title: Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.
abstract: The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dürnberger
authors.forename: Lily L
authors.initials: LL
authors.lastname: Remsing Rix
authors.forename: Melanie
authors.initials: M
authors.lastname: Planyavsky
authors.forename: Nora V
authors.initials: NV
authors.lastname: Fernbach
authors.forename: Ines
authors.initials: I
authors.lastname: Kaupe
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Thomas
authors.initials: T
authors.lastname: Köcher
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D001549:Benzamides; D000069439:Dasatinib; D000070819:Discoidin Domain Receptor 1; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011808:Quinone Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; C498826:nilotinib; D000069439:Dasatinib