INSRR

Summary

INSRR (insulin receptor related receptor, HGNC:6093) is a protein-coding gene on chromosome 1q23.1, encoding Insulin receptor-related protein (P14616). Receptor with tyrosine-protein kinase activity.

Enables transmembrane receptor protein tyrosine kinase activity. Involved in actin cytoskeleton organization; cellular response to alkaline pH; and protein autophosphorylation. Part of receptor complex.

Source: NCBI Gene 3645 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (No Known Disease Relationship, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 219 total
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014215

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6093
Approved symbol	INSRR
Name	insulin receptor related receptor
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	IRR
Ensembl gene	ENSG00000027644
Ensembl biotype	protein_coding
OMIM	147671
Entrez	3645

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000368195

RefSeq mRNA: 1 — MANE Select: NM_014215 NM_014215

CCDS: CCDS1160

Canonical transcript exons

ENST00000368195 — 22 exons

Exon	Start	End
ENSE00000448998	156844707	156844843
ENSE00000448999	156844462	156844624
ENSE00000608753	156845619	156845814
ENSE00000608765	156849246	156849460
ENSE00000608772	156845076	156845296
ENSE00000608781	156842112	156842271
ENSE00000788791	156841394	156841528
ENSE00000788797	156842398	156842508
ENSE00000788798	156843004	156843233
ENSE00000788800	156843427	156843479
ENSE00000788801	156844175	156844280
ENSE00000788806	156845372	156845413
ENSE00000788809	156845952	156846119
ENSE00000788810	156846519	156846757
ENSE00000788812	156848921	156849047
ENSE00000788816	156851290	156851434
ENSE00000788818	156851646	156851788
ENSE00000788820	156851888	156852191
ENSE00000816624	156853752	156854303
ENSE00001446543	156840063	156841104
ENSE00001446544	156858537	156859117
ENSE00001727424	156841665	156841794

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 69.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1415 / max 38.4550, expressed in 55 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15237	0.1364	52
15236	0.0051	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
myocardium	UBERON:0002349	69.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	64.89	gold quality
adult mammalian kidney	UBERON:0000082	62.55	gold quality
body of stomach	UBERON:0001161	62.13	gold quality
vena cava	UBERON:0004087	61.36	gold quality
cartilage tissue	UBERON:0002418	60.42	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	60.19	gold quality
stomach	UBERON:0000945	58.41	gold quality
body of uterus	UBERON:0009853	58.28	gold quality
right testis	UBERON:0004534	57.98	gold quality
apex of heart	UBERON:0002098	57.65	gold quality
myometrium	UBERON:0001296	57.54	gold quality
endocervix	UBERON:0000458	57.51	gold quality
fundus of stomach	UBERON:0001160	57.47	gold quality
decidua	UBERON:0002450	56.97	gold quality
tendon of biceps brachii	UBERON:0008188	55.90	gold quality
sperm	CL:0000019	55.73	gold quality
left testis	UBERON:0004533	55.64	gold quality
nasal cavity epithelium	UBERON:0005384	55.09	gold quality
testis	UBERON:0000473	54.53	gold quality
pons	UBERON:0000988	54.47	gold quality
trabecular bone tissue	UBERON:0002483	54.44	gold quality
esophagus squamous epithelium	UBERON:0006920	54.38	gold quality
cranial nerve II	UBERON:0000941	54.32	silver quality
kidney	UBERON:0002113	54.25	gold quality
peritoneum	UBERON:0002358	54.04	gold quality
omental fat pad	UBERON:0010414	54.04	gold quality
skeletal muscle tissue	UBERON:0001134	53.97	gold quality
medial globus pallidus	UBERON:0002477	53.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	53.67	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	21.16
E-ANND-3	no	3.09

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 11)

• IRR mRNA expression was found in 25 (51%) neuroblastomas and correlated with stages 1, 2, 3, and 4S disease and with age. (PMID:14654552)
• Phosphotyrosine detection revealed a lack in the constitutive activation of the IRR described for analogous constructs of the two other members of the family (PMID:15629149)
• The IRR gene is expressed in the same ovarian compartment, IRR mRNA content increases strikingly in these cells in the afternoon of the first proestrus. (PMID:16195402)
• Insulin receptor-related receptor as an extracellular pH sensor involved in the regulation of acid-base balance. (Review) (PMID:23220417)
• Analysis of structural determinants of alkali sensor IRR positive cooperativity. (PMID:23824460)
• IRR activation is not based on a single residue deprotonation in the IRR ectodomain but rather involves synergistic conformational changes at multiple points. (PMID:24121506)
• IRR activation involves two separate centers of pH-dependent rearrangements that act synergistically to induce a major conformational change in the IRR molecule, resulting in internal kinase domains rapprochement and autophosphorylation. (PMID:25597417)
• the extensive glycosylation of FnIII-2/3 provides steric hindrance for the alkali-induced rearrangement of the IRR ectodomain. (PMID:29156593)
• ectoIRR’s sensing of alkaline conditions involves additional molecular mechanisms, for example engagement of receptor juxtamembrane regions or the surrounding lipid environment. (PMID:31615897)
• Probing Structure and Function of Alkali Sensor IRR with Monoclonal Antibodies. (PMID:32708676)
• Identification of INSRR as an immune-related gene in the tumor microenvironment of glioblastoma by integrated bioinformatics analysis. (PMID:37099121)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Insrr	ENSMUSG00000005640
rattus_norvegicus	Insrr	ENSRNOG00000057702

Paralogs (53): 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), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Insulin receptor-related protein — P14616 (reviewed: P14616)

Alternative names: IR-related receptor

All UniProt accessions (1): P14616

UniProt curated annotations — full annotation on UniProt →

Function. Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB.

Subunit / interactions. Probable tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand-binding domain, while the beta chains carry the kinase domain.

Subcellular location. Membrane.

Post-translational modifications. Autophosphorylated on tyrosine residues between pH 7.9 and pH 10.5.

Domain organisation. The extracellular domain is required for sensing alterations in external pH.

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

RefSeq proteins (1): NP_055030* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000494	Rcpt_L-dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002011	Tyr_kinase_rcpt_2_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR006211	Furin-like_Cys-rich_dom	Domain
IPR006212	Furin_repeat	Repeat
IPR008266	Tyr_kinase_AS	Active_site
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016246	Tyr_kinase_insulin-like_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036941	Rcpt_L-dom_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF00041, PF00757, PF01030, PF07714

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 (128 total): strand 55, helix 15, glycosylation site 10, disulfide bond 10, turn 8, sequence variant 8, domain 4, chain 3, region of interest 3, compositionally biased region 2, binding site 2, modified residue 2, topological domain 2, signal peptide 1, active site 1, mutagenesis site 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7TYJ	ELECTRON MICROSCOPY	3.3
7TYM	ELECTRON MICROSCOPY	3.4
7TYK	ELECTRON MICROSCOPY	3.5
7PL4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14616-F1	78.47	0.36

Functional residue map

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

Catalytic / active sites (1): 1115 (proton acceptor)

Ligand- & substrate-binding residues (2): 985–993; 1013

Post-translational modifications (2): 1145, 1146

Disulfide bonds (10): 214–222, 216–228, 229–237, 233–246, 249–258, 262–274, 280–300, 304–317, 320–324, 657–864

Glycosylation sites (10): 47, 311, 411, 492, 528, 616, 634, 756, 885, 898

Mutagenesis-validated functional residues (1):

Position	Phenotype
1145–1146	abolishes autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 114 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GCANCTGNY_MYOD_Q6, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GOBP_MALE_SEX_DETERMINATION, GOBP_SEX_DETERMINATION, FOXO4_01, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, EFC_Q6, DING_LUNG_CANCER_BY_MUTATION_RATE, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (7): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), insulin receptor signaling pathway (GO:0008286), actin cytoskeleton organization (GO:0030036), male sex determination (GO:0030238), protein autophosphorylation (GO:0046777), cellular response to alkaline pH (GO:0071469), protein phosphorylation (GO:0006468)

GO Molecular Function (11): transmembrane receptor protein tyrosine kinase activity (GO:0004714), insulin receptor activity (GO:0005009), ATP binding (GO:0005524), phosphatidylinositol 3-kinase binding (GO:0043548), insulin receptor substrate binding (GO:0043560), 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)

GO Cellular Component (5): plasma membrane (GO:0005886), insulin receptor complex (GO:0005899), axon (GO:0030424), signaling receptor complex (GO:0043235), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
enzyme-linked receptor protein signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
cytoskeleton organization	1
actin filament-based process	1
multicellular organism development	1
sex determination	1
protein phosphorylation	1
response to alkaline pH	1
cellular response to pH	1
phosphorylation	1
protein modification process	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
transmembrane receptor protein tyrosine kinase activity	1
insulin receptor signaling pathway	1
protein-hormone receptor activity	1
insulin binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein kinase activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
membrane	1
cell periphery	1
plasma membrane signaling receptor complex	1
protein kinase complex	1
neuron projection	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSRR	IGF1	P01343	682
INSRR	INSR	P06213	670
INSRR	INS	P01308	616
INSRR	IGF2	P01344	567
INSRR	IGF1R	P08069	518
INSRR	SRY	Q05066	496
INSRR	PPP2CA	P05323	485
INSRR	SOX9	P48436	477
INSRR	TCF7L1	Q9HCS4	422
INSRR	TBC1D10A	Q9BXI6	420
INSRR	H3BTC1	H3BTC1	405
INSRR	IRS4	O14654	405
INSRR	PIR	O00625	400
INSRR	NTRK3	Q16288	397
INSRR	GHRHR	Q02643	388

IntAct

15 interactions, top by confidence:

A	B	Type	Score
HSP90AB1	INSRR	psi-mi:“MI:0915”(physical association)	0.690
INSR	INSRR	psi-mi:“MI:0915”(physical association)	0.650
INSRR	INSR	psi-mi:“MI:0914”(association)	0.650
INSRR	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CTDSP2	INSRR	psi-mi:“MI:0915”(physical association)	0.370
STYX	INSRR	psi-mi:“MI:0915”(physical association)	0.370
INSR	HAX1	psi-mi:“MI:0914”(association)	0.350
INSRR	MYO1B	psi-mi:“MI:0914”(association)	0.350
DEFB116	SRC	psi-mi:“MI:0914”(association)	0.350
INSRR	SETD1A	psi-mi:“MI:0914”(association)	0.350
AXL	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
INSRR	HNRNPCL2	psi-mi:“MI:2364”(proximity)	0.270
INSRR	MEOX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (109): CTDSP2 (Two-hybrid), STYX (Two-hybrid), INSRR (PCA), MEOX2 (Two-hybrid), INSRR (Affinity Capture-Western), IDH2 (Affinity Capture-MS), INSR (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), OTULIN (Affinity Capture-MS), IGF1R (Affinity Capture-MS), ARHGEF40 (Affinity Capture-MS), VASN (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), HSP90AB3P (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RPR8, O02740, O08644, O09127, O15197, O19179, O73875, O73878, P0C0K6, P0C0K7, P14616, P16067, P20594, P21709, P26770, P29317, P29322, P35590, P46197, P51839, P51840, P51841, P51842, P52333, P52785, P54753, P54754, P54760, P54761, P55203, P55205, Q02846, Q03146, Q06805, Q06806, Q08345, Q1KL86, Q5JZY3, Q5SDA5, Q60750

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

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	167
Likely benign	38
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

4134 predictions. Top by Δscore:

Variant	Effect	Δscore
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
1:156844705:A:AT	donor_loss	1.0000
1:156844706:CCT:C	donor_gain	1.0000
1:156845071:CCTA:C	donor_gain	1.0000
1:156845072:CTACT:C	donor_loss	1.0000
1:156845073:TA:T	donor_loss	1.0000

AlphaMissense

8419 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156841718:C:A	W1158C	1.000
1:156841718:C:G	W1158C	1.000
1:156841720:A:G	W1158R	1.000
1:156841720:A:T	W1158R	1.000
1:156842149:G:C	N1120K	1.000
1:156842149:G:T	N1120K	1.000
1:156842156:G:T	A1118D	1.000
1:156842165:T:A	D1115V	1.000
1:156842165:T:C	D1115G	1.000
1:156842165:T:G	D1115A	1.000
1:156842423:A:G	L1071P	1.000
1:156842431:C:A	K1068N	1.000
1:156842431:C:G	K1068N	1.000
1:156846055:C:A	W625C	1.000
1:156846055:C:G	W625C	1.000
1:156846057:A:G	W625R	1.000
1:156846057:A:T	W625R	1.000
1:156841442:A:T	V1205D	0.999
1:156841479:A:C	Y1193D	0.999
1:156841481:G:T	P1192H	0.999
1:156841505:T:A	E1184V	0.999
1:156841505:T:G	E1184A	0.999
1:156841506:C:T	E1184K	0.999
1:156841520:C:T	G1179D	0.999
1:156841666:A:G	W1176R	0.999
1:156841666:A:T	W1176R	0.999
1:156841719:C:G	W1158S	0.999
1:156841723:G:T	R1157S	0.999
1:156841793:G:C	D1133E	0.999
1:156841793:G:T	D1133E	0.999

dbSNP variants (sampled 300 via entrez): RS1000057562 (1:156842361 C>A,T), RS1000197102 (1:156848441 C>T), RS1000242834 (1:156854417 G>A), RS1000484224 (1:156848765 A>G), RS1000546977 (1:156858909 C>G,T), RS1001030943 (1:156843928 T>TGGC), RS1001177013 (1:156842686 C>T), RS1001212776 (1:156856176 T>C), RS1001897623 (1:156839677 C>T), RS1002000706 (1:156859508 C>A,T), RS1002056072 (1:156847433 T>C), RS1002120732 (1:156859202 C>A,T), RS1002154069 (1:156853687 C>T), RS1002185894 (1:156841455 C>A,T), RS1002406912 (1:156847669 G>A)

Disease associations

OMIM: gene MIM:147671 | disease phenotypes: MIM:256800, MIM:155240

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	No Known Disease Relationship	Unknown

Mondo (3): hereditary sensory and autonomic neuropathy type 4 (MONDO:0009746), familial medullary thyroid carcinoma (MONDO:0007958), schizophrenia (MONDO:0005090)

Orphanet (3): Hereditary sensory and autonomic neuropathy type 4 (Orphanet:642), Multiple endocrine neoplasia type 2 (Orphanet:653), Isolated familial medullary thyroid carcinoma (Orphanet:99361)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004058_3	Uric acid clearance	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536911	Familial medullary thyroid carcinoma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5483 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 134,629 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL575448	BMS-754807	2	406
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10908521	Toxicity	3	glucarpidase	Nephrotoxicity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10908521	INSRR, NTRK1	3	0.00	1	glucarpidase

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — Type II RTKs: Insulin receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
linsitinib	Inhibition	7.12	pIC50

ChEMBL bioactivities

45 potent at pChembl≥5 of 45 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.21	Kd	6.2	nM	TAE-684
8.12	IC50	7.59	nM	STAUROSPORINE
8.07	Kd	8.6	nM	CHEMBL464552
7.88	IC50	13.2	nM	STAUROSPORINE
7.82	IC50	15	nM	STAUROSPORINE
7.68	IC50	21	nM	LINSITINIB
7.68	Kd	21	nM	NINTEDANIB
7.35	IC50	45	nM	BRIGATINIB
7.35	IC50	45	nM	CHEMBL6165880
7.30	Kd	50	nM	BMS-754807
7.28	Kd	53	nM	FORETINIB
7.12	IC50	75	nM	LINSITINIB
7.09	Kd	81	nM	STAUROSPORINE
6.56	Kd	276	nM	TOZASERTIB
6.54	Kd	290	nM	TOZASERTIB
6.38	Kd	420	nM	KW-2449
6.37	Kd	430	nM	SUNITINIB
6.31	IC50	488	nM	CHEMBL466397
6.22	Kd	600	nM	CRIZOTINIB
6.12	IC50	750	nM	LINSITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.92	IC50	1200	nM	CHEMBL1235786
5.92	Kd	1200	nM	CHEMBL1235786
5.92	Kd	1200	nM	CHEMBL1908395
5.85	Kd	1400	nM	AST-487
5.80	IC50	1600	nM	CHEMBL4764610
5.80	Kd	1600	nM	FEDRATINIB
5.75	Kd	1800	nM	LESTAURTINIB
5.75	IC50	1800	nM	CHEMBL1234833
5.70	Kd	2000	nM	SU-014813
5.46	Kd	3500	nM	PHA-665752
5.41	Kd	3900	nM	LINIFANIB
5.34	Kd	4600	nM	NERATINIB
5.34	Kd	4600	nM	R-406

PubChem BioAssay actives

37 with measured affinity, of 745 total; 25 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
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625075: Binding constant for INSRR kinase domain	kd	0.0062	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	1715313: Inhibition of human IRR using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0076	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	625075: Binding constant for INSRR kinase domain	kd	0.0086	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625075: Binding constant for INSRR kinase domain	kd	0.0210	uM
Brigatinib	2182818: Inhibition of human INSRR using MBP as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0450	uM
(2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methylpyrrolidine-2-carboxamide	2167399: Binding affinity to IRR (unknown origin) by phage based competition assay	kd	0.0500	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625075: Binding constant for INSRR kinase domain	kd	0.0530	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	389059: Binding affinity to human IRR	kd	0.2760	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625075: Binding constant for INSRR kinase domain	kd	0.4200	uM
Sunitinib	435430: Binding constant for INSRR kinase domain	kd	0.4300	uM
N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]imidazo[1,2-a]pyridin-2-yl]-2-methoxybenzamide	2167080: Inhibition of N-terminal 6His-tagged recombinant human IRR (944 to 1266 residues) expressed in baculovirus infected Sf21 cells by filter binding assay	ic50	0.4880	uM
Crizotinib	625075: Binding constant for INSRR kinase domain	kd	0.6000	uM
3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	2161102: Inhibition of IRR (unknown origin) in presence of 100 uM ATP treated at 2 hrs followed by IGF1 ligand addition for 15 mins by ELISA analysis	ic50	0.7500	uM
1-[3-methoxy-4-[[4-(2-propan-2-ylsulfonylanilino)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]phenyl]piperidin-4-ol	2185958: Binding affinity to INSRR (unknown origin) assessed as dissociation constant by Ambit kinase binding assay	kd	1.2000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625075: Binding constant for INSRR kinase domain	kd	1.2000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435430: Binding constant for INSRR kinase domain	kd	1.4000	uM
4-fluoro-2-methoxy-11-oxo-5-propan-2-yl-3-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-6H-indolo[2,3-b]quinoline-8-carbonitrile	1700706: Inhibition of human INSRR	ic50	1.6000	uM
Fedratinib	625075: Binding constant for INSRR kinase domain	kd	1.6000	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507568: Binding affinity to INSRR	kd	1.8000	uM
(2S,3S)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol	604576: Inhibition of IRR	ic50	1.8000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435430: Binding constant for INSRR kinase domain	kd	2.0000	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	625075: Binding constant for INSRR kinase domain	kd	3.5000	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	435430: Binding constant for INSRR kinase domain	kd	3.9000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	625075: Binding constant for INSRR kinase domain	kd	4.6000	uM
Neratinib	625075: Binding constant for INSRR kinase domain	kd	4.6000	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrous chloride	decreases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Diazinon	increases methylation	1
Formaldehyde	increases expression	1
Niclosamide	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Particulate Matter	increases expression, increases abundance	1

ChEMBL screening assays

251 unique, capped per target: 250 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1035903	Binding	Binding affinity to human IRR at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem
CHEMBL5209908	Functional	Affinity Phenotypic Cellular interaction (CellTiterGlo™ luciferase-based cellular ATP assay (Promega; cell proliferation in SW620 cells)) EUB0000614a INSRR	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety