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Linsitinib

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Also known as ASP-7487OSI-906OSI-906AAOSI906OSI 906LINSITINIB (OSI-906)MMV676605OSI-906 (LINSITINIB)C0237134

Summary

Linsitinib (CHEMBL1091644) is a phase-3 clinical-stage small-molecule insulin-like growth factor receptor 1 antagonist targeting INSR, IGF1R, and INSRR; indicated across 15 conditions including adrenal cortex carcinoma and neoplasm; with CIViC clinical evidence for 8 variant-indication associations (e.g. MYB::NFIB Fusion in doid:0080202).

At a glance

  • Status: Max clinical phase 3 (not approved)
  • Modality: Small molecule
  • Targets: 3 (INSR, IGF1R, INSRR)
  • Indications: 15 conditions
  • Clinical trials: 24
  • Precision-oncology evidence (CIViC): 8 variant–indication associations
  • Chemistry: 421.5 Da · C26H23N5O

Identifiers

Drug identity and classification

FieldValue
ChEMBL IDCHEMBL1091644
NameLinsitinib
TypeSmall molecule
Max phase3
FDA approvedno
PubChem CID11640390
ChEBICHEBI:91402
Molecular formulaC26H23N5O
Molecular weight421.5
InChIKeyPKCDDUHJAFVJJB-UHFFFAOYSA-N

SMILES: CC1(CC(C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=C4)C=CC(=N5)C6=CC=CC=C6)O

IUPAC name: 3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol

ChEBI definition: An imidazopyrazine that is imidazo[1,5-a]pyrazine substituted by 2-phenylquinolin-7-yl, cis-3-hydroxy-3-methylcyclobutyl, and amino groups at positions 1, 3, and 8, respectively. It is dual inhibitor of the IGF-1 receptor and insulin receptor (IC50 = 35 and 75 nM, respectively) that was previously in clinical development for the treatment of cancer and thyroid eye disease.

Pharmacological roles (ChEBI): insulin-like growth factor receptor 1 antagonist, antimycobacterial drug, antineoplastic agent, apoptosis inducer.

Also known as: ASP-7487, Linsitinib, OSI-906, OSI-906AA, LINSITINIB, OSI906, OSI 906, LINSITINIB (OSI-906), MMV676605, OSI-906 (LINSITINIB), linsitinib, OSI-906 (Linsitinib)

Patent coverage: 572 distinct patent families (1,446 SureChEMBL compound mentions), from 1 matched compound structure(s). Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

GeneTargetActionpAffinityCancer dependencyUniProt
INSRInsulin receptorInhibition7.120.8%P06213
IGF1RInsulin-like growth factor I receptorInhibition7.4619%P08069
INSRRInsulin receptor-related receptorInhibition7.120.4%P14616

Broader ChEMBL bioactivity targets: 23 (assay-derived). Sample: Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma, Receptor-interacting serine/threonine-protein kinase 3, Mitogen-activated protein kinase; ERK1/ERK2, Insulin-like growth factor 1 receptor, Receptor-type tyrosine-protein kinase FLT3, Insulin receptor, Aurora kinase B, Dual specificity mitogen-activated protein kinase kinase 2, Dual specificity mitogen-activated protein kinase kinase 1, Hepatocyte growth factor receptor.

Bioactivity

ChEMBL activities: 53 potent at pChembl ≥ 5 of 54 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

TargetpChemblTypeValueUnitActivity ID
IGF1R8.7IC502nMCHEMBL_ACT_15189356
IGF1R8.55IC502.8nMCHEMBL_ACT_16539598
IGF1R8.12IC507.6nMCHEMBL_ACT_16539621
MAPK118Kd10nMCHEMBL_ACT_17915182
IGF1R7.92IC5012nMCHEMBL_ACT_13393290
IGF1R7.89IC5013nMCHEMBL_ACT_13393287
IGF1R7.85IC5014nMCHEMBL_ACT_16539575
INSR7.8IC5016nMCHEMBL_ACT_16540673
INSR7.75IC5018nMCHEMBL_ACT_14652576
IGF1R7.75IC5018nMCHEMBL_ACT_3240784
IGF1R7.68IC5021nMCHEMBL_ACT_24953740
INSR7.68IC5021nMCHEMBL_ACT_24953741
INSRR7.68IC5021nMCHEMBL_ACT_24953742
IGF1R7.62IC5024nMCHEMBL_ACT_13393269
IGF1R7.62IC5024nMCHEMBL_ACT_24953964
IGF1R7.62IC5024nMCHEMBL_ACT_26240366
IGF1R7.62IC5024nMCHEMBL_ACT_26240428
IGF1R7.62IC5024nMCHEMBL_ACT_5197012
MAPK37.55IC5028nMCHEMBL_ACT_26240429
INSR7.47IC5034nMCHEMBL_ACT_16540666
IGF1R7.46IC5035nMCHEMBL_ACT_24954200
IGF1R7.46IC5035nMCHEMBL_ACT_24974948
IGF1R7.46IC5035nMCHEMBL_ACT_25036517
IGF1R7.46IC5035nMCHEMBL_ACT_26240421
IGF1R7.46IC5035nMCHEMBL_ACT_29186998
IGF1R7.41IC5039nMCHEMBL_ACT_26240565
MAP4K27.17Kd67nMCHEMBL_ACT_17913673
INSR7.12IC5075nMCHEMBL_ACT_24954201
INSRR7.12IC5075nMCHEMBL_ACT_24954202
INSR7.12IC5075nMCHEMBL_ACT_24974949

Target pathways

Aggregated over 3 target gene(s): INSR, IGF1R, INSRR.

Top Reactome pathways

16 total, by targets touching each:

PathwayTargetsGenes
PIP3 activates AKT signaling1INSR
Signal Transduction1INSR
Negative regulation of the PI3K/AKT network1INSR
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)1IGF1R
IRS-related events triggered by IGF1R1IGF1R
SHC-related events triggered by IGF1R1IGF1R
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling1INSR
IRS activation1INSR
Signal attenuation1INSR
Insulin receptor signalling cascade1INSR
Signaling by Insulin receptor1INSR
Insulin receptor recycling1INSR
Intracellular signaling by second messengers1INSR
Signaling by Receptor Tyrosine Kinases1INSR
Extra-nuclear estrogen signaling1IGF1R
Respiratory syncytial virus (RSV) attachment and entry1IGF1R

Dominant GO biological processes

GO termTargets
insulin receptor signaling pathway3
protein autophosphorylation3
protein phosphorylation3
cell surface receptor protein tyrosine kinase signaling pathway3
positive regulation of cell population proliferation2
male sex determination2
positive regulation of cell migration2
positive regulation of protein-containing complex disassembly2
positive regulation of MAPK cascade2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction2
dendritic spine maintenance2
amyloid-beta clearance2
positive regulation of receptor internalization1
heart morphogenesis1
regulation of DNA-templated transcription1

Indications & clinical

Indications

15 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

IndicationTrial phaseMONDOEFO
adrenal cortex carcinoma3MONDO:0006639EFO:1000796
neoplasm2MONDO:0005070EFO:0000616
small cell lung carcinoma2MONDO:0008433EFO:0000702
hepatocellular carcinoma2MONDO:0007256EFO:0000182
prostate adenocarcinoma2MONDO:0005082EFO:0000673
Ewing sarcoma2MONDO:0012817EFO:0000174
non-small cell lung carcinoma2MONDO:0005233EFO:0003060
head and neck cancer2MONDO:0005627EFO:0006859
breast neoplasm2MONDO:0021100MONDO:0007254
head and neck squamous cell carcinoma1MONDO:0010150EFO:0000181
ovarian cancer1MONDO:0008170MONDO:0008170
skin neoplasm1MONDO:0002531MONDO:0002898
squamous cell carcinoma1MONDO:0005096EFO:0000707
colorectal neoplasm1MONDO:0005335MONDO:0005575

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 24.

Phase distribution

PhaseTrials
PHASE211
PHASE17
PHASE1/PHASE23
PHASE2/PHASE32
PHASE31

Top trials by phase / activity

NCTPhaseStatusTitle
NCT05276063PHASE2/PHASE3ACTIVE_NOT_RECRUITINGA Phase 2b, Study of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT06112340PHASE2/PHASE3RECRUITINGExtension Study of Two Doses of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED)
NCT00924989PHASE3COMPLETEDA Study of OSI-906 in Patients With Locally Advanced or Metastatic Adrenocortical Carcinoma
NCT00889382PHASE1/PHASE2COMPLETEDA Study Evaluating Intermittent and Continuous OSI-906 and Weekly Paclitaxel in Patients With Recurrent Epithelial Ovarian Cancer (and Other Solid Tumors)
NCT01101906PHASE2TERMINATEDA Randomized, Placebo-controlled, Double-blind Phase 2 Study With OSI-906 in Patients With Advanced HCC
NCT01186861PHASE2COMPLETEDPhase 2 Study of Maintenance OSI-906 Plus Erlotinib (Tarceva®), or Placebo Plus Erlotinib in Patients With Nonprogression Following 4 Cycles of Platinum-based Chemotherapy
NCT01205685PHASE2TERMINATEDEndocrine Therapy + OSI-906 With or Without Erlotinib for Hormone-Sensitive Metastatic Breast Cancer
NCT01221077PHASE2COMPLETEDStudy of Erlotinib (Tarceva®) in Combination With OSI-906 in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) With Activating Mutations of the Epidermal Growth Factor Receptor (EGFR) Gene
NCT01334710PHASE2TERMINATEDA Phase II Trial of OSI-906 and Sorafenib in Advanced Hepatocellular Cancer
NCT01427205PHASE2WITHDRAWNPhase II Study of Cetuximab With or Without OSI-906 in Head and Neck Squamous Cell Carcinoma (HNSCC)
NCT01465815PHASE1/PHASE2WITHDRAWNPhase I/II Study of Postoperative Adjuvant Chemoradiation for Advanced-Stage Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN)
NCT01533181PHASE2COMPLETEDLinsitinib or Topotecan Hydrochloride in Treating Patients With Relapsed Small Cell Lung Cancer
NCT01533246PHASE2COMPLETEDLinsitinib in Treating Patients With Asymptomatic or Mildly Symptomatic Metastatic Prostate Cancer
NCT01560260PHASE2COMPLETEDLinsitinib in Treating Patients With Gastrointestinal Stromal Tumors
NCT01600807PHASE1/PHASE2WITHDRAWNOSI-906 With Gemcitabine and Erlotinib for Metastatic Ductal Adenocarcinoma of the Pancreas
NCT02057380PHASE2COMPLETEDA Rollover Study for Subjects That Have Participated in an Astellas Sponsored Linsitinib Trial
NCT02546544PHASE2COMPLETEDEurosarc Trial of Linsitinib in Advanced Ewing Sarcoma
NCT00514007PHASE1COMPLETEDStudy of Continuous OSI-906 Dosing
NCT00514306PHASE1COMPLETEDStudy of Intermittent OSI-906 Dosing
NCT00739453PHASE1COMPLETEDA Phase 1 Dose-escalation Study of OSI-906 and Erlotinib (Tarceva®)
NCT01016860PHASE1TERMINATEDOSI-906 and Irinotecan in Patients With Advanced Cancer
NCT01154335PHASE1COMPLETEDEverolimus and OSI-906 for Patients With Refractory Metastatic Colorectal Cancer
NCT01529684PHASE1COMPLETEDA Study to Look at How a Single Oral Dose of 14C-OSI-906 is Absorbed, Broken Down and Eliminated in the Body
NCT01567384PHASE1WITHDRAWNA Phase I Study of OSI-906 in Combination With Pemetrexed in Advanced Solid Tumor Malignancies

Clinical evidence (CIViC)

Variant × indication × effect (8 predictive associations from 8 curated evidence items):

VariantIndicationEffectTherapyLevelCIViC
MYB::NFIB FusionDOID:0080202Sensitivity/ResponseGefitinib + Crizotinib + LinsitinibCIViC BEID12167
CDKN2A LossEwing SarcomaSensitivity/ResponseLinsitinib + PalbociclibCIViC DEID1879
CDKN2B LossEwing SarcomaSensitivity/ResponsePalbociclib + LinsitinibCIViC DEID1880
IGF1R OverexpressionSalivary Gland Adenoid Cystic CarcinomaSensitivity/ResponseCrizotinib + Gefitinib + LinsitinibCIViC DEID9024
IGF2 OverexpressionProstate CancerSensitivity/ResponseCabazitaxel + LinsitinibCIViC DEID12428
IGF2 OverexpressionProstate CancerSensitivity/ResponseLinsitinibCIViC DEID412
IGF2 OverexpressionProstate CancerSensitivity/ResponseDocetaxel + Cabazitaxel + LinsitinibCIViC DEID414
MYB::NFIB FusionDOID:0080202Sensitivity/ResponseLinsitinibCIViC DEID12164

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

52 molecules share ≥1 primary target. Top 52 by shared-target count:

MoleculeSourceStatusShared targets
BRIGATINIBChEMBL + PubChemPhase 4 (approved)IGF1R, INSR, INSRR
CRIZOTINIBChEMBL + PubChemPhase 4 (approved)IGF1R, INSR, INSRR
FEDRATINIBChEMBL + PubChemPhase 4 (approved)IGF1R, INSR, INSRR
PazopanibChEMBL + PubChemPhase 4 (approved)IGF1R, INSR, INSRR
SUNITINIBChEMBL + PubChemPhase 4 (approved)IGF1R, INSR, INSRR
NINTEDANIBChEMBLPhase 4 (approved)IGF1R, INSR, INSRR
LESTAURTINIBChEMBLPhase 3IGF1R, INSR, INSRR
BMS-754807ChEMBLPhase 2IGF1R, INSR, INSRR
FORETINIBChEMBLPhase 2IGF1R, INSR, INSRR
R-406ChEMBLPhase 2IGF1R, INSR, INSRR
TOZASERTIBChEMBLPhase 2IGF1R, INSR, INSRR
AfatinibPubChemApprovedIGF1R, INSR, INSRR
GefitinibPubChemApprovedIGF1R, INSR, INSRR
IdelalisibPubChemApprovedIGF1R, INSR, INSRR
SelumetinibPubChemApprovedIGF1R, INSR, INSRR
LAPATINIBChEMBL + PubChemPhase 4 (approved)INSR, INSRR
NERATINIBChEMBL + PubChemPhase 4 (approved)INSR, INSRR
SORAFENIBChEMBL + PubChemPhase 4 (approved)INSR, INSRR
CERITINIBChEMBLPhase 4 (approved)IGF1R, INSR
ENTRECTINIBChEMBLPhase 4 (approved)IGF1R, INSR
LINIFANIBChEMBLPhase 3INSR, INSRR
CENISERTIBChEMBLPhase 2IGF1R, INSR
ELLAGIC ACIDChEMBLPhase 2IGF1R, INSR
ILORASERTIBChEMBLPhase 2IGF1R, INSR
SU-014813ChEMBLPhase 2INSR, INSRR
belumosudilPubChemApprovedIGF1R, INSR
BinimetinibPubChemApprovedIGF1R, INSR
dacomitinibPubChemApprovedIGF1R, INSR
FostamatinibPubChemApprovedIGF1R, INSR
regorafenibPubChemApprovedIGF1R, INSR
TrametinibPubChemApprovedIGF1R, INSR
INFIGRATINIBChEMBLPhase 4 (approved)INSR
OSIMERTINIBChEMBLPhase 4 (approved)INSR
DOVITINIBChEMBLPhase 3INSR
QUERCETINChEMBLPhase 3IGF1R
OSI-632ChEMBLPhase 2INSR
AbemaciclibPubChemApprovedINSRR
AcalabrutinibPubChemApprovedINSRR
AxitinibPubChemApprovedINSRR
BelzutifanPubChemApprovedINSR
BosutinibPubChemApprovedINSRR
DuvelisibPubChemApprovedINSRR
ErlotinibPubChemApprovedINSRR
ImatinibPubChemApprovedINSRR
MidostaurinPubChemApprovedINSRR
NilotinibPubChemApprovedINSRR
QuizartinibPubChemApprovedINSRR
RuxolitinibPubChemApprovedINSRR
SirolimusPubChemApprovedINSRR
TivozanibPubChemApprovedINSRR
TofacitinibPubChemApprovedINSRR
VandetanibPubChemApprovedINSRR

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
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Sources 30

This page pulls from 30 datasets indexed by BioBTree:

chebichembl_activitychembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsdepmapefoensemblentrezgogoparentgtopdbgtopdb_interactiongtopdb_ligandhgncmeshmondomsigdbpatent_compoundpharmgkbpharmgkb_guidelinepubchempubchem_activityreactomereactomeparentrefseqtranscriptuniprot