INSR

Summary

INSR (insulin receptor, HGNC:6091) is a protein-coding gene on chromosome 19p13.2, encoding Insulin receptor (P06213). Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.

This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3643 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Donohue syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 144
• Clinical variants (ClinVar): 816 total — 43 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 138
• Druggable target: yes — 36 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000208

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6091
Approved symbol	INSR
Name	insulin receptor
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	CD220
Ensembl gene	ENSG00000171105
Ensembl biotype	protein_coding
OMIM	147670
Entrez	3643

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 4 retained_intron

ENST00000302850, ENST00000341500, ENST00000593970, ENST00000597211, ENST00000598216, ENST00000600492, ENST00000601099, ENST00000904790, ENST00000904791

RefSeq mRNA: 2 — MANE Select: NM_000208 NM_000208, NM_001079817

CCDS: CCDS12176, CCDS42487

Canonical transcript exons

ENST00000302850 — 22 exons

Exon	Start	End
ENSE00001157509	7150497	7150532
ENSE00001157513	7119449	7119583
ENSE00001157539	7125283	7125527
ENSE00001157546	7126584	7126651
ENSE00001157555	7128852	7128954
ENSE00001157563	7132158	7132317
ENSE00001157569	7141677	7141816
ENSE00001157577	7142816	7143090
ENSE00001157582	7152726	7152927
ENSE00001283493	7293792	7294414
ENSE00003059467	7112265	7117410
ENSE00003469979	7122879	7122989
ENSE00003491310	7120620	7120749
ENSE00003536394	7170537	7170751
ENSE00003580729	7172290	7172434
ENSE00003613738	7167968	7168094
ENSE00003645740	7122614	7122773
ENSE00003658215	7163032	7163199
ENSE00003659630	7174583	7174731
ENSE00003664284	7267345	7267896
ENSE00003682994	7184316	7184637
ENSE00003683391	7166154	7166404

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 98.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.6673 / max 301.9451, expressed in 1638 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178838	6.7122	1501
178840	2.0992	807
178825	1.1707	520
178841	1.1052	429
178839	0.8233	538
178842	0.3978	205
178837	0.3278	195
178827	0.0311	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.56	gold quality
palpebral conjunctiva	UBERON:0001812	98.13	gold quality
visceral pleura	UBERON:0002401	97.66	gold quality
eye	UBERON:0000970	96.92	gold quality
middle temporal gyrus	UBERON:0002771	96.67	gold quality
nephron tubule	UBERON:0001231	96.46	gold quality
renal medulla	UBERON:0000362	96.27	gold quality
adrenal tissue	UBERON:0018303	96.24	gold quality
tibia	UBERON:0000979	96.05	gold quality
seminal vesicle	UBERON:0000998	95.85	gold quality
epithelium of nasopharynx	UBERON:0001951	95.67	gold quality
nasopharynx	UBERON:0001728	95.65	gold quality
body of pancreas	UBERON:0001150	95.23	gold quality
medial globus pallidus	UBERON:0002477	94.48	gold quality
tendon of biceps brachii	UBERON:0008188	94.32	gold quality
pylorus	UBERON:0001166	94.27	gold quality
nipple	UBERON:0002030	94.11	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.80	gold quality
parotid gland	UBERON:0001831	93.74	gold quality
pancreatic ductal cell	CL:0002079	93.61	gold quality
epithelium of mammary gland	UBERON:0003244	93.58	gold quality
globus pallidus	UBERON:0001875	93.42	gold quality
kidney epithelium	UBERON:0004819	93.41	gold quality
pleura	UBERON:0000977	93.30	gold quality
saphenous vein	UBERON:0007318	93.25	gold quality
parietal pleura	UBERON:0002400	93.22	gold quality
mammary duct	UBERON:0001765	93.17	gold quality
endothelial cell	CL:0000115	93.14	gold quality
mucosa of urinary bladder	UBERON:0001259	93.10	gold quality
left ovary	UBERON:0002119	92.54	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	1287.44
E-MTAB-10553	yes	45.04
E-MTAB-6678	yes	26.82
E-MTAB-8410	yes	25.37
E-GEOD-135922	yes	22.69
E-MTAB-5061	yes	6.84
E-CURD-114	no	19.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, CEBPA, CEBPB, CEBPG, E2F1, ESR1, ESR2, FOXC1, FOXO1, GCFC2, HMGA1, INS, KLF6, MYC, NFKB, NR3C1, NR3C2, NUCKS1, PAX1, PAX6, PDX1, PPARG, SP1, SPI1, STAT5B, TCF3, TFAP2A, TLX3, TP53, TP63, TP73, WT1, ZNF91

miRNA regulators (miRDB)

205 targeting INSR, 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-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-LET-7I-5P	99.98	72.37	1788
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Literature-anchored findings (GeneRIF, showing 40)

• Chiral mutagenesis of insulin’s hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue (PMID:11866509)
• Role of insulin receptor dimerization domains in ligand binding, cooperativity, and modulation by anti-receptor antibodies (PMID:11875066)
• cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation (PMID:12031977)
• an arginine to cysteine(252) mutation from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events (PMID:12107746)
• Sam68 associates with the SH3 domains of Grb2 recruiting GAP to the Grb2-SOS complex in insulin receptor signaling (PMID:12112020)
• Transactivation of INSR by calcitrol (PMID:12125099)
• Insulin-IGF1 hybrid receptors have different tissue-specific responses based on their isoforms (PMID:12138094)
• insulin receptor may play a role in the regulation of ovarian cancer cell growth (PMID:12193537)
• alanine-scanning mutagenesis of the insulin receptor A and B isoforms has identified several new side chains contributing to insulin binding and indicates that the energetic contributions of certain side chains differ in each (PMID:12270939)
• A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome. (PMID:12477518)
• inhibition of insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor (PMID:12493740)
• Donohue’s syndrome (leprechaunism) was found to be homozygous for an in-frame trinucleotide deletion within the insulin receptor gene resulting in the deletion of valine 335. (PMID:12538626)
• The IR may serve as a cellular substrate for both protein tyrosine phosphatase forms TC48 and TC45. Differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo. (PMID:12612081)
• Cornea and conjunctiva express insulin receptor in cytoplasm of epithelium. (PMID:12613967)
• dynamics of the interaction between this receptor and protein tyrosine-phosphatase 1B in living cells (PMID:12634852)
• This protein is activated both by human and Caenorhabditis elegans insulin. (PMID:12654724)
• HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the insulin receptor promoter (PMID:12665574)
• the human insulin receptor gene promoter has a vitamin D response element (PMID:12711007)
• Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. (PMID:12734206)
• High glucose impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in islets of Langerhans. (PMID:12738810)
• the presence of a free heavy chain IgG in the circulation from spinal cord-injured subjects blocked insulin receptor binding sites and also blocked the prostacyclin receptor interaction in platelets; insulin-induced NO synthesis was markedly impaired. (PMID:12850828)
• Fibroblasts from leprechaunism patients with mutant insulin receptors have altered gene expression. (PMID:12878213)
• INSR-A, the predominant isoform in fetal tissues and malignant cells, binds with a high affinity insulin and IGF-II, which differentially regulate gene expression. (PMID:12881524)
• None of the polymorphisms in INSR or IRS1 was associated with metabolic syndrome findings. (PMID:14693412)
• Human micro- and macrovascular endothelial cells express more IGF-I receptor than insulin receptor. (PMID:14722023)
• Insulin receptor splicing alteration is associated with myotonic dystrophy type 2 (PMID:15114529)
• Linkage analysis and mutation screening revealed missense mutation (Arg1174Gln) in tyrosine kinase domain of insulin receptor gene that cosegregated with disease phenotype. (PMID:15161766)
• Data show that in adipocytes the insulin receptor is localized to caveolae,and that part of insulin receptor substrate 1 (IRS1), the immediate downstream signal mediator, colocalizes with the insulin receptor in the plasma membrane and caveolae. (PMID:15182363)
• The C and D domains of IGF-II promote higher affinity binding to the IR-A than the equivalent domains of IGF-I. (PMID:15205474)
• The exon-definition model explains alternative splicing of exon 11 in the insulin receptor gene in-vivo but not in-vitro. (PMID:15233842)
• Mrna elevated in polycystic ovary syndrome. Granulosa cell insulin receptor heterogeneity, together with adiposity-dependent intrafollicular insulin availability, is novel mechanism by which insulin may affect granulosa cell function within follicle. (PMID:15240646)
• Increased systolic and diastolic blood pressure, heart rate, plasma insulin, and decreased erythrocyte insulin receptors preexist in healthy offspring of patients with essential hypertension. (PMID:15485753)
• Molecular modeling of the IRK domain indicated that the ATP-binding site becomes distorted after releasing the nucleotide unless the IRK domain is oxidatively derivatized at Cys1245. (PMID:15563471)
• the G972R naturally occurring polymorphism of IRS-1 not only reduces phosphorylation of the substrate but allows IRS-1 to act as an inhibitor of the insulin receptor kinase, producing global insulin resistance (PMID:15590636)
• Our findings suggest, for the first time, that AMPK activation could reduce the expression of insulin receptor, at least in part, by a down-regulation of the transcriptional level, and this effect may be liver specific. (PMID:15694368)
• This study suggests an association between the affinity of insulin receptors and number of IGF-1 receptors with placental and/or fetal growth. (PMID:15708546)
• This study provides evidence to suggest cross down-regulation of leptin and insulin receptors at both receptor and downstream signalling levels. (PMID:15715521)
• analysis of insulin receptor functional insulin binding epitopes (PMID:15799978)
• Transcriptional repression of the human insulin receptor gene mediated by estrogen receptor beta in U-937 cells. (PMID:15862945)
• Polymorphism in exon 17 of insulin receptor leads to increased risk of insulin resistance in women with polycystic ovary syndrome. (PMID:15938783)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	insra	ENSDARG00000011948
danio_rerio	insrb	ENSDARG00000071524
mus_musculus	Insr	ENSMUSG00000005534
rattus_norvegicus	Insr	ENSRNOG00000029986

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

Insulin receptor — P06213 (reviewed: P06213)

All UniProt accessions (2): P06213, M0R3E6

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis.

Subunit / interactions. Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with ‘Tyr-27’phosphorylation of CAV2. Interacts with ARRB2. Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating INSR autophosphorylation and endocytosis. Interacts with the cone snail venom insulin Con-Ins G1. Interacts with the insulin receptor SORL1; this interaction strongly increases its surface exposure, hence strengthens insulin signal reception. Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the INSR C-terminal region. Interacts with GNAI3; the interaction is probably mediated by CCDC88A/GIV. Interacts with LMBRD1. Interacts (in response to insulin stimulation) with NCK1; this interaction may recruit PTPN1 to mediate INSR dephosphorylation. Interacts with CD248; this interaction diminishes INSR autophosphorylation.

Subcellular location. Cell membrane. Late endosome. Lysosome.

Tissue specificity. Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.

Post-translational modifications. After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane. Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and Tyr-1190. May also be phosphorylated at Tyr-1185 and Tyr-1190 by mTORC2. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling. Dephosphorylation at Tyr-1189 and Tyr-1190 requires the SH2/SH3 adapter protein NCK1, probably to recruit its interaction partner PTPN1. S-nitrosylation at Cys-1083 by BLVRB inhibits the receptor tyrosine kinase, thereby inhibiting insulin signaling. Ubiquitinated by MARCHF1; leading to degradation thereby reducing surface INSR expression.

Disease relevance. Rabson-Mendenhall syndrome (RMS) [MIM:262190] Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Leprechaunism (LEPRCH) [MIM:246200] Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. The gene represented in this entry may be involved in disease pathogenesis. Hyperinsulinemic hypoglycemia, familial, 5 (HHF5) [MIM:609968] A form of hyperinsulinemic hypoglycemia, a clinically and genetically heterogeneous disorder characterized by inappropriate insulin secretion from the pancreatic beta-cells in the presence of low blood glucose levels. HHF5 clinical features include loss of consciousness due to hypoglycemia and hypoglycemic seizures. HHF5 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549] Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated in response to insulin. Autophosphorylation activates the kinase activity. PTPN1, PTPRE and PTPRF dephosphorylate important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates.

Domain organisation. The tetrameric insulin receptor binds insulin via non-identical regions from two alpha chains, primarily via the C-terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin-binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P06213-1	Long, HIR-B	yes
P06213-2	Short, HIR-A

RefSeq proteins (2): NP_000199, NP_001073285 (=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
IPR040969	Insulin_TMD	Domain
IPR050122	RTK	Family

Pfam: PF00757, PF01030, PF07714, PF17870

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 (309 total): sequence variant 82, strand 81, helix 32, mutagenesis site 22, disulfide bond 19, glycosylation site 18, turn 14, modified residue 12, region of interest 6, binding site 5, domain 4, sequence conflict 3, topological domain 3, chain 2, signal peptide 1, active site 1, site 1, transmembrane region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

88 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3BU3	X-RAY DIFFRACTION	1.65
5HHW	X-RAY DIFFRACTION	1.79
4IBM	X-RAY DIFFRACTION	1.8
5U1M	X-RAY DIFFRACTION	1.8
1IR3	X-RAY DIFFRACTION	1.9
1P14	X-RAY DIFFRACTION	1.9
3BU6	X-RAY DIFFRACTION	1.95
1IRK	X-RAY DIFFRACTION	2.1
3BU5	X-RAY DIFFRACTION	2.1
3EKK	X-RAY DIFFRACTION	2.1
8DWN	X-RAY DIFFRACTION	2.15
3EKN	X-RAY DIFFRACTION	2.2
5E1S	X-RAY DIFFRACTION	2.26
2B4S	X-RAY DIFFRACTION	2.3
4XLV	X-RAY DIFFRACTION	2.3
2HR7	X-RAY DIFFRACTION	2.32
1I44	X-RAY DIFFRACTION	2.4
1RQQ	X-RAY DIFFRACTION	2.6
3ETA	X-RAY DIFFRACTION	2.6
7KD6	X-RAY DIFFRACTION	2.6
1GAG	X-RAY DIFFRACTION	2.7
9NCN	ELECTRON MICROSCOPY	2.86
9SA8	ELECTRON MICROSCOPY	2.88
6VEP	X-RAY DIFFRACTION	2.9
4XSS	X-RAY DIFFRACTION	3
4XST	X-RAY DIFFRACTION	3
7U6E	ELECTRON MICROSCOPY	3
6PXW	ELECTRON MICROSCOPY	3.1
2AUH	X-RAY DIFFRACTION	3.2
6HN5	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06213-F1	78.35	0.45

Antibody-complex structures (SAbDab): 10 — 3W11, 3W12, 3W13, 4OGA, 4ZXB, 5J3H, 5KQV, 6VEP, 6VEQ, 7KD6

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 (2): 1159 (proton donor/acceptor); 66 (insulin-binding)

Ligand- & substrate-binding residues (5): 1033; 1057; 1104–1110; 1163–1164; 1177

Post-translational modifications (13): 400, 401, 407, 992, 999, 1011, 1083, 1185, 1189, 1190, 1355, 1361, 1079

Disulfide bonds (19): 35–53, 153–182, 186–209, 196–215, 219–228, 223–234, 235–243, 239–252, 255–264, 268–280, 286–311, 293–301, 315–328, 331–335, 339–360, 462–495, 551, 674–899, 825–834

Glycosylation sites (18): 43, 52, 105, 138, 242, 282, 322, 364, 424, 445, 541, 633, 651, 698, 769, 782, 920, 933

Mutagenesis-validated functional residues (22):

Position	Phenotype
462	does not affect s-nitrosylation.
825	does not affect s-nitrosylation.
834	does not affect s-nitrosylation.
991	reduces interaction with irs1 but has no effect on interaction with shc1.
992	reduces interaction with irs1 but has no effect on interaction with shc1.
996–997	abolishes interaction with irs1. severely disrupts, but does not abolish interaction with shc1.
996	abolishes interaction with irs1 and significantly reduces interaction with shc1. has no effect on interaction with pik3r
997	abolishes interaction with irs1 and significantly reduces interaction with shc1. has no effect on interaction with pik3r
998	does not affect interaction with irs1, shc1 or pik3r1.
999	abolishes interaction with irs1 and shc1.
999	has no effect on insulin-stimulated autophosphorylation, but inhibits the biological activity of the receptor. abolishes
1000	severely reduces interaction with shc1. has no effect on interaction with irs1.
1002	reduces interaction with irs1 but has no effect on interaction with shc1.
1011	increases kinase activity.
1057	abolishes the kinase activity and abolishes interaction with irs1, shc1, grb7 and pik3r1.
1057	abolishes the kinase activity.
1079	increased cell surface stability.
1083	reduced s-nitrosylation by blvrb, leading to increased receptor tyrosine kinase activity.
1159	loss of kinase activity.
1163	loss of kinase activity.
1189	reduced interaction with grb7.
1190	strongly reduced interaction with grb7.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-74713	IRS activation
R-HSA-74749	Signal attenuation
R-HSA-74751	Insulin receptor signalling cascade
R-HSA-74752	Signaling by Insulin receptor
R-HSA-77387	Insulin receptor recycling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 838 (showing top): GOBP_REGULATION_OF_RESPIRATORY_BURST, GOBP_MEMORY, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_COGNITION, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_NUCLEAR_DIVISION

GO Biological Process (51): positive regulation of receptor internalization (GO:0002092), heart morphogenesis (GO:0003007), regulation of DNA-templated transcription (GO:0006355), receptor-mediated endocytosis (GO:0006898), G protein-coupled receptor signaling pathway (GO:0007186), learning (GO:0007612), memory (GO:0007613), positive regulation of cell population proliferation (GO:0008284), insulin receptor signaling pathway (GO:0008286), epidermis development (GO:0008544), male gonad development (GO:0008584), male sex determination (GO:0030238), adrenal gland development (GO:0030325), positive regulation of cell migration (GO:0030335), exocrine pancreas development (GO:0031017), receptor internalization (GO:0031623), cellular response to insulin stimulus (GO:0032869), glucose homeostasis (GO:0042593), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of protein-containing complex disassembly (GO:0043243), positive regulation of MAPK cascade (GO:0043410), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of glycogen biosynthetic process (GO:0045725), positive regulation of glycolytic process (GO:0045821), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of DNA-templated transcription (GO:0045893), regulation of embryonic development (GO:0045995), positive regulation of D-glucose import across plasma membrane (GO:0046326), symbiont entry into host cell (GO:0046718), protein autophosphorylation (GO:0046777), positive regulation of developmental growth (GO:0048639), positive regulation of meiotic cell cycle (GO:0051446), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of respiratory burst (GO:0060267), cellular response to growth factor stimulus (GO:0071363), dendritic spine maintenance (GO:0097062), amyloid-beta clearance (GO:0097242), transport across blood-brain barrier (GO:0150104), neuron projection maintenance (GO:1990535), regulation of female gonad development (GO:2000194)

GO Molecular Function (23): amyloid-beta binding (GO:0001540), protein tyrosine kinase activity (GO:0004713), insulin receptor activity (GO:0005009), insulin-like growth factor receptor binding (GO:0005159), ATP binding (GO:0005524), GTP binding (GO:0005525), protein domain specific binding (GO:0019904), protein kinase activator activity (GO:0030295), insulin-like growth factor I binding (GO:0031994), insulin-like growth factor II binding (GO:0031995), cargo receptor activity (GO:0038024), identical protein binding (GO:0042802), phosphatidylinositol 3-kinase binding (GO:0043548), insulin binding (GO:0043559), insulin receptor substrate binding (GO:0043560), protein-containing complex binding (GO:0044877), PTB domain binding (GO:0051425), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transmembrane receptor protein tyrosine kinase activity (GO:0004714), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (16): lysosome (GO:0005764), late endosome (GO:0005770), plasma membrane (GO:0005886), insulin receptor complex (GO:0005899), caveola (GO:0005901), external side of plasma membrane (GO:0009897), endosome membrane (GO:0010008), membrane (GO:0016020), axon (GO:0030424), dendrite membrane (GO:0032590), neuronal cell body membrane (GO:0032809), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), nuclear envelope (GO:0005635), endosome (GO:0005768), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Insulin receptor signalling cascade	2
Signaling by Insulin receptor	2
Signal Transduction	2
Negative regulation of the PI3K/AKT network	1
Signaling by Receptor Tyrosine Kinases	1
Intracellular signaling by second messengers	1
PIP3 activates AKT signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	5
learning or memory	2
gland development	2
protein kinase activity	2
purine ribonucleoside triphosphate binding	2
insulin-like growth factor binding	2
endosome	2
nucleus	2
endomembrane system	2
regulation of receptor internalization	1
receptor internalization	1
positive regulation of receptor-mediated endocytosis	1
heart development	1
animal organ morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
endocytosis	1
G protein-coupled receptor activity	1
signal transduction	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
tissue development	1
gonad development	1
development of primary male sexual characteristics	1
multicellular organism development	1
sex determination	1
endocrine system development	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
pancreas development	1
exocrine system development	1
digestive system development	1
receptor-mediated endocytosis	1
response to insulin	1
cellular response to peptide hormone stimulus	1

Protein interactions and networks

STRING

3742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSR	INS	P01308	999
INSR	IGF1	P01343	995
INSR	IRS1	P35568	991
INSR	IGF2	P01344	972
INSR	TXNDC9	O14530	953
INSR	IRS2	Q9Y4H2	903
INSR	GRB14	Q14449	826
INSR	SLC2A4	P14672	800
INSR	PIK3R1	P27986	795
INSR	GRB10	Q13322	787
INSR	PTPN1	P18031	760
INSR	SHC1	P29353	752
INSR	IRS4	O14654	747
INSR	GRB2	P29354	747
INSR	LEP	P41159	744

IntAct

221 interactions, top by confidence:

A	B	Type	Score
PTPN1	INSR	psi-mi:“MI:0203”(dephosphorylation reaction)	0.980
INSR	PTPN1	psi-mi:“MI:0915”(physical association)	0.980
PTPN1	INSR	psi-mi:“MI:0915”(physical association)	0.980
INSR	PTPN1	psi-mi:“MI:2364”(proximity)	0.980
PTPN1	INSR	psi-mi:“MI:0407”(direct interaction)	0.980
INSR	PTPN1	psi-mi:“MI:0407”(direct interaction)	0.980
PTPN1	INSR	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
PTPN1	INSR	psi-mi:“MI:2364”(proximity)	0.980

BioGRID (483): ARRB2 (Affinity Capture-Western), KRT31 (Two-hybrid), INSR (Affinity Capture-Western), INSR (Affinity Capture-Western), SQSTM1 (Biochemical Activity), ATIC (Affinity Capture-Western), PTPLAD1 (Affinity Capture-Western), PRKAA1 (Affinity Capture-Western), PRKAA2 (Affinity Capture-Western), KIF5A (Affinity Capture-Western), INSR (Affinity Capture-MS), INSR (Affinity Capture-MS), INSR (Affinity Capture-MS), INSR (Reconstituted Complex), INSR (Reconstituted Complex)

ESM2 similar proteins: A0M8R7, A0M8S8, A1X150, B2RXS4, O45657, O60486, P06213, P08581, P15127, P15208, P16056, P28827, P97523, Q00PJ8, Q02763, Q07DV8, Q07DY1, Q07DZ1, Q07E01, Q07E24, Q07E37, Q07E48, Q09YH7, Q09YI9, Q09YK0, Q09YL1, Q09YN5, Q108U6, Q24323, Q2IBA6, Q2IBC0, Q2IBD8, Q2IBF2, Q2IBG7, Q2QL89, Q2QLA9, Q2QLC0, Q2QLE0, Q2QLF1, Q2QLG5

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

SIGNOR signaling

163 interactions.

A	Effect	B	Mechanism
INSR	up-regulates	DOK4
INSR	up-regulates	DOK5
CBL	down-regulates	INSR	ubiquitination
SH2B2	down-regulates	INSR	binding
PTPN13	down-regulates	INSR	dephosphorylation
PTPN9	down-regulates	INSR	dephosphorylation
PTPRF	down-regulates	INSR	dephosphorylation
GRB10	down-regulates	INSR	binding
PTPN2	down-regulates	INSR	dephosphorylation
4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone	down-regulates	INSR	“chemical inhibition”
BMS-554417	down-regulates	INSR	“chemical inhibition”
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	down-regulates	INSR	“chemical inhibition”
N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide	down-regulates	INSR	“chemical inhibition”
NVP-AEW541	down-regulates	INSR	“chemical inhibition”
PRKAA2	up-regulates	INSR	phosphorylation
PTPRJ	down-regulates	INSR	dephosphorylation
AMPK	up-regulates	INSR	phosphorylation
INS	“up-regulates activity”	INSR	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by EGFRvIII	6	42.0×	6e-07
Tie2 Signaling	7	41.2×	5e-08
Insulin receptor signalling cascade	6	39.5×	6e-07
Signaling by ERBB2 ECD mutants	6	39.5×	6e-07
Erythropoietin activates RAS	5	37.3×	6e-06
Signaling by FLT3 ITD and TKD mutants	5	37.3×	6e-06
Downstream signal transduction	9	33.6×	2e-09
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	33.6×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine dephosphorylation	7	47.8×	4e-08
insulin-like growth factor receptor signaling pathway	7	26.7×	2e-06
insulin receptor signaling pathway	13	22.2×	2e-11
positive regulation of D-glucose import across plasma membrane	5	17.5×	9e-04
negative regulation of insulin receptor signaling pathway	6	17.3×	3e-04
negative regulation of T cell receptor signaling pathway	6	16.9×	3e-04
T cell costimulation	5	14.4×	2e-03
cellular response to epidermal growth factor stimulus	5	12.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	27
Uncertain significance	338
Likely benign	144
Benign	148

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069695	NM_000208.4(INSR):c.1348C>T (p.Gln450Ter)	Pathogenic
1459005	NM_000208.4(INSR):c.1246C>T (p.Arg416Ter)	Pathogenic
14679	NM_000208.4(INSR):c.3104G>T (p.Gly1035Val)	Pathogenic
14681	NM_000208.4(INSR):c.1177G>A (p.Gly393Arg)	Pathogenic
14682	NM_000208.4(INSR):c.2095C>T (p.Gln699Ter)	Pathogenic
14683	NM_000208.4(INSR):c.3680G>C (p.Trp1227Ser)	Pathogenic
14684	NM_000208.4(INSR):c.2286G>T (p.Arg762Ser)	Pathogenic
14685	INSR, EX17, ALU	Pathogenic
14686	NM_000208.4(INSR):c.2770C>T (p.Arg924Ter)	Pathogenic
14687	NM_000208.4(INSR):c.3481G>A (p.Ala1161Thr)	Pathogenic
14689	NM_000208.4(INSR):c.779T>C (p.Leu260Pro)	Pathogenic
14690	NM_000208.4(INSR):c.1225T>G (p.Phe409Val)	Pathogenic
14691	NM_000208.4(INSR):c.126C>A (p.Asn42Lys)	Pathogenic
14692	NM_000208.4(INSR):c.3079C>T (p.Arg1027Ter)	Pathogenic
14693	NM_000208.4(INSR):c.707A>G (p.His236Arg)	Pathogenic
14694	NM_000208.4(INSR):c.479G>A (p.Trp160Ter)	Pathogenic
14696	NM_000208.3(INSR):c.2683-542_2842+544del	Pathogenic
14699	NM_000208.4(INSR):c.172G>A (p.Gly58Arg)	Pathogenic
14700	NM_000208.4(INSR):c.3572G>A (p.Arg1191Gln)	Pathogenic
14702	NM_000208.4(INSR):c.164T>C (p.Val55Ala)	Pathogenic
14703	NM_000208.4(INSR):c.338G>C (p.Arg113Pro)	Pathogenic
14704	NM_000208.4(INSR):c.3485C>A (p.Ala1162Glu)	Pathogenic
14705	NM_000208.4(INSR):c.442A>T (p.Lys148Ter)	Pathogenic
14708	NM_000208.4(INSR):c.3602G>A (p.Arg1201Gln)	Pathogenic
14710	NM_000208.4(INSR):c.1316G>C (p.Trp439Ser)	Pathogenic
14711	NM_000208.4(INSR):c.438C>G (p.Ile146Met)	Pathogenic
14712	NM_000208.4(INSR):c.1124-2A>G	Pathogenic
14713	NM_000208.4(INSR):c.2480_2487del (p.Gln827fs)	Pathogenic
14714	NM_000208.4(INSR):c.1372A>G (p.Asn458Asp)	Pathogenic
2027676	NM_000208.4(INSR):c.25dup (p.Ala9fs)	Pathogenic

SpliceAI

3371 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7117406:CAGTG:C	acceptor_gain	1.0000
19:7117407:AGTG:A	acceptor_gain	1.0000
19:7117408:GTG:G	acceptor_gain	1.0000
19:7117409:TG:T	acceptor_gain	1.0000
19:7117410:GCTG:G	acceptor_loss	1.0000
19:7117411:C:CA	acceptor_loss	1.0000
19:7117411:C:CC	acceptor_gain	1.0000
19:7117412:T:C	acceptor_loss	1.0000
19:7119443:ACTTA:A	donor_loss	1.0000
19:7119444:CTTAC:C	donor_loss	1.0000
19:7119445:TTAC:T	donor_loss	1.0000
19:7119446:T:TC	donor_loss	1.0000
19:7119447:A:AC	donor_gain	1.0000
19:7119447:A:AT	donor_loss	1.0000
19:7119447:ACACT:A	donor_gain	1.0000
19:7119448:C:CC	donor_gain	1.0000
19:7119448:CA:C	donor_gain	1.0000
19:7119448:CACT:C	donor_gain	1.0000
19:7119448:CACTC:C	donor_gain	1.0000
19:7120616:TCACC:T	donor_loss	1.0000
19:7120618:ACCAC:A	donor_loss	1.0000
19:7120619:CCA:C	donor_gain	1.0000
19:7120619:CCACA:C	donor_gain	1.0000
19:7120746:AAGT:A	acceptor_gain	1.0000
19:7120748:GT:G	acceptor_gain	1.0000
19:7120749:TC:T	acceptor_loss	1.0000
19:7120750:C:CC	acceptor_gain	1.0000
19:7120750:CTG:C	acceptor_loss	1.0000
19:7120757:C:CT	acceptor_gain	1.0000
19:7122553:T:TA	donor_gain	1.0000

AlphaMissense

9081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:7117365:C:A	R1280S	1.000
19:7117365:C:G	R1280S	1.000
19:7117366:C:A	R1280M	1.000
19:7117366:C:G	R1280T	1.000
19:7117388:A:G	W1273R	1.000
19:7117388:A:T	W1273R	1.000
19:7119497:A:T	V1249D	1.000
19:7119517:A:C	N1242K	1.000
19:7119517:A:T	N1242K	1.000
19:7119524:A:G	L1240P	1.000
19:7119528:C:G	G1239R	1.000
19:7119534:A:C	Y1237D	1.000
19:7119536:G:C	P1236R	1.000
19:7119536:G:T	P1236H	1.000
19:7119537:G:A	P1236S	1.000
19:7119537:G:T	P1236T	1.000
19:7119560:T:A	E1228V	1.000
19:7119560:T:G	E1228A	1.000
19:7119561:C:T	E1228K	1.000
19:7119564:A:G	W1227R	1.000
19:7119564:A:T	W1227R	1.000
19:7119575:C:A	G1223V	1.000
19:7119575:C:T	G1223D	1.000
19:7119576:C:G	G1223R	1.000
19:7119583:C:A	W1220C	1.000
19:7119583:C:G	W1220C	1.000
19:7120621:A:G	W1220R	1.000
19:7120621:A:T	W1220R	1.000
19:7120626:T:A	D1218V	1.000
19:7120626:T:C	D1218G	1.000

dbSNP variants (sampled 300 via entrez): RS1000014468 (19:7233948 G>A), RS1000026985 (19:7249336 A>G), RS1000039008 (19:7156806 T>G), RS1000050380 (19:7222364 C>A,T), RS1000068782 (19:7155316 C>G), RS1000095421 (19:7137423 G>A,C), RS1000104283 (19:7265279 T>C), RS1000150413 (19:7180872 T>C), RS1000164259 (19:7262988 T>C), RS1000184891 (19:7205901 C>T), RS1000214266 (19:7225281 T>C), RS1000215687 (19:7190283 C>G,T), RS1000220530 (19:7253673 G>A), RS1000230205 (19:7260211 G>A), RS1000235634 (19:7243683 A>G,T)

Disease associations

OMIM: gene MIM:147670 | disease phenotypes: MIM:610549, MIM:262190, MIM:246200, MIM:609968, MIM:125853, MIM:255995

GenCC curated gene-disease

Disease	Classification	Inheritance
Donohue syndrome	Definitive	Autosomal recessive
insulin-resistance syndrome type A	Definitive	Autosomal dominant
hyperinsulinism due to INSR deficiency	Strong	Autosomal dominant
Rabson-Mendenhall syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Donohue syndrome	Definitive	AR

Mondo (10): insulin-resistance syndrome type A (MONDO:0012520), Rabson-Mendenhall syndrome (MONDO:0009874), Donohue syndrome (MONDO:0009517), hyperinsulinism due to INSR deficiency (MONDO:0012381), type 2 diabetes mellitus (MONDO:0005148), Bailey-Bloch congenital myopathy (MONDO:0009722), monogenic diabetes (MONDO:0015967), 46 XY differences of sex development (MONDO:0020040), esophageal atresia (MONDO:0001044), pyloric stenosis (MONDO:0001561)

Orphanet (7): Insulin-resistance syndrome type A (Orphanet:2297), Rabson-Mendenhall syndrome (Orphanet:769), Hyperinsulinism due to INSR deficiency (Orphanet:263458), Donohue syndrome (Orphanet:508), Native American myopathy (Orphanet:168572), Rare genetic diabetes mellitus (Orphanet:183625), 46,XY difference of sex development (Orphanet:98085)

HPO phenotypes

138 total (30 of 138 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000040	Long penis
HP:0000065	Labial hypertrophy
HP:0000105	Enlarged kidney
HP:0000121	Nephrocalcinosis
HP:0000138	Ovarian cyst
HP:0000141	Amenorrhea
HP:0000147	Polycystic ovaries
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000221	Furrowed tongue
HP:0000252	Microcephaly
HP:0000274	Small face
HP:0000280	Coarse facial features
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000403	Recurrent otitis media
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000445	Wide nose
HP:0000463	Anteverted nares

GWAS associations

144 associations (top):

Study	Trait	p-value
GCST000817_100	Height	2.000000e-12
GCST001017_16	Diabetic retinopathy	3.000000e-06
GCST001474_2	Hypothyroidism	5.000000e-06
GCST001634_10	Polycystic ovary syndrome	1.000000e-08
GCST001791_31	Urate levels	1.000000e-07
GCST001856_3	Thyroid hormone levels	2.000000e-06
GCST001856_40	Thyroid hormone levels	3.000000e-10
GCST002216_29	Triglycerides	5.000000e-10
GCST002647_160	Height	7.000000e-18
GCST003482_3	Asthma (childhood onset)	7.000000e-06
GCST003988_1	Hypothyroidism	1.000000e-07
GCST004067_115	Hip circumference adjusted for BMI	1.000000e-10
GCST004067_153	Hip circumference adjusted for BMI	7.000000e-06
GCST004067_46	Hip circumference adjusted for BMI	3.000000e-07
GCST004237_12	Triglyceride levels	6.000000e-10
GCST004279_28	Systolic blood pressure	3.000000e-08
GCST004776_71	Systolic blood pressure	3.000000e-06
GCST004777_56	Diastolic blood pressure	6.000000e-07
GCST004864_16	Perceived unattractiveness to mosquitoes	8.000000e-06
GCST006166_43	Diastolic blood pressure x alcohol consumption interaction (2df test)	4.000000e-29
GCST006167_71	Mean arterial pressure x alcohol consumption interaction (2df test)	2.000000e-11
GCST006187_43	Diastolic blood pressure (cigarette smoking interaction)	6.000000e-19
GCST006188_13	Systolic blood pressure (cigarette smoking interaction)	4.000000e-21
GCST006228_15	Systolic blood pressure	3.000000e-09
GCST006230_9	Pulse pressure	3.000000e-10
GCST006258_16	Diastolic blood pressure	2.000000e-22
GCST006259_22	Systolic blood pressure	1.000000e-18
GCST006434_71	Systolic blood pressure x alcohol consumption interaction (2df test)	2.000000e-34
GCST006479_97	Diverticular disease	2.000000e-06
GCST006611_59	HDL cholesterol	1.000000e-13

EFO canonical traits (25, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004730	hormone measurement
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0006527	smoking status measurement
EFO:0005763	pulse pressure measurement
EFO:0009959	diverticular disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004761	uric acid measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004344	birth weight
EFO:0008328	chronotype measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D058490	Disorder of Sex Development, 46,XY	C12.050.351.875.253.096; C12.200.706.316.096; C12.800.316.096; C16.131.939.316.096; C19.391.119.096
D056731	Donohue Syndrome	C05.660.207.325; C16.131.077.313; C16.320.215; C18.452.394.750.654; C19.246.537
D004933	Esophageal Atresia	C06.198.330; C06.405.117.260; C16.131.314.330
D017219	Gastric Outlet Obstruction	C06.405.748.340
D011707	Pyloric Stenosis	C06.405.748.340.690
C562710	Diabetes Mellitus, Insulin-Resistant, with Acanthosis Nigricans (supp.)
C566494	Hyperinsulinemic Hypoglycemia, Familial, 5 (supp.)
C538343	Native American myopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1981 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

36 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 313,531 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL3353410	OSIMERTINIB	4	8,898
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL554	LAPATINIB	4	69,326
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL1091644	LINSITINIB	3	1,446
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2
CHEMBL253969	OSI-632	2
CHEMBL475251	R-406	2
CHEMBL572878	TOZASERTIB	2
CHEMBL575448	BMS-754807	2
CHEMBL6246	ELLAGIC ACID	2
CHEMBL1084546	PF-00562271	1
CHEMBL1908397	KW-2449	1
CHEMBL1980391	RG-1530	1
CHEMBL3545085	XL-228	1

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs142244113	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia
rs2396185	Efficacy	3	topiramate
rs41412545	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2396185	INSR	3	0.00	1	topiramate
rs142244113	INSR	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil
rs41412545	INSR	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

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 (9 total), top 9:

Ligand	Action	Affinity	Parameter
GSK-1838705A	Inhibition	8.8	pIC50
ceritinib	Inhibition	8.15	pIC50
NVP-TAE 226	Inhibition	7.59	pIC50
BMS-536924	Inhibition	7.14	pIC50
linsitinib	Inhibition	7.12	pIC50
brigatinib	Inhibition	6.71	pIC50
compound 15 [PMID: 24900237]	Inhibition	6.22	pIC50
dovitinib	Inhibition	5.7	pIC50
myricetin	Inhibition	5.59	pKi

Binding affinities (BindingDB)

270 measured of 330 human assays (333 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
8-methyl-N-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.05 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-methoxy-4-(4-propan-2-ylpiperazin-1-yl)phenyl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.05 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-N-[1-(3-pyrrolidin-1-ylpropyl)pyrazol-3-yl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.08 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[3-(dimethylamino)propyl]-3-methoxy-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.08 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-methoxy-4-[4-(oxan-4-yl)piperazin-1-yl]phenyl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.08 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
2-[4-[3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]phenyl]piperazin-1-yl]ethanol	IC50	0.08 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-8-methyl-9-[4-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-4-yl]phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.09 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
9-[4-[1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazol-4-yl]phenyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.09 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.09 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N,N-dimethyl-2-[4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]pyrazol-1-yl]acetamide	IC50	0.1 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl]pyrazol-3-yl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.1 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-9-[[3-[1-(2-methoxyethyl)pyrazol-4-yl]phenyl]methyl]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.1 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-8-methyl-9-[4-[1-(2-piperazin-1-ylethyl)pyrazol-4-yl]phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.1 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.1 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-9-[4-[1-[2-(2-methoxyethylamino)ethyl]pyrazol-4-yl]phenyl]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.11 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-8-methyl-9-[4-[1-(2-pyrrolidin-1-ylethyl)pyrazol-4-yl]phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.11 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]-8-methyl-9-[4-(1-propan-2-ylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.12 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]-9-[4-[1-(2-methoxyethyl)pyrazol-4-yl]phenyl]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
9-[4-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]phenyl]-N-(1-ethylpyrazol-3-yl)-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
2-[4-[2-[4-[4-[2-[(1-ethylpyrazol-3-yl)amino]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-9-yl]phenyl]pyrazol-1-yl]ethyl]piperazin-1-yl]ethanol	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-9-[4-[1-[2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl]pyrazol-4-yl]phenyl]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-(dimethylamino)ethyl]-3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[3-(dimethylamino)propyl]-3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.13 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]-N-(1-methylpiperidin-4-yl)benzamide	IC50	0.14 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-[1-(2-methoxyethyl)piperidin-4-yl]-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.14 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]-N-(2-pyrrolidin-1-ylethyl)benzamide	IC50	0.14 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-methyl-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]-N-(1-methylpiperidin-4-yl)benzamide	IC50	0.14 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]-8-methyl-9-[4-(1-propylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.15 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-methyl-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.15 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-(dimethylamino)ethyl]-3-methoxy-N-methyl-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.15 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-[3-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]pyrazol-1-yl]propan-1-ol	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]-8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-4-yl)-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-(1-ethylpyrazol-3-yl)-8-methyl-9-[4-(1-piperidin-4-ylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
2-[4-[4-[2-[(1-ethylpyrazol-3-yl)amino]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-9-yl]phenyl]pyrazol-1-yl]ethanol	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
[3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]phenyl]-(4-methylpiperazin-1-yl)methanone	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-[1-(2-methoxyethyl)piperidin-4-yl]-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]-N-[(1-methylpiperidin-4-yl)methyl]benzamide	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[1-(2-methoxyethyl)piperidin-4-yl]pyrazol-4-yl]-8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.16 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
1-[4-[4-[[8-methyl-9-[4-(1-propan-2-ylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]pyrazol-1-yl]piperidin-1-yl]ethanone	IC50	0.17 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-N-[1-(2-morpholin-4-ylethyl)pyrazol-3-yl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.17 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
8-methyl-N-[1-[2-(4-methylpiperazin-1-yl)ethyl]pyrazol-3-yl]-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.17 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N,N-dimethyl-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.17 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[2-(dimethylamino)ethyl]-3-methoxy-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.17 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]-9-[4-(1-ethylpyrazol-4-yl)phenyl]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.18 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-methyl-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.18 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
N-[1-(2-methoxyethyl)pyrazol-3-yl]-8-methyl-9-[4-(1-propan-2-ylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-amine	IC50	0.19 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-N-(1-methylazetidin-3-yl)-4-[[8-methyl-9-[4-(1-methylpyrazol-4-yl)phenyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]benzamide	IC50	0.19 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
2-[4-[4-[2-[[1-[2-(dimethylamino)ethyl]pyrazol-3-yl]amino]-8-methyl-5,6-dihydropyrazolo[3,4-h]quinazolin-9-yl]phenyl]pyrazol-1-yl]ethanol	IC50	0.2 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors
3-methoxy-4-[[8-methyl-9-[[3-(1-methylpyrazol-4-yl)phenyl]methyl]-5,6-dihydropyrazolo[3,4-h]quinazolin-2-yl]amino]-N-(1-methylpiperidin-4-yl)benzamide	IC50	0.2 nM	US-9150578: 5,8-dihydro-6H-pyrazolo[3,4-h]quinazolines as IGF-1R/IR inhibitors

ChEMBL bioactivities

1033 potent at pChembl≥5 of 1085 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Kd	0.02	nM	CHEMBL4226003
9.40	IC50	0.4	nM	CHEMBL514873
9.10	IC50	0.8	nM	CHEMBL515519
9.06	IC50	0.88	nM	CHEMBL3824326
9.00	IC50	1	nM	CHEMBL5182271
8.89	Ki	1.3	nM	CHEMBL466397
8.80	IC50	1.6	nM	CHEMBL507625
8.77	IC50	1.7	nM	BMS-754807
8.77	Kd	1.7	nM	CHEMBL464552
8.74	IC50	1.8	nM	CHEMBL464552
8.74	IC50	1.8	nM	CHEMBL4081656
8.72	IC50	1.9	nM	TAE-684
8.72	IC50	1.9	nM	CHEMBL4078406
8.70	IC50	2	nM	CHEMBL3608524
8.68	IC50	2.1	nM	CHEMBL4092174
8.68	IC50	2.1	nM	CHEMBL5990800
8.67	IC50	2.16	nM	CHEMBL3824301
8.66	IC50	2.2	nM	CHEMBL4071384
8.66	Ki	2.2	nM	CHEMBL507714
8.64	IC50	2.3	nM	CHEMBL5907234
8.64	IC50	2.3	nM	CHEMBL4099660
8.62	Kd	2.4	nM	TAE-684
8.60	Ki	2.512	nM	CHEMBL2000271
8.60	Ki	2.512	nM	CHEMBL1981725
8.59	IC50	2.6	nM	CHEMBL4080869
8.59	IC50	2.6	nM	CHEMBL4084168
8.55	IC50	2.8	nM	CHEMBL4081925
8.52	IC50	3	nM	CHEMBL1760035
8.52	IC50	3	nM	CHEMBL370967
8.49	IC50	3.2	nM	CHEMBL4062466
8.47	IC50	3.4	nM	CHEMBL3824246
8.46	IC50	3.5	nM	CHEMBL4091928
8.46	IC50	3.5	nM	CHEMBL5764344
8.42	IC50	3.8	nM	CHEMBL4067503
8.41	IC50	3.9	nM	CHEMBL4089672
8.40	EC50	4.01	nM	CHEMBL4457859
8.40	IC50	4	nM	CHEMBL1086731
8.40	IC50	4	nM	CHEMBL1644798
8.33	IC50	4.7	nM	CHEMBL3823256
8.32	IC50	4.8	nM	CHEMBL4097392
8.30	IC50	5	nM	CHEMBL507714
8.30	Ki	5.012	nM	CHEMBL458997
8.29	IC50	5.1	nM	CHEMBL3608523
8.29	IC50	5.1	nM	CHEMBL3822475
8.28	IC50	5.2	nM	CHEMBL3608522
8.28	IC50	5.2	nM	CHEMBL1945931
8.24	IC50	5.7	nM	CHEMBL4070217
8.22	IC50	6.05	nM	CHEMBL3823016
8.22	IC50	6	nM	CHEMBL4099922
8.22	IC50	6	nM	CHEMBL4105099

PubChem BioAssay actives

784 with measured affinity, of 4394 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
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[2-[[(2R)-1-[(2S)-2-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-(carboxymethylamino)-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-sulfanylpropan-2-yl]amino]-2-oxoethyl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid	1388444: Displacement of [TyrA14-125I]-human insulin from human insulin receptor isoform A expressed in baby hamster kidney cells after 2 days by gamma counting method	kd	<0.0001	uM
3-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]thiophene-2-carboxamide	392352: Inhibition of IR	ic50	0.0004	uM
3-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]furan-2-carboxamide	392352: Inhibition of IR	ic50	0.0008	uM
1-[2-[[5-chloro-2-(4-dimethylphosphoryl-2-methoxyanilino)pyrimidin-4-yl]amino]phenyl]ethanone	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0009	uM
N-[1-[2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl]pyrazol-3-yl]-2,5-dimethyl-1-phenyl-4,5-dihydropyrazolo[4,3-f]quinazolin-7-amine	1845575: Inhibition of human InsR expressed in mouse IGF1R knockout MEF cells	ic50	0.0010	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	2166450: Inhibition of intracellular domain of GST-tagged IR (979 to 1382 residues) (unknown origin) expressed in baculovirus expression system using biotin-aminohexyl-AEEEEYMMMMAKKKK-NH2 as substrate pre incubated for 6 hrs followed by substrate addition and measured after 2 hrs in presence of [gamma-33P]-ATP by liquid scintillation counting method	ki	0.0013	uM
2-fluoro-6-[[2-[2-methoxy-4-(4-propan-2-ylpiperazin-1-yl)anilino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzamide	392240: Inhibition of IR	ic50	0.0016	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	1533344: Inhibition of IR (unknown origin)	ic50	0.0017	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	624784: Binding constant for INSR kinase domain	kd	0.0017	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0019	uM
5-chloro-2-N-(7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1243154: Inhibition of insulin receptor (unknown origin) by homogeneous time resolved fluorescence assay	ic50	0.0020	uM
5-chloro-2-N-(10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrazino[2,1-a]isoquinolin-9-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1449871: Inhibition of insulin receptor kinase (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0021	uM
1-[2-[[5-chloro-2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]amino]phenyl]ethanone	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0022	uM
10-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-9-methoxy-1,2,3,6,7,11b-hexahydropyrazino[2,1-a]isoquinolin-4-one	1449871: Inhibition of insulin receptor kinase (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0022	uM
N-(2,6-difluorophenyl)-3-[3-[2-[2-methoxy-4-[4-(4-methylsulfonylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]imidazo[1,2-a]pyridin-2-yl]benzamide	371631: Binding affinity to insulin receptor by liquid scintillation counting	ki	0.0022	uM
9-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-10-methoxy-1,2,3,6,7,11b-hexahydropyrazino[2,1-a]isoquinolin-4-one	1449871: Inhibition of insulin receptor kinase (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0028	uM
4-N-quinolin-3-yl-2-N-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine	591158: Inhibition of INSR	ic50	0.0030	uM
N,N-dimethyl-4-[(E)-2-(3-methyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]aniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0030	uM
2-[[5-chloro-2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]amino]benzamide	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0034	uM
(4S)-4-[[2-[[(1R,6S,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,42S,47R,50S,53S,56S,59S,62S,65S,68S,71S,74S,77S,80S,83S,88R)-88-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[(2-aminoacetyl)amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]-6-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-47-[[(1S)-3-amino-1-carboxy-3-oxopropyl]carbamoyl]-53-(2-amino-2-oxoethyl)-62-(3-amino-3-oxopropyl)-77-[(2S)-butan-2-yl]-24,56-bis(2-carboxyethyl)-83-[(1R)-1-hydroxyethyl]-12,71,80-tris(hydroxymethyl)-33,50,65-tris[(4-hydroxyphenyl)methyl]-15-(1H-imidazol-5-ylmethyl)-27-methyl-18,30,36,59,68-pentakis(2-methylpropyl)-7,10,13,16,19,22,25,28,31,34,37,40,49,52,55,58,61,64,67,70,73,76,79,82,85,87-hexacosaoxo-21,39-di(propan-2-yl)-3,4,44,45,90,92-hexathia-8,11,14,17,20,23,26,29,32,35,38,41,48,51,54,57,60,63,66,69,72,75,78,81,84,86-hexacosazabicyclo[72.11.8]trinonacontane-42-carbonyl]amino]acetyl]amino]-5-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[(2S)-2-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1528347: Agonist activity at human IR-beta signalling expressed in mouse 3T3 cells assessed as AKT phosphorylation at Ser473 residue after 30 mins by HTRF assay	ec50	0.0040	uM
N-[3-[[1-(6-aminopyrimidin-4-yl)benzimidazol-2-yl]amino]-4-methylphenyl]-5-tert-butylthiophene-2-carboxamide	469077: Inhibition of Tel-fused InsR expressed in mouse BAF3 cells	ic50	0.0040	uM
2-[[5-chloro-2-[(1-methyl-2-oxo-4,5-dihydro-3H-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]benzamide	552873: Inhibition of IR kinase	ic50	0.0040	uM
5-chloro-2-N-(4-dimethylphosphoryl-2-methoxyphenyl)-4-N-(2-methylsulfonylphenyl)pyrimidine-2,4-diamine	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0047	uM
5-chloro-2-N-(7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1243154: Inhibition of insulin receptor (unknown origin) by homogeneous time resolved fluorescence assay	ic50	0.0051	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-methylsulfonylphenyl)pyrimidine-2,4-diamine	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0051	uM
5-chloro-2-N-(8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1243154: Inhibition of insulin receptor (unknown origin) by homogeneous time resolved fluorescence assay	ic50	0.0052	uM
4-[(E)-2-(5-chloro-3-methyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0052	uM
2-[[5-chloro-2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]amino]-N,N-dimethylbenzamide	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0060	uM
5-chloro-2-N-(9-methoxy-3-methyl-1,2,5,6-tetrahydro-[1,2,4]triazino[4,3-a]quinolin-8-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1449871: Inhibition of insulin receptor kinase (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0060	uM
4-[(E)-2-(3,6-dimethyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0060	uM
4-[(E)-2-(3-ethyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0060	uM
2-[[2-[2-methyl-4-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)anilino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]benzamide	417119: Inhibition of human IR	ic50	0.0063	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148593: Binding affinity to human INSR incubated for 45 mins by Kinobead based pull down assay	kd	0.0065	uM
N-(2,6-difluorophenyl)-3-[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]benzamide	371613: Inhibition of GST-tagged insulin receptor expressed in baculovirus by time-resolved fluorescence assay	ic50	0.0070	uM
Ceritinib	758017: Inhibition of insulin receptor (unknown origin) after 60 mins	ic50	0.0070	uM
1-[7-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-8-methoxy-1-methyl-4,5-dihydrobenzo[e]indazol-2-yl]-2-hydroxyethanone	1449871: Inhibition of insulin receptor kinase (unknown origin) using TK as substrate after 30 mins by HTRF assay	ic50	0.0075	uM
4-[(E)-2-(3,5-dimethyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0075	uM
N-[5-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide	1584372: Inhibition of recombinant His-tagged human InsR (1011 to 1382 residues) expressed in baculovirus expression system by Z-LYTE assay	ic50	0.0080	uM
4-[(E)-2-(6-methoxy-3-methyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0080	uM
2-[[5-chloro-2-[(1-methyl-2-oxo-4,5-dihydro-3H-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]-N-prop-2-ynylbenzamide	552873: Inhibition of IR kinase	ic50	0.0080	uM
2-[[5-chloro-2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-4-yl]amino]-N,N-dimethylbenzenesulfonamide	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0084	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	350275: Inhibition of IR	ic50	0.0085	uM
N-[5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide	1167161: Inhibition of INSR (unknown origin)	ic50	0.0090	uM
1-[4-[4-[(5-chloro-4-imidazo[1,2-a]pyridin-3-ylpyrimidin-2-yl)amino]-3-methoxyphenyl]piperazin-1-yl]ethanone	609521: Inhibition of insulin receptor	ic50	0.0090	uM
5-chloro-2-N-(4-dimethylphosphoryl-2-methoxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1310803: Inhibition of human InsR using myelin basic protein as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0099	uM
4-[(6-methoxy-3-methyl-1,3-benzothiazol-3-ium-2-yl)diazenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0100	uM
2-[[5-chloro-2-[(1-methyl-2-oxo-4,5-dihydro-3H-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	668753: Inhibition of insulin receptor	ic50	0.0100	uM
N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide	662109: Inhibition of IRK	ic50	0.0100	uM
4-[(E)-2-(5-fluoro-3-methyl-1,3-benzothiazol-3-ium-2-yl)ethenyl]-N,N-dimethylaniline	644391: Displacement of thioflavin T from insulin receptor by thioflavin-T fluorescent dye assay	ic50	0.0100	uM
8-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-7-methoxy-1,2,3,5-tetrahydro-3-benzazepin-4-one	1243154: Inhibition of insulin receptor (unknown origin) by homogeneous time resolved fluorescence assay	ic50	0.0110	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases phosphorylation, decreases phosphorylation, affects methylation, decreases reaction	6
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	5
bisphenol A	decreases reaction, increases phosphorylation, decreases expression, decreases methylation	4
Rosiglitazone	decreases reaction, increases phosphorylation, decreases phosphorylation	3
Arsenic	affects expression, increases expression, affects cotreatment, increases abundance	3
Glucose	decreases degradation, increases expression, affects reaction, decreases expression, decreases reaction (+1 more)	3
pyrazolanthrone	decreases reaction, increases phosphorylation, decreases expression	2
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	decreases reaction, affects cotreatment, increases phosphorylation, decreases phosphorylation	2
Resveratrol	increases phosphorylation, decreases phosphorylation, decreases reaction	2
Acetaminophen	decreases expression	2
Copper	affects binding, increases expression, affects cotreatment, increases abundance	2
Metformin	affects cotreatment, decreases expression, increases phosphorylation	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, increases methylation	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
fumosorinone	increases phosphorylation	1
tributyltin	affects methylation	1
quercitrin	affects expression	1
benzo(e)pyrene	affects methylation, decreases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
AICA ribonucleotide	decreases activity, decreases reaction, decreases expression	1
3,3’,4,5’-tetrahydroxystilbene	decreases activity	1
arsenic trichloride	increases expression, affects cotreatment, increases abundance	1
fenugreek seed meal	increases phosphorylation	1
5’-amino-5’-deoxyadenosine	decreases activity, decreases reaction, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

954 unique, capped per target: 900 binding, 49 functional, 4 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000177	Binding	Binding affinity to insulin receptor	Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists. — J Med Chem
CHEMBL1963759	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: INSR	PubChem BioAssay data set
CHEMBL4407587	ADMET	Inhibition of recombinant human GST-tagged INSR cytoplasmic domain (1011 to 1382 residues) expressed in baculovirus expression system at 25 uM using FRET-labeled Tyr 01 peptide as substrate measured after 1 hr by Z’-lyte assay relative to c	Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. — J Med Chem

Cellosaurus cell lines

38 cell lines: 20 spontaneously immortalized cell line, 9 finite cell line, 4 cancer cell line, 4 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0300	HIRcB	Spontaneously immortalized cell line	Male
CVCL_9701	CHO.T	Spontaneously immortalized cell line	Female
CVCL_9W99	GM05241	Finite cell line	Female
CVCL_9X15	GM10267	Transformed cell line	Female
CVCL_9X16	GM10277	Finite cell line	Female
CVCL_9Y49	GM20031	Finite cell line	Male
CVCL_9Y50	GM20032	Finite cell line	Female
CVCL_9Y51	GM20033	Finite cell line	Male
CVCL_9Y52	GM20034	Finite cell line	Male
CVCL_9Y53	GM20035	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus