title: The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL.
abstract: The BCR-ABL fusion kinase is the driving mutation of chronic myelogenous leukemias and is also expressed in a subset of acute lymphoblastic leukemias. Recent advances in elucidating the structure, regulation, and signaling of BCR-ABL have led to the identification of allosteric sites that are distant from the ATP-binding pocket and are critical for BCR-ABL-dependent oncogenic transformation. Here, we review the available data regarding the molecular mechanism of action and the specificity of ATP-competitive tyrosine kinase inhibitors targeting BCR-ABL. In addition, we discuss how targeting of allosteric sites could provide new opportunities to inhibit resistant BCR-ABL mutants, either alone or in combination with conventional ATP-competitive inhibitors.
authors.affiliation: École Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000495:Allosteric Site / Q000187:drug effects / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl