptor activity (GO:0005030), neurotrophin p75 receptor binding (GO:0005166), ATP binding (GO:0005524), nerve growth factor receptor activity (GO:0010465), kinase binding (GO:0019900), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), neurotrophin binding (GO:0043121), nerve growth factor binding (GO:0048406), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (18): mitochondrion (GO:0005739), early endosome (GO:0005769), late endosome (GO:0005770), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), axon (GO:0030424), dendrite (GO:0030425), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), protein-containing complex (GO:0032991), neuronal cell body (GO:0043025), signaling receptor complex (GO:0043235), recycling endosome membrane (GO:0055038), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020), recycling endosome (GO:0055037)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by NTRK1 (TRKA)	4
Signalling to ERKs	2
Prolonged ERK activation events	2
Activation of TRKA receptors	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	4
cellular anatomical structure	3
endosome membrane	3
programmed cell death	2
neurotrophin signaling pathway	2
neurotrophin binding	2
neuron projection	2
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
developmental process involved in reproduction	1
male gamete generation	1
axonogenesis	1
neuron projection guidance	1
behavior	1
cognition	1
rhythmic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to chemical	1
cell development	1
cellular developmental process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
cranial nerve development	1
lymphocyte differentiation	1
B cell activation	1
neuron development	1
plasma membrane bounded cell projection organization	1
response to stimulus	1
peptidyl-tyrosine phosphorylation	1
protein autophosphorylation	1
cellular response to nerve growth factor stimulus	1
neuron differentiation	1
apoptotic process	1
regulation of apoptotic process	1

Protein interactions and networks

STRING

6865 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTRK1	NGFR	P08138	999
NTRK1	NGF	P01138	999
NTRK1	NTF3	P20783	999
NTRK1	BDNF	P23560	999
NTRK1	NTF4	P34130	999
NTRK1	KITLG	P21583	996
NTRK1	HGF	P14210	993
NTRK1	EGF	P01133	991
NTRK1	GDNF	P39905	991
NTRK1	ANGPT1	Q15389	991
NTRK1	INS	P01308	989
NTRK1	ANGPT2	O15123	981
NTRK1	NTRK2	Q16620	978
NTRK1	IGF1	P01343	972
NTRK1	SHC1	P29353	971

IntAct

60 interactions, top by confidence:

A	B	Type	Score
NGF	NTRK1	psi-mi:“MI:0407”(direct interaction)	0.680
NTRK1	NTRK1	psi-mi:“MI:0915”(physical association)	0.620
PIK3R1	NTRK1	psi-mi:“MI:0914”(association)	0.620
PLCG1	NTRK1	psi-mi:“MI:0914”(association)	0.620
NTRK1	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.600
TIE1	NTRK1	psi-mi:“MI:0915”(physical association)	0.590
NTRK1	TIE1	psi-mi:“MI:0407”(direct interaction)	0.590
NTRK1	TIE1	psi-mi:“MI:0403”(colocalization)	0.590
NGF	NTRK1	psi-mi:“MI:0407”(direct interaction)	0.540
NTRK1	NGF	psi-mi:“MI:0915”(physical association)	0.540
Pirb	NTRK1	psi-mi:“MI:0915”(physical association)	0.520
NTRK1	Pirb	psi-mi:“MI:0915”(physical association)	0.520
APP	NTRK1	psi-mi:“MI:0915”(physical association)	0.510
NTRK1	ULK1	psi-mi:“MI:0914”(association)	0.500
SQSTM1	NTRK1	psi-mi:“MI:0915”(physical association)	0.500
ULK1	NTRK1	psi-mi:“MI:0915”(physical association)	0.500
NTRK1	NTRK3	psi-mi:“MI:0915”(physical association)	0.500
SHC1	NTRK1	psi-mi:“MI:0914”(association)	0.460

BioGRID (2256): NTRK1 (Affinity Capture-Western), NTRK1 (Affinity Capture-Western), GAREML (Affinity Capture-MS), SHC1 (Affinity Capture-MS), SH2B2 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), SOS2 (Affinity Capture-MS), GRB2 (Affinity Capture-MS), PIK3CA (Affinity Capture-MS), GAREM (Affinity Capture-MS), PIK3C2B (Affinity Capture-MS), ARHGEF40 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS), PIK3R2 (Affinity Capture-MS), SOS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A2AWP8, A2RRH5, C9J798, O43374, O70277, O95294, P04629, P59926, Q0GA42, Q13368, Q14318, Q16512, Q29RM4, Q2HY40, Q2T9P3, Q2TBA3, Q5BIM1, Q5M7W1, Q5R5M3, Q5R811, Q5T7P8, Q5XIS9, Q62746, Q6PFQ7, Q6PFY8, Q7TNM2, Q7TP90, Q7Z4K8, Q8BG60, Q8BHT7, Q8BQC3, Q8C6N3, Q8CIW5, Q8IZ69, Q8NCT1, Q920N2, Q92546, Q925B4

Diamond homologs: A8WGA3, B1H134, B1H234, D3ZTV3, D4ABX8, F1NUK7, G5EFX6, O42235, O43155, O55226, O60938, O75093, O88279, O88280, O94769, O94991, P04629, P13224, P14770, P24014, P50608, P50609, P56400, P59383, P83503, Q04785, Q06828, Q3UHC2, Q5R6T0, Q5RAC4, Q5RI43, Q6RKD8, Q6WRH9, Q70AK3, Q7Z2Q7, Q80TR4, Q80XU8, Q810B7, Q810C1, Q8BGT1

SIGNOR signaling

31 interactions.

A	Effect	B	Mechanism
NTRK1	up-regulates	SH2B1	binding
anthra[1,9-cd]pyrazol-6(2H)-one	down-regulates	NTRK1	“chemical inhibition”
regorafenib	“down-regulates activity”	NTRK1	“chemical inhibition”
PTPN1	“down-regulates activity”	NTRK1	dephosphorylation
DUSP26	“down-regulates activity”	NTRK1	dephosphorylation
CBLB	“down-regulates quantity”	NTRK1	ubiquitination
NTRK1	“up-regulates activity”	CTNNB1	phosphorylation
SRC	“up-regulates activity”	NTRK1	phosphorylation
FYN	“up-regulates activity”	NTRK1	phosphorylation
NTRK1	up-regulates	PLCG1	phosphorylation
NTRK1	up-regulates	NTRK1	phosphorylation
NTRK1	up-regulates	SH2B2	phosphorylation
NTRK1	up-regulates	FRS2	binding
NTRK1	up-regulates	ABL1	binding
NTRK1	up-regulates	PLCG1	binding
NTRK1	up-regulates	SHC1	binding
NGF	up-regulates	NTRK1	binding
NTF4	up-regulates	NTRK1	binding
NTRK1	up-regulates	ARHGAP32	relocalization
PTPN6	“down-regulates activity”	NTRK1	dephosphorylation
RAB7A	“down-regulates activity”	NTRK1	binding
LSM-1231	“down-regulates activity”	NTRK1	“chemical inhibition”
NTRK1	“up-regulates activity”	SHC3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein dephosphorylation	6	47.5×	1e-06
negative regulation of cell population proliferation	6	9.0×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BRCA.

Clinical variants and AI predictions

ClinVar

1563 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	105
Likely pathogenic	74
Uncertain significance	457
Likely benign	719
Benign	59

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070409	NM_002529.4(NTRK1):c.1877dup (p.Leu627fs)	Pathogenic
1070814	NM_002529.4(NTRK1):c.2025_2026del (p.Tyr676fs)	Pathogenic
1072190	NM_002529.4(NTRK1):c.229C>T (p.Gln77Ter)	Pathogenic
1072893	NM_002529.4(NTRK1):c.1796_1803dup (p.Arg602fs)	Pathogenic
1073488	NM_002529.4(NTRK1):c.989_990del (p.Thr330fs)	Pathogenic
1074362	NM_002529.4(NTRK1):c.1649_1650insGGCAGGAAGTCGGCACTGAA (p.Ser550_Glu551insAlaGlySerArgHisTer)	Pathogenic
1076078	NM_002529.4(NTRK1):c.2133G>A (p.Trp711Ter)	Pathogenic
1076204	NM_002529.4(NTRK1):c.1294del (p.Leu432fs)	Pathogenic
12303	NM_002529.4(NTRK1):c.2339G>C (p.Arg780Pro)	Pathogenic
12312	NM_002529.4(NTRK1):c.1759A>G (p.Met587Val)	Pathogenic
1323379	NM_002529.4(NTRK1):c.1354+1G>A	Pathogenic
1388110	NM_002529.4(NTRK1):c.1804del (p.Arg602fs)	Pathogenic
1391432	NM_002529.4(NTRK1):c.513del (p.Glu172fs)	Pathogenic
1408081	NM_002529.4(NTRK1):c.595C>T (p.Gln199Ter)	Pathogenic
1419925	NM_002529.4(NTRK1):c.1094del (p.Asn365fs)	Pathogenic
1420732	NM_002529.4(NTRK1):c.850+1G>C	Pathogenic
1433100	NM_002529.4(NTRK1):c.1981G>T (p.Gly661Ter)	Pathogenic
1441298	NM_002529.4(NTRK1):c.2078G>A (p.Trp693Ter)	Pathogenic
1451941	NM_002529.4(NTRK1):c.1438G>T (p.Glu480Ter)	Pathogenic
1453767	NM_002529.4(NTRK1):c.1298del (p.Ser433fs)	Pathogenic
1455199	NC_000001.10:g.(?156837886)(156841557_?)del	Pathogenic
1455865	NM_002529.4(NTRK1):c.1552del (p.Glu518fs)	Pathogenic
1457786	NM_002529.4(NTRK1):c.850+1G>A	Pathogenic
1460329	NM_002529.4(NTRK1):c.1633-1G>A	Pathogenic
1895701	NM_002529.4(NTRK1):c.574+1G>T	Pathogenic
1930182	NM_002529.4(NTRK1):c.226C>T (p.Gln76Ter)	Pathogenic
1969209	NM_002529.4(NTRK1):c.2233G>T (p.Glu745Ter)	Pathogenic
2021551	NM_002529.4(NTRK1):c.914del (p.Val305fs)	Pathogenic
2022583	NM_002529.4(NTRK1):c.1730_1736dup (p.Cys579fs)	Pathogenic
2023504	NM_002529.4(NTRK1):c.1738_1777del (p.Thr580fs)	Pathogenic

SpliceAI

7401 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156816001:CTCA:C	donor_loss	1.0000
1:156816002:TCA:T	donor_loss	1.0000
1:156816003:CA:C	donor_loss	1.0000
1:156816005:CCG:C	donor_gain	1.0000
1:156816091:CTCC:C	acceptor_gain	1.0000
1:156841389:CTCA:C	donor_loss	1.0000
1:156841390:TCACA:T	donor_loss	1.0000
1:156841391:CA:C	donor_loss	1.0000
1:156841392:A:AC	donor_gain	1.0000
1:156841392:AC:A	donor_loss	1.0000
1:156841393:C:CT	donor_gain	1.0000
1:156841393:CA:C	donor_gain	1.0000
1:156841393:CAG:C	donor_gain	1.0000
1:156841632:T:TA	donor_gain	1.0000
1:156841633:C:A	donor_gain	1.0000
1:156841671:T:TA	donor_gain	1.0000
1:156842132:T:TA	donor_gain	1.0000
1:156842385:T:TA	donor_gain	1.0000
1:156842392:CCCTA:C	donor_loss	1.0000
1:156842393:CCTA:C	donor_loss	1.0000
1:156842394:CTAC:C	donor_loss	1.0000
1:156842395:TA:T	donor_loss	1.0000
1:156842397:CCT:C	donor_gain	1.0000
1:156842507:ACCTG:A	acceptor_loss	1.0000
1:156842508:CCTG:C	acceptor_loss	1.0000
1:156842509:CTG:C	acceptor_loss	1.0000
1:156842510:T:A	acceptor_loss	1.0000
1:156843041:T:TA	donor_gain	1.0000
1:156844702:CCTA:C	donor_loss	1.0000
1:156844704:TACC:T	donor_loss	1.0000

AlphaMissense

5169 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156876139:T:C	F521L	1.000
1:156876141:T:A	F521L	1.000
1:156876141:T:G	F521L	1.000
1:156876210:G:C	K544N	1.000
1:156876210:G:T	K544N	1.000
1:156879258:C:G	H648D	1.000
1:156879262:G:C	R649P	1.000
1:156879265:A:C	D650A	1.000
1:156879265:A:G	D650G	1.000
1:156879265:A:T	D650V	1.000
1:156879279:A:G	N655D	1.000
1:156879280:A:C	N655T	1.000
1:156879280:A:T	N655I	1.000
1:156879281:C:A	N655K	1.000
1:156879281:C:G	N655K	1.000
1:156879318:G:C	D668H	1.000
1:156879319:A:T	D668V	1.000
1:156880021:C:A	P690H	1.000
1:156880021:C:G	P690R	1.000
1:156880029:T:A	W693R	1.000
1:156880029:T:C	W693R	1.000
1:156880031:G:C	W693C	1.000
1:156880031:G:T	W693C	1.000
1:156880044:A:C	S698R	1.000
1:156880046:C:A	S698R	1.000
1:156880046:C:G	S698R	1.000
1:156880062:T:C	F704L	1.000
1:156880064:C:A	F704L	1.000
1:156880064:C:G	F704L	1.000
1:156880083:T:A	W711R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002692 (1:156836107 C>A,T), RS1000015934 (1:156824969 AACCTCC>A), RS1000024828 (1:156879472 A>G,T), RS1000057562 (1:156842361 C>A,T), RS1000103507 (1:156879701 C>A), RS1000197102 (1:156848441 C>T), RS1000224901 (1:156874513 G>A,C), RS1000235259 (1:156837213 A>G), RS1000242834 (1:156854417 G>A), RS1000286514 (1:156836371 C>G), RS1000315789 (1:156824619 G>A,T), RS1000463666 (1:156819906 T>C), RS1000470343 (1:156830522 A>G), RS1000484224 (1:156848765 A>G), RS1000501242 (1:156865217 C>T)

Disease associations

OMIM: gene MIM:191315 | disease phenotypes: MIM:256800, MIM:155240, MIM:118220, MIM:266200, MIM:167000, MIM:308240, MIM:142623, MIM:162400

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy type 4	Definitive	Autosomal recessive
familial medullary thyroid carcinoma	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy type 4	Definitive	AR

Mondo (11): hereditary sensory and autonomic neuropathy type 4 (MONDO:0009746), familial medullary thyroid carcinoma (MONDO:0007958), Charcot-Marie-Tooth disease (MONDO:0015626), neurodevelopmental disorder (MONDO:0700092), pyruvate kinase deficiency of red cells (MONDO:0009950), ovarian cancer (MONDO:0008170), intellectual disability (MONDO:0001071), X-linked lymphoproliferative disease due to SH2D1A deficiency (MONDO:0024551), primary ovarian failure (MONDO:0005387), Hirschsprung disease (MONDO:0018309), hereditary sensory and autonomic neuropathy (MONDO:0015364)

Orphanet (12): Hereditary sensory and autonomic neuropathy type 4 (Orphanet:642), Multiple endocrine neoplasia type 2 (Orphanet:653), Isolated familial medullary thyroid carcinoma (Orphanet:99361), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Hemolytic anemia due to red cell pyruvate kinase deficiency (Orphanet:766), Rare ovarian cancer (Orphanet:213500), X-linked lymphoproliferative disease (Orphanet:2442), X-linked lymphoproliferative disease due to SAP deficiency (Orphanet:538931), Hirschsprung disease (Orphanet:388), Hereditary sensory and autonomic neuropathy (Orphanet:140471), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000168	Abnormality of the gingiva
HP:0000272	Malar flattening
HP:0000490	Deeply set eye
HP:0000491	Keratitis
HP:0000495	Recurrent corneal erosions
HP:0000559	Corneal scarring
HP:0000712	Emotional lability
HP:0000736	Short attention span
HP:0000742	Self-mutilation
HP:0000752	Hyperactivity
HP:0000958	Dry skin
HP:0000970	Anhidrosis
HP:0000975	Hyperhidrosis
HP:0000978	Bruising susceptibility
HP:0000987	Atypical scarring of skin
HP:0001058	Poor wound healing
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001328	Specific learning disability
HP:0001510	Growth delay
HP:0001903	Anemia
HP:0001954	Recurrent fever
HP:0001955	Unexplained fevers
HP:0002015	Dysphagia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002404_431	Red cell distribution width	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D009477	Hereditary Sensory and Autonomic Neuropathies	C10.500.250; C10.574.500.493; C10.668.829.800.175; C16.131.666.310; C16.320.400.415
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
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
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C536911	Familial medullary thyroid carcinoma (supp.)
C564858	Pyruvate Kinase Deficiency of Red Cells (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2815 (SINGLE PROTEIN), CHEMBL3559684 (PROTEIN FAMILY), CHEMBL3883331 (CHIMERIC PROTEIN), CHEMBL4523622 (PROTEIN FAMILY), CHEMBL4742268 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

66 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 341,897 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3301610	ABEMACICLIB	4	7,045
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
CHEMBL629	AMITRIPTYLINE	4	52,595
CHEMBL2105728	CRENOLANIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL3137331	DEFACTINIB	3
CHEMBL3265032	ENTOSPLETINIB	3
CHEMBL3989926	SITRAVATINIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2

Clinical evidence (CIViC)

Drug × variant × indication: 15 predictive associations from 15 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
NTRK1 Amplification OR NTRK3 Amplification OR NTRK2 Amplification	Entrectinib	Cancer	Sensitivity/Response	CIViC B	EID2958
NTRK1 Amplification	Larotrectinib	Solid Tumor	Sensitivity/Response	CIViC C	EID10170
NTRK1 Amplification	Larotrectinib	Esophageal Carcinoma	Sensitivity/Response	CIViC C	EID12120
LMNA::NTRK1 Fusion AND NTRK1 G595R AND NTRK1 G667C	Entrectinib	Colorectal Adenocarcinoma	Resistance	CIViC C	EID2961
NTRK1 G595R AND NTRK1 G667S	Larotrectinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID9593
LMNA::NTRK1 Fusion AND NTRK1 F589L	Repotrectinib	Cancer	Sensitivity/Response	CIViC D	EID11348
LMNA::NTRK1 Fusion AND NTRK1 F589L	Entrectinib	Cancer	Sensitivity/Response	CIViC D	EID11355
LMNA::NTRK1 Fusion AND NTRK1 G595R	Repotrectinib	Cancer	Sensitivity/Response	CIViC D	EID11347
LMNA::NTRK1 Fusion AND NTRK1 F589L	Larotrectinib	Cancer	Resistance	CIViC D	EID11351
LMNA::NTRK1 Fusion AND NTRK1 G595R	Larotrectinib	Cancer	Resistance	CIViC D	EID11350
LMNA::NTRK1 Fusion AND NTRK1 G595R	Entrectinib	Cancer	Resistance	CIViC D	EID11356
LMNA::NTRK1 Fusion AND NTRK1 G595R AND NTRK1 F589L	Larotrectinib	Cancer	Resistance	CIViC D	EID11353
LMNA::NTRK1 Fusion AND NTRK1 G595R AND NTRK1 F589L	Entrectinib	Cancer	Resistance	CIViC D	EID11358
LMNA::NTRK1 Fusion AND NTRK1 G667C	Entrectinib	Cancer	Resistance	CIViC D	EID11357
LMNA::NTRK1 Fusion AND NTRK1 G667C	Larotrectinib	Cancer	Resistance	CIViC D	EID11359

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10908521	Toxicity	3	glucarpidase	Nephrotoxicity
rs2768759	Efficacy	3	aspirin
rs2768759	Efficacy	3	aspirin;prasugrel

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2768759	NTRK1, PEAR1	3	1.50	2	aspirin;aspirin;prasugrel
rs10908521	INSRR, NTRK1	3	0.00	1	glucarpidase

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 (30 total), top 25:

Ligand	Action	Affinity	Parameter
GR-389988	Inhibition	9.52	pIC50
selitrectinib	Inhibition	9.3	pIC50
repotrectinib	Inhibition	9.28	pIC50
taletrectinib	Inhibition	9.21	pIC50
zurletrectinib	Inhibition	9.09	pIC50
emzeltrectinib	Inhibition	9.0	pIC50
anizatrectinib	Inhibition	8.96	pIC50
gilteritinib	Inhibition	8.96	pIC50
CH7057288	Inhibition	8.92	pIC50
DZX19	Inhibition	8.88	pIC50
compound 2c [PMID: 24900538]	Inhibition	8.85	pIC50
utatrectinib	Inhibition	8.52	pIC50
compound 1d [PMID: 21493067]	Inhibition	8.52	pIC50
CEP-11981	Inhibition	8.52	pIC50
eratrectinib	Inhibition	8.37	pIC50
AZD1332	Inhibition	8.3	pIC50
sitravatinib	Inhibition	8.3	pIC50
larotrectinib	Inhibition	8.01	pIC50
paltimatrectinib	Inhibition	8.0	pIC50
GNF-5837	Inhibition	7.96	pIC50
K-252a	Inhibition	7.89	pIC50
JNJ-28312141	Inhibition	7.82	pIC50
RIPK1 inhibitor 22b	Inhibition	7.59	pIC50
MK-2461	Inhibition	7.34	pIC50
zidesamtinib	Inhibition	7.3	pKi

Binding affinities (BindingDB)

2370 measured of 3183 human assays (3183 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-fluoro-2-methyl-10-oxa-2,14,18,19,22-pentazatetracyclo[14.5.2.04,9.019,23]tricosa-1(22),4(9),5,7,16(23),17,20-heptaen-15-one	KD	0.015 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
6-fluoro-3-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	0.065 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(5-oxo-2- phenyl-5,6,7,8-tetrahydro-1,6- naphthyridin-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.069 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
6-fluoro-2-propan-2-yl-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	0.082 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
N-(2-((2,5-dioxoimidazolidin-1- yl)methyl)-4-phenylpyrimidin-5- yl)-2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.083 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-ethyl-6-fluoro-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	0.086 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
6-fluoro-2-methyl-10-oxa-2,13,17,21,22-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15,17,19-heptaen-14-one	KD	0.088 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
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
2-fluoro-N-[2-[(3-methyl-2,5-dioxoimidazolidin-1-yl)methyl]-4-phenylpyrimidin-5-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	IC50	0.11 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methylpyrazol-3-yl)-N-[2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-4-phenylpyrimidin-5-yl]-4-(trifluoromethyl)benzamide	IC50	0.14 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4,6,8,15(22),16,19-heptaen-14-one	KD	0.14 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
2-fluoro-N-[6-(2-hydroxypropan-2-yl)-2-phenylpyrazolo[4,3-b]pyridin-3-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	IC50	0.16 nM	US-9862707: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-N-(6-((2- methoxyacetamido)methyl)-2- phenylpyridin-3-yl)-5-(1- methyl-1H-pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.19 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methylpyrazol-3-yl)-N-[6-(2-oxo-1,3-oxazolidin-4-yl)-2-phenyl-3-pyridinyl]-4-(trifluoromethyl)benzamide	IC50	0.19 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
5-[(2R)-2-(5-fluoro-2-methoxy-3-pyridinyl)pyrrolidin-1-yl]-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.2 nM	US-9782415: Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
6-(6-dimethylphosphoryl-3-pyridinyl)-3-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[[6-(trifluoromethyl)-3-pyridinyl]methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[4-[(6-cyclopropyl-3-pyridinyl)methoxy]-3-methoxyphenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[[4-(trifluoromethoxy)phenyl]methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[(6-propan-2-yl-3-pyridinyl)methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[[2-(trifluoromethyl)-1,3-thiazol-4-yl]methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.2 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
6-fluoro-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	0.2 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
N-(6-((2,5-dioxoimidazolidin-1- yl)methyl)-2-phenylpyridin-3- yl)-2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.22 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(2-((2-oxo-1,3- oxazinan-3-yl)methyl)-4- phenylpyrimidin-5-yl)-4- (trifluoromethyl)benzamide	IC50	0.22 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(6-((2- (methylsulfonyl)acetamido)methyl)- 2-phenylpyridin-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.23 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(2-((5-oxo-1,5- dihydro-4H-1,2,4-triazol-4- yl)methyl)-4-phenylpyrimidin-5- yl)-4- (trifluoromethyl)benzamide	IC50	0.24 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
N-(2-((2,4-dioxooxazolidin-3- yl)methyl)-4-phenylpyrimidin-5- yl)-2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.25 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methylpyrazol-3-yl)-N-[4-phenyl-2-(1H-1,2,4-triazol-5-ylmethyl)pyrimidin-5-yl]-4-(trifluoromethyl)benzamide	IC50	0.25 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-N-[6-(1-hydroxyethyl)-2-phenylpyrazolo[4,3-b]pyridin-3-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	IC50	0.25 nM	US-9862707: TrkA kinase inhibitors, compositions and methods thereof
3-[[2-fluoro-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzoyl]amino]-2-phenyl-6,8-dihydro-5H-1,7-naphthyridine-7-carboxamide	IC50	0.26 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-N-(5-(2- hydroxypropan-2-yl)-6’-phenyl- [2,3’-bipyridin]-5’-yl)-5-(1- methyl-1H-pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.26 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
N-(5-(1-aminoethyl)-6’-phenyl- [2,3’-bipyridin]-5’-yl)-2-fluoro-5- (1-methyl-1H-pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.29 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
3-[[3-methoxy-4-[(6-methoxy-3-pyridinyl)methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.3 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.3 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
3-[[3-methoxy-4-[[4-(2,2,2-trifluoroethyl)phenyl]methoxy]phenyl]methyl]-6-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-amine	IC50	0.3 nM	US-9067914: Tropomyosin-related kinase (TRK) inhibitors
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(2-((2- oxopyrrolidin-1-yl)methyl)-4- phenylpyrimidin-5-yl)-4- (trifluoromethyl)benzamide	IC50	0.32 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
N-(2-((2,4-dioxo-3,4- dihydropyrimidin-1(2H)- yl)methyl)-4-phenylpyrimidin-5- yl)-2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.35 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methylpyrazol-3-yl)-N-[6-(2-oxoimidazolidin-4-yl)-2-phenyl-3-pyridinyl]-4-(trifluoromethyl)benzamide	IC50	0.36 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
(14R)-11,17-difluoro-14-methyl-7-oxa-3,9,15,19,20,23-hexazapentacyclo[14.5.2.14,6.08,13.019,22]tetracosa-1(22),8(13),9,11,16(23),17,20-heptaen-2-one	IC50	0.36 nM	US-12428433: Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
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-chloro-5-(1-methylpyrazol-3-yl)-N-(1-phenyl-3-pyridin-4-ylpyrazol-5-yl)-4-(trifluoromethyl)benzamide	IC50	0.37 nM	US-9914736: TrKA kinase inhibitors, compositions and methods thereof
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(5-oxo-2- phenyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-3-yl)-4- (trifluoromethyl)benzamide	IC50	0.38 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
5-[[2-fluoro-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzoyl]amino]-1-(5-methylpyrazolidin-3-yl)-N-(pyridin-3-ylmethyl)pyrazole-3-carboxamide	IC50	0.39 nM	US-9914736: TrKA kinase inhibitors, compositions and methods thereof
9-fluoro-13-oxa-2,11,17,21,22,25-hexazahexacyclo[17.5.2.114,16.02,6.07,12.022,26]heptacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one	IC50	0.39 nM	US-12428433: Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof
5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[2-(1H-imidazol-5-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.4 nM	US-8791123: Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
1-[2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]pyrimidin-5-yl]-3-[2-methylsulfonyl-5-(trifluoromethyl)phenyl]urea	IC50	0.4 nM	US-9463192: Trk-inhibiting compound
5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[2-(1H-imidazol-5-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.4 nM	US-9796724: Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
2-fluoro-5-(1-methyl-1H- pyrazol-3-yl)-N-(2-((2- (methylsulfonyl)acetamido)methyl)- 4-phenylpyrimidin-5-yl)-4- (trifluoromethyl)benzamide	IC50	0.4 nM	US-9815846: TrkA kinase inhibitors, compositions and methods thereof
2-fluoro-N-[1-(4-fluorophenyl)-3-[(1-methyltetrazol-5-yl)methyl]pyrazol-5-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	IC50	0.4 nM	US-9914736: TrKA kinase inhibitors, compositions and methods thereof

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.82	Kd	0.015	nM	CHEMBL5914333
10.51	Kd	0.031	nM	CHEMBL6044141
10.29	Kd	0.051	nM	CHEMBL5770246
10.19	Kd	0.065	nM	CHEMBL5831552
10.16	IC50	0.069	nM	CHEMBL5963783
10.15	IC50	0.07	nM	SELITRECTINIB
10.09	Kd	0.082	nM	CHEMBL5971833
10.08	IC50	0.083	nM	CHEMBL6060567
10.07	Kd	0.086	nM	CHEMBL5902091
10.06	Kd	0.088	nM	CHEMBL5938707
10.00	IC50	0.1	nM	CHEMBL4562879
10.00	IC50	0.1	nM	CHEMBL5170464
10.00	IC50	0.1	nM	CHEMBL5170096
10.00	IC50	0.1	nM	CHEMBL5189971
9.96	IC50	0.11	nM	REPOTRECTINIB
9.96	IC50	0.11	nM	CHEMBL5806122
9.92	IC50	0.12	nM	CHEMBL5943003
9.85	IC50	0.14	nM	CHEMBL5756492
9.85	Kd	0.14	nM	CHEMBL5990506
9.80	IC50	0.16	nM	CHEMBL4518176
9.72	IC50	0.19	nM	CHEMBL5832003
9.72	IC50	0.19	nM	CHEMBL5975522
9.70	IC50	0.2	nM	CHEMBL3676026
9.70	IC50	0.2	nM	CHEMBL3673477
9.70	IC50	0.2	nM	CHEMBL3673478
9.70	IC50	0.2	nM	CHEMBL3673479
9.70	IC50	0.2	nM	CHEMBL3678283
9.70	IC50	0.2	nM	CHEMBL3678284
9.70	IC50	0.2	nM	CHEMBL3678285
9.70	IC50	0.2	nM	CHEMBL3678286
9.70	IC50	0.2	nM	CHEMBL3678287
9.70	IC50	0.2	nM	CHEMBL4449648
9.70	IC50	0.2	nM	CHEMBL4554856
9.70	IC50	0.2	nM	CHEMBL4462919
9.70	IC50	0.2	nM	CHEMBL4555442
9.70	IC50	0.2	nM	CHEMBL5092943
9.70	IC50	0.2	nM	CHEMBL5088000
9.70	IC50	0.2	nM	REPOTRECTINIB
9.70	IC50	0.2	nM	CHEMBL5175608
9.70	IC50	0.2	nM	CHEMBL5170464
9.70	IC50	0.2	nM	CHEMBL5170096
9.70	IC50	0.2	nM	CHEMBL5188045
9.70	IC50	0.2	nM	CHEMBL5173256
9.70	IC50	0.2	nM	CHEMBL5198983
9.70	IC50	0.2	nM	CHEMBL5200318
9.70	IC50	0.2	nM	CHEMBL5078405
9.70	Kd	0.2	nM	CHEMBL5812952
9.70	IC50	0.2	nM	CHEMBL5897302
9.69	Kd	0.204	nM	CHEMBL457614
9.68	IC50	0.21	nM	CHEMBL5961512

PubChem BioAssay actives

2314 with measured affinity, of 4830 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
(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	1829828: Inhibition of wildtype human TRKA using poly (Glu,Tyr) 4:1 as substrate in presence of [gamma-33P]ATP by hotspot kinase assay	ic50	0.0001	uM
Repotrectinib	1829828: Inhibition of wildtype human TRKA using poly (Glu,Tyr) 4:1 as substrate in presence of [gamma-33P]ATP by hotspot kinase assay	ic50	0.0001	uM
N-[(1S)-1-(2,4-difluorophenyl)ethyl]-3-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-amine	1598144: Inhibition of N-terminal GST-tagged human TrkA kinase domain (436 to 790 residues) expressed in baculovirus expression system using biotin-poly-GT as substrate pre-incubated for 5 mins followed by ATP addition and measured after 60 mins by alpha screen assay	ic50	0.0001	uM
3-[1-(difluoromethyl)pyrazol-4-yl]-N-[(1R)-1-(2,5-difluorophenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	1855570: Inhibition of TRKA F589L mutant (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0001	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-(1-ethylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine	1855570: Inhibition of TRKA F589L mutant (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0001	uM
3-(1-cyclobutylpyrazol-4-yl)-N-[(1R)-1-(2,5-difluorophenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	1855570: Inhibition of TRKA F589L mutant (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0001	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0002	uM
N-[(1R)-1-[2-(2,2-difluoroethoxy)-5-fluorophenyl]ethyl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine	2121718: Inhibition of TRKA G595R mutant (unknown origin)	ic50	0.0002	uM
5,7-difluoro-2-propan-2-yl-9-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.14,8.018,22]tricosa-1(21),4(23),5,7,15(22),16,19-heptaen-14-one	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0002	uM
N-[(5-fluoro-2-methylsulfonylphenyl)methyl]-3-pyridin-3-yl-1H-indazol-5-amine	1552228: Inhibition of human GST-tagged TRKA (436 to 790) expressed in baculovirus expression system using TK-biotin peptide as substrate incubated for 45 min by TR-FRET assay	ic50	0.0002	uM
(15S)-20-chloro-19-fluoro-15-methyl-3-propan-2-yl-16-oxa-3,6,8,9,13-pentazatetracyclo[15.3.1.14,8.07,11]docosa-1(20),4(22),5,7(11),9,17(21),18-heptaen-12-one	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0002	uM
N-[(5-fluoro-2-methylsulfonylphenyl)methyl]-3-(1-methylpyrazol-4-yl)-1H-indazol-5-amine	1552228: Inhibition of human GST-tagged TRKA (436 to 790) expressed in baculovirus expression system using TK-biotin peptide as substrate incubated for 45 min by TR-FRET assay	ic50	0.0002	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	1813234: Inhibition of TRKA GS95R 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	0.0002	uM
5-chloro-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-4-N-(3-propan-2-yloxy-1H-pyrazol-5-yl)pyrimidine-2,4-diamine	1512263: Binding affinity to wild type human biotinylated and N-terminal DYKDDDDK-tagged TrkA kinase domain (436 to 790 residues) expressed in Sf21 cells assessed as equilibrium rate constant by single cycle kinetics analysis	kd	0.0002	uM
5-[(2R)-2-[2-(2,2-difluoroethoxy)-5-fluorophenyl]pyrrolidin-1-yl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	1813234: Inhibition of TRKA GS95R 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	0.0002	uM
3-(1-cyclopropylpyrazol-4-yl)-N-[(1R)-1-(2,5-difluorophenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0002	uM
2-[4-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]pyrazol-1-yl]ethanol	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0002	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-[1-(oxolan-3-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0002	uM
5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	1868151: Inhibition of recombinant human His-tagged TRKA cytoplasmic domain (441 to 796 residues) expressed in insect cells using TK-sub biotin peptide substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins by FRET assay	ic50	0.0002	uM
Entrectinib	1601014: Inhibition of human wild type TrkA kinase domain expressed in mouse NIH/3T3 cells by HTRF assay	ic50	0.0002	uM
2-fluoro-N-[6-(2-hydroxypropan-2-yl)-2-phenylpyrazolo[4,3-b]pyridin-3-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0002	uM
2-fluoro-N-[6-(1-hydroxyethyl)-2-phenylpyrazolo[4,3-b]pyridin-3-yl]-5-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0003	uM
N-[(5-fluoro-2-methylsulfonylphenyl)methyl]-3-(6-piperazin-1-yl-3-pyridinyl)-1H-indazol-5-amine	1552228: Inhibition of human GST-tagged TRKA (436 to 790) expressed in baculovirus expression system using TK-biotin peptide as substrate incubated for 45 min by TR-FRET assay	ic50	0.0003	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-[1-(oxan-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0003	uM
3-[4-[5-[[(1R)-1-(2,5-difluorophenyl)ethyl]amino]pyrazolo[1,5-a]pyrimidin-3-yl]pyrazol-1-yl]propanenitrile	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0003	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-(1-methylsulfonylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine	1855570: Inhibition of TRKA F589L mutant (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0003	uM
3-(1-cyclopentylpyrazol-4-yl)-N-[(1R)-1-(2,5-difluorophenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0003	uM
N-(2-fluoroethyl)-6-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboxamide	1934073: Inhibition of TRKA (unknown origin)	ic50	0.0003	uM
1-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methyl]-5-(1-methylpyrazol-4-yl)benzimidazol-2-amine	1322469: Inhibition of N-terminal GST tagged human TrkA cytoplasmic domain (436 to 790 amino acids) pre-incubated for 15 mins before peptide substrate addition for 180 mins by fluorescence based assay	ic50	0.0003	uM
N-[6-(2-hydroxypropan-2-yl)-2-phenylimidazo[1,2-a]pyridin-3-yl]-3-(1-methylpyrazol-3-yl)-4-(trifluoromethyl)benzamide	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0003	uM
5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	1813233: Inhibition of wildtype TRKA (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	0.0004	uM
N-(2,4-dimorpholin-4-ylphenyl)-2-phenyltriazole-4-carboxamide	1710655: Inhibition of human TRKA at active state by kinetic based analysis	ki	0.0004	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-[1-(2-methoxyethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0004	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	2026390: Inhibition of N-terminal His-tagged human recombinant wild type TRKA	ic50	0.0004	uM
Larotrectinib	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0004	uM
N-[(1R)-1-(2,5-difluorophenyl)ethyl]-3-[1-(oxetan-3-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidin-5-amine	1855572: Inhibition of wild type TRKA (unknown origin) using TK-sub-biotin peptide as substrate incubated for 30 mins followed by treated with ATP and substrate for 40 mins by FRET-based-Z’-lyte kinase assay	ic50	0.0005	uM
(3Z)-5-[(5-fluoro-2-methoxyphenyl)methylamino]-3-(1H-imidazol-5-ylmethylidene)-1H-indol-2-one	2009255: Inhibition of N-terminal GST-tagged human recombinant wild type TRKA (440 to end residues) expressed in baculovirus infected Sf9 insect cells incubated for 30 mins in presence of ATP by HTRF assay	ic50	0.0005	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	1308984: Inhibition of TRKA (unknown origin) incubated for 1 hr by spectrophotometric analysis	ic50	0.0005	uM
1-[(1R,3S,10bS)-6,6-difluoro-3-(2-methoxyethyl)-2,3,5,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-1-yl]-3-[4-methyl-3-(1-methylpyrazol-4-yl)-1-phenylpyrazol-5-yl]urea	1551959: Inhibition of human TRKA expressed in human TF1 cells by CellTiter-Glo Luminescent assay	ic50	0.0006	uM
1-[(1R,3aS,9bR)-3-(2,2,2-trifluoroethyl)-2,3a,4,9b-tetrahydro-1H-chromeno[3,4-b]pyrrol-1-yl]-3-[4-methyl-3-[(1-methylpiperidin-4-yl)methoxy]-1-phenylpyrazol-5-yl]urea	1551959: Inhibition of human TRKA expressed in human TF1 cells by CellTiter-Glo Luminescent assay	ic50	0.0006	uM
1-[(1S,3aR,9bS)-3-(2-methoxyethyl)-1,2,3a,4,5,9b-hexahydrobenzo[e]indol-1-yl]-3-[4-methyl-3-(1-methylpyrazol-4-yl)-1-phenylpyrazol-5-yl]urea	1551959: Inhibition of human TRKA expressed in human TF1 cells by CellTiter-Glo Luminescent assay	ic50	0.0006	uM
(6S,15S)-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	1673947: Inhibition of N-terminal His6-tagged TRKA (unknown origin) (486 to 786 residues) expressed in Escherichia coli using poly-EAY substrate incubated for 60 mins in presence of [gamma33P]ATP by liquid scintillation method	ic50	0.0006	uM
N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-7-(4-methylpiperazin-1-yl)quinazolin-4-amine	2107044: Inhibition of wild type TRKA (unknown origin) preincubated for 30 mins followed by ATP and U Light-poly GT addition and measured after 2 hrs by multilabel plate reader method	ic50	0.0006	uM
2-amino-1-[4-[5-[[2-[(6-bromo-2-pyridinyl)amino]-1,3-thiazol-5-yl]sulfanyl]-2-methylbenzoyl]piperazin-1-yl]ethanone	313712: Inhibition of TrkA	ic50	0.0006	uM
2-[(3R,4S)-3-fluoro-1-[2-[4-(trifluoromethoxy)phenyl]acetyl]piperidin-4-yl]oxy-5-(1-methylimidazol-4-yl)pyridine-3-carboxamide	1381391: Binding affinity to un phosphorylated C-terminal His6/N-terminal BAP-tagged TrkA (441 to 796 residues) (unknown origin) by SPR assay	kd	0.0007	uM
2-fluoro-5-(1-methylpyrazol-3-yl)-N-(2-phenylpyrazolo[4,3-b]pyridin-3-yl)-4-(trifluoromethyl)benzamide	1551955: Inhibition of recombinant full length human TRKA expressed in U2OS cells using Poly(Glu:Tyr) as substrate after 30 mins by scintillation counting assay	ic50	0.0007	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	1601016: Inhibition of human TrkA G667C mutant expressed in mouse NIH/3T3 cells by HTRF assay	ic50	0.0007	uM
5-[(2R)-2-[5-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]pyrrolidin-1-yl]-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine	1868153: Inhibition of TRKA G667C mutant (unknown origin) using TK-sub biotin peptide substrate preincubated for 30 mins followed by substrate addition and measured after 40 mins by FRET assay	ic50	0.0007	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	1812767: Inhibition of TrKA G667C mutant (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0007	uM
N-tert-butyl-2-[2-[8-(methanesulfonamido)-6,6-dimethyl-11-oxonaphtho[2,3-b][1]benzofuran-3-yl]ethynyl]pyridine-4-carboxamide	1864432: Inhibition of TRKA (unknown origin)	ic50	0.0007	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
Rotenone	decreases phosphorylation, decreases reaction, decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
Arsenic Trioxide	decreases expression, increases expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
bisphenol F	decreases methylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases reaction, increases phosphorylation	1
sulforaphane	decreases reaction, increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
staurosporine aglycone	decreases phosphorylation, decreases reaction	1
echinacoside	decreases phosphorylation, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases activity	1
bisphenol S	decreases methylation	1
ponatinib	decreases activity	1

ChEMBL screening assays

1194 unique, capped per target: 1182 binding, 7 admet, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000439	Binding	Inhibition of human TrkA expressed in baculovirus insect cell system	Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. — J Med Chem
CHEMBL1176961	Functional	Antagonist activity at human TrkA expressed in mouse NIH/3T3 assessed as inhibition of NGF-induced cytoprotection at 20 uM by MTT assay relative to NGF	Bivalent diketopiperazine-based tropomysin receptor kinase C (TrkC) antagonists. — J Med Chem
CHEMBL4407575	ADMET	Inhibition of recombinant human His-tagged NTRK1 cytoplasmic domain (441 to 796 residues) expressed in baculovirus expression system at 25 uM using FRET-labeled tyr 07 peptide as substrate measured after 1 hr by Z’-lyte assay relative to co	Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. — J Med Chem

Cellosaurus cell lines

25 cell lines: 17 cancer cell line, 5 factor-dependent cell line, 2 spontaneously immortalized cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1331	KM12	Cancer cell line	Male
CVCL_4M93	KM12-HX	Cancer cell line	Male
CVCL_4M94	KM12-LX	Cancer cell line	Male
CVCL_5920	KM12-OxR	Cancer cell line	Male
CVCL_5946	KM12-L4	Cancer cell line	Male
CVCL_8747	PMF-ko14	Cancer cell line	Male
CVCL_9547	KM12-C	Cancer cell line	Male
CVCL_9548	KM12-SM	Cancer cell line	Male
CVCL_AU12	KM12L4/OXR	Cancer cell line	Male
CVCL_C8TE	CUTO-3	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05777993	PHASE4	ENROLLING_BY_INVITATION	A Study to Provide Continued Access to Mitapivat for Participants Who Previously Completed an Agios-Sponsored Mitapivat Study
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT07383246	PHASE3	RECRUITING	CTR-FAPI-guided Precision Surgery for Newly Diagnosed MTC
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT03548220	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03559699	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03853798	PHASE3	COMPLETED	Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007
NCT01736878	PHASE2	WITHDRAWN	Efficacy and Safety Study of Sorafenib to Treat Advanced Medullary Thyroid Carcinoma
NCT04787328	PHASE2	UNKNOWN	A Study of HA121-28 Tablets in Patients With Medullary Thyroid Carcinoma (MTC)
NCT06121271	PHASE2	NOT_YET_RECRUITING	Trial of Lu-177 DOTATATE (Lutathera®) in Unlicensed Indications
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02476916	PHASE2	COMPLETED	A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
NCT06422351	PHASE2	SUSPENDED	Clinical Trial to Evaluate the Efficacy of Gene Therapy for Pyruvate Kinase Deficiency
NCT03246659	PHASE1	COMPLETED	Radiolabelled CCK-2/Gastrin Receptor Analogue for Personalized Theranostic Strategy in Advanced MTC
NCT06520319	PHASE1	RECRUITING	Head-to-head Study of 68Ga-MGS5 Versus 68Ga-DOTATATE PET/CT in Patients With Medullary Thyroid Carcinoma
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT04105166	PHASE1	COMPLETED	Gene Therapy for Pyruvate Kinase Deficiency (PKD)
NCT07612345	PHASE1	NOT_YET_RECRUITING	High-Dose Vitamin C in G6PDA and Pyruvate Kinase Deficiency: A Safety Study
NCT02586350	PHASE2/PHASE3	COMPLETED	Study of Anlotinib in Patients With Medullary Thyroid Carcinoma(ALTER01031)
NCT00514046	PHASE1/PHASE2	COMPLETED	Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer
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