Kinase Bcr-Abl

Kopt Ta M, Falinski R, Nowicki MO et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006 108 319-327. 

Several of the new Bcr-Abl kinase inhibitors reported subsequent to imatinib also inhibit Src, a non-receptor tyrosine kinase. In 2000, il was re-porled lhat the known Src inhibitor PD180970 (12) also inhibited Abl kinase [73] (Scheme 5). This property was soon found to be shared by several other pyrido[2,3-d]pyrimidine Src inhibitors including PD173955 (13) [74] (Scheme 5). A crystal structure of PD 173955 demonstrated that this compound could bind to both the active and inactive form of Abl [37]. While the conformation of active Src kinase is similar to that of active Abl, the conformations of the inactive kinases are quite different. Unlike PD 173955, imatinib only binds the inactive form of Abl. The inability of imatinib to inhibit Src is... 

Increased expression of BCR-ABL kinase from genomic amplification BCR-ABL independent mechanisms Clonal evolution (non- BCR-ABL-dependent mechanism) o Clonal evolution o Aneuploidy... 

Fig. 4. Map of BCR-ABL kinase domain mutations associated with clinical resistance to imatinib. Abbreviations P, P-loop B, imatinib binding site C, catalytic domain A, activation loop. Amino-acid substitutions in green indicate mutations detected in 2-10% and in red in >10% of patients with mutations. (Reprinted with permission from Ref (52)).

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