Linsitinib

Protein target name:

IGF1R, INSR, INSRR

Mechanism of action:

Inhibitor

Reviewer suggested Concentration for use in cells:

100 - 1000 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:6091 HGNC:5465 HGNC:6093

Entrez gene ID:

3480 3643 3645

UNIPROT ID:

P08069 P06213 P14616

Target alias:

insulin like growth factor 1 receptor, CD221, IGFIR, IGFR, JTK13, insulin receptor, CD220, HHF5, insulin receptor related receptor,

Probe Details

Chemical Probes Portal ID:

CPP1628

Probe alias:

OSI-906, OSI906, OSI 906

PubChem CID:

11640390

ChEMBL ID:

CHEMBL1091644

SMILES string:

O[C@@]1(C)C[C@@H](C2=NC(C3=CC=C4C=CC(C5=CC=CC=C5)=NC4=C3)=C6C(N)=NC=CN62)C1

InChi Key:

PKCDDUHJAFVJJB-UHFFFAOYSA-N

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

IGF1R: 35 nM; INSR: 75 nM; INSRR: 75 nM

Potency assay:

In-house ELISA assays (IGF1R), R&D systems commercial assays (INSR and INSRR)

Structure-activity relationship:

Yes, see Future Chem paper

Off target activity

Potency assay (off target):

Linsitinib was tested against 88 kinases (Kinase Profiler, Upstate Inc) and 42 receptor tyrosine kinases (RTK, R&D systems). At 1 uM, none of the 88 kinases was inhibited >50%. In the RTK panel, 40 of the 42 kinases had IC50s >10 uM (INSR and INSRR, with IC50s ~75 nM, are listed as targets above).

Probe Selectivity in Vitro:

Negligible inhibition of CYP3A4, CYP2D6 and CYP1A2 (IC50 > 10 uM)

In cell validation

On target activity in cells

Potency in cells:

IC50

IGF1R: 24 nM; INSR: 39 nM

Potency assay (cells):

In LISN cells, inhibition of IGF-1-dependent IGF1R autophosphorylation; in Hepa1 cells, inhibition of INSR autophosphorylation - both assay quantifed via ELISA.

Target engagement assay (cells):

Indirect, dose-dependent inhibition of autophosphorylation.

In vivo validation

Organism:

CD-1 female mouse, Sprague Dawley female rat

Dose:

5 mg/kg50-75 mg/Kg Oral (Reviewer Suggested)

Route of delivery:

OralIntravenous

Plasma half life:

2.14 h (mouse, IV), 2.64 h (rat, IV)

Systemic clearance:

12 mL/min/kg (mouse, IV), 4 mL/min/kg (rat, IV)

Cmax:

3.42 uM (mouse, oral)

Organ of Interest

Organ (O):

LISN xenograft

Target engagement assay:

In xenografts, linsitinib dose-dependently inhibited IGF1R autophosphorylation (IC50=1.28 uM).

Primary Reference

Reference (doi):

10.4155/fmc.09.89

Reference (PMID):

21425998

External Resources

Available data:

GDSC1 GDSC2

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This is the best available probe for INSRR and IRR. A panel of 88 kinases was profiled when selectivity was assessed.

Aug 3 2017 - 3:34pm

Linsitinib (OSI-906) has excellent kinase selectivity, and is quite potent against the indicated kinases that it does inhibit. It shows very good in vivo activity, and is orally bioavailable. Together, these properties make linsitinib a high-quality probe for INSR and IGF-1R activity in cells and in vivo.

Nov 10 2020 - 12:16pm

This is a dual selective IGF1R & INSR (and related INSRR) kinase inhibitor with demonstrated kinase selectivity an cell-based assay activity with oral bioavailability.

Nov 16 2020 - 8:46pm

Linsitinib

Probe Availability

Probe Information

Target Details

insulin like growth factor 1 receptor, CD221, IGFIR, IGFR, JTK13, insulin receptor, CD220, HHF5, insulin receptor related receptor,

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

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Linsitinib

Probe Availability

Probe Information

Target Details

insulin like growth factor 1 receptor, CD221, IGFIR, IGFR, JTK13, insulin receptor, CD220, HHF5, insulin receptor related receptor,

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?