Capmatinib

Protein target name:

MET

Mechanism of action:

Inhibitor, ATP competitive

Recommended Concentration for use in cells:

up to 100 nM

Probe Availability

MedChemExpress

Selleck Chemcals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:7029

Entrez gene ID:

4233

UNIPROT ID:

P08581

Target alias:

HGFR; AUTS9; RCCP2; c-Met; DFNB97

Probe Details

Chemical Probes Portal ID:

CPP2065

Probe alias:

INC280, INCB28060

PubChem CID:

25145656

ChEMBL ID:

CHEMBL3188267

SMILES string:

O=C(NC)C1=CC=C(C2=NN3C(N=C2)=NC=C3CC4=CC=C5N=CC=CC5=C4)C=C1F

InChi Key:

LIOLIMKSCNQPLV-UHFFFAOYSA-N

Orthogonal probe:

MK-8033AMG 337SGX-523

PAINs evaluation:

PAINS-Free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50, KD

0.13 nM, 0.31 nM (KD)

Potency assay:

Cell-Free Assay

Off target activity

Probe Selectivity in Vitro:

inactive against RONβ; profiled against a panel of 57 human kinases representing a structurally diverse cross-section of all known human kinases: no more than 30% inhibition; screened at 2000 fold IC90

In cell validation

On target activity in cells

Potency in cells:

IC50

0.3-1.1 nM

Potency assay (cells):

Western blot of phospho c-MET and downstream targets ERK1/2, AKT, FAK, GAB1, STAT3/5; ELISA-based detections of phospho-c-MET in cell protein extracts

In vivo validation

Organism:

Mouse

Dose:

0.03, 0.1, 0.3, 1, 3, or 10 mg/kgReviewer suggested: 3, 10, and 30 mg/kg BID

Route of delivery:

Oral

Primary Reference

Reference (doi):

10.1158/1078-0432.CCR-11-1157 10.1158/1078-0432.CCR-18-2814

Reference (PMID):

21918175 30674502

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

INCB28060 / capmatinib is a potent c-MET inhibitor, which shows excellent selectivity in a broad panel of 442 kinases. Sub nM-activity is observed at wt and mutant (M1250T, Y1235D) c-Met, with most-active off targets being IRAK1 (500nM) and AXL (1100nM). Capmatibib resistance is observed in clinically-relevant mutants D1228 and Y1230, observed in lung cancer. The molecule has physchem properties supporting good cell permeability, and shows potent inhibition of c-MET signalling in a range of cell lines. Capmatinib was tested against >600 cancer cell lines, (only) 13 cell lines were sensitive, these all showed MET gene amplification or high expression of HGF (Met ligand). In Vivo, a concentration-dependent effect on phospho c-Met is observed, although detailed pharmacokinetic data is not provided, and anti-tumour effects are observed in several MET amplified, overexpressed or mutated models.

Dec 3 2020 - 10:22am

Capmatinib (INC280) is an exceptionally potent and kinome-selective inhibitor of c-Met. The on-target potency is sub-nM. Using both a limited panel of 57 kinases and the larger 442 kinases KINOMEscan panels, no off-target kinases within >1000-fold potency (Kd or IC50) were identified. The kinome selectivity is consistent with its narrow spectrum of anti-proliferative activities in a large cell line panel screen (>600 cell lines), where the sensitive cell lines are characterized by MET amplification, MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand HGF. The compound has acceptable PK and has demonstrated dose- and time-dependent inhibition of phospho-c-MET in vivo. Tumour growth inhibition and even regression has been achieved when dosed orally at 1 mg/kg up to 30 mg/kg BID. When using this compound in vitro, please note that c-MET signalling is potently inhibited in the nM range, however, very few cell lines (e.g., EBC-1, MKN45, SNU-5) critically depend on c-MET for proliferation. For others, growth inhibition curves are often shallow and do not reach 100%.

Dec 14 2020 - 8:51am

Capmatinib

Probe Availability

Probe Information

Target Details

HGFR; AUTS9; RCCP2; c-Met; DFNB97

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Capmatinib

Probe Availability

Probe Information

Target Details

HGFR; AUTS9; RCCP2; c-Met; DFNB97

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?