Bafetinib

Reagent Authentication Certificate:

Chemical Probes Portal Bafetinib.pdf

Protein target name:

BCR-ABL, LYN

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

10 nM - 1 uM

Probe Availability

MedChem Express (859212-16-1)

Cayman (859212-16-1)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

HUGO ID:

HGNC:76 HGNC:6735

Entrez gene ID:

25 4067

UNIPROT ID:

P00519 P07948

Target alias:

ABL, JTK7, c-ABL, c-ABL1, p150, v-abl, JTK8, p53Lyn, p56Lyn

Probe Details

Chemical Probes Portal ID:

CPP130

Probe alias:

Lyn-IN-1, INNO-406, NS-187

PubChem CID:

24853523

ChEMBL ID:

CHEMBL206834

SMILES string:

O=C(C1=CC=C(C(C(F)(F)F)=C1)CN2C[C@@H](N(C)C)CC2)NC3=CC=C(C)C(NC4=NC=CC(C5=CN=CN=C5)=N4)=C3

InChi Key:

ZOPBZHLJXQAQON-VWLOTQADSA-N

Orthogonal probe:

GNF-5AsciminibImatinib

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

5.8 nM

Potency assay:

Kinase Profiler

Off target activity

Potency (off target):

IC50

Off target protein and potency:

LYN 19 nM

Potency assay (off target):

In Kinase Profiler assay testing 79 kinases, at 0.1 uM, Bafetinib inhibited ABL, ARG, FYN, and LYN; at 1.0 uM, Bafetinib inhibited the same four and also BLK, FLT3, PDGFR (alpha and beta), p70SK6.

In cell validation

On target activity in cells

Potency in cells:

IC50

11 nM

Potency assay (cells):

In K562 and 293T cells, bafetinib dose-dependently inhbited BCR-ABL autophosphorylation and phosphorylation of its substrates. IC50 was 11 nM in K562 cells and 22 nM in 293T cells.

Target engagement assay (cells):

Indirect, inhibition of autophosphorylation and substrate phosphorylation

Off target activity in cells

Probe Selectivity in Cell:

Activity was detected in cells on PDGFR and KIT, but not EGFR.

In vivo validation

Organism:

Balb/c mice

Dose:

30 mg/kg

Route of delivery:

Oral

Plasma half life:

1 h

Cmax:

66 ng/mL

Tmax:

2 h

Organ of Interest

Organ (O):

xenograft

Primary Reference

Reference (doi):

10.1182/blood-2005-06-2209

Reference (PMID):

16105974

SAB Rating

Rating for use in Cells

4 review(s)

Rating for use in Model Organisms

4 review(s)

SAB Members

SAB Comments

Bafetinib is a more selective probe compound than imatinib (see Kimura, S. et al, Blood, 2005, 106, 3948-3954) based on cellular and non-cellular kinase inhibition selectivity data. Additionally, bafetinib has a superior in vitro kinase inhibition profile against BCR-ABL variants with point mutations in the kinase domain. The above reference details cellular selectivity only against relatively small panels of kinases in cellular and in vitro kinase assays.

Jun 30 2016 - 12:13am

There are better compounds to study ABL in cells and animal models (e.g., GNF-2 and GNF-5). I do not recommend using bafetinib as a probe for ABL.

Jun 30 2016 - 12:13am

This probe is similar to imatinib and was designed to inhibit mutant ABL kinases that are resistant to imatinib. This probe was intended to inhibit LYN kinase. Overexpression of LYN is usually associated with imatinib resistance. Bafetinib inhibits four tyrosine kinases >50%: ABL, ABL-related gene (ARG), FYN, and LYN at 100 nM in vitro. The IC50 for ABL is 5.8 nM, and for LYN is 19 nM. It is more selective than imatinib and does not inhibit PDGFR or c-KIT kinases in vitro, which are inhibited by imatinib. Bafetinib inhibits clinically resistant ABL mutants (in vitro IC50 ranges 72 nM to 760nM). This probe does not inhibit T315I mutant ABL. Bafetinib inhibits tumor growth in vivo in mice that were subcutaneously injected with BCR-ABL positive KU812 cells, followed by oral administration of 200 mg/kg/day bafetinibat.

Jun 30 2016 - 12:14am

If using bafetinib (INNO-406) as a probe, it is highly recommended to consult the publication by U. Rix et al (Leukemia 2010, 24, 44–50). They've exhaustively profiled it through unbiased chemical proteomics and biochemical assays to better understand the selectivity profile. Notably, some known off-targets of imatinib and nilotinib were not present (NQO2) in the profile and the pattern of other kinases inhibited were different.

Another point to consider is the favorable CNS activity in comparison to imatinib (Yokota et al, Blood 2007, 109:306-314).

Jul 6 2016 - 3:34pm

Bafetinib

Probe Availability

Probe Information

Target Details

ABL, JTK7, c-ABL, c-ABL1, p150, v-abl, JTK8, p53Lyn, p56Lyn

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Bafetinib

Probe Availability

Probe Information

Target Details

ABL, JTK7, c-ABL, c-ABL1, p150, v-abl, JTK8, p53Lyn, p56Lyn

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?