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.

Figure 1

Mutations, inhibitors, and targeting sites on BCR–ABL. A, type 1 versus type 2 kinase-inhibitor complexes. Residues Asp-381 and Phe-382 of the DFG motif are shown in stick representation. Note the dramatically different position of the Asp and Phe side chains, rotated by 180° in the type 1 and 2 inhibitor complexes. B, structure of the Abl kinase domain bound to imatinib [Protein Data Base (PDB) entry 1OPJ]. The activation loop is shown in green, the Gly-rich loop is shown in yellow, and positions of resistance mutation are shown as red balls. C, surface representation of the SH2-kinase domain unit of BCR–ABL. The kinase domain is shown in blue and the SH2 domain bound to the N-lobe of the kinase domain is shown in green (PDB entry 1OPL chain B). The primary drug-binding site in the ATP-binding cleft, the allosteric myristate-binding pocket, and the SH2-kinase interface are highlighted. Prototypic binders of the ATP and myristate pocket are indicated in dark gray. The conformation of the TKIs from the superimposed structures of the respective Abl kinase domain-drug complexes is indicated as a stick model. The orientation of the drugs is uniformly rotated 90° clockwise around the y axis with respect to the orientation of the SH2-kinase domain structure on the left and translated on the xy plane for graphical convenience. The following PDB entries of the Abl kinase domain were used: imatinib (1OPJ), nilotinib (3CS9), dasatinib (2GQG), ponatinib (3IK3), DCC-2036 (3QRJ), PHA-739358 (2V7A), VX-680 (2F4J), and GNF-2 (3K5V). Structural data for bosutinib or SGX393 are not publically available.