A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells.
Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.
Rix
U
U
CeMM - Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
Remsing Rix
L L
LL
Terker
A S
AS
Fernbach
N V
NV
Hantschel
O
O
Planyavsky
M
M
Breitwieser
F P
FP
Herrmann
H
H
Colinge
J
J
Bennett
K L
KL
Augustin
M
M
Till
J H
JH
Heinrich
M C
MC
Valent
P
P
Superti-Furga
G
G
D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040901:Proteomics; D011743:Pyrimidines / Q000494:pharmacology*; D011808:Quinone Reductases / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011975:Receptors, Mitogen; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D011494:Protein Kinases; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D016044:Fusion Proteins, bcr-abl; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human; C506918:bafetinib