CML - imatinib

This included knowledge of the N-Terminal BCR sequences being joined upstream of the c-ABL SH3 and SH2 domains as well as several functional motifs including actin binding, as well as nuclear imort and export sequences. Further analysis indicated that BCR, through the use of its coiled-coil domain allowed the BCR-ABL protein to oligomerize. Conserved C-terminal F-actin binding domain in the BCR-ABL fusion protein localizes it in the cytoplasm as opposed to normal c-Abl activity which involves shuttling between the nucleus and cytoplasm to effect DNA damage pathways. The BCR-ABL fusion protein also was determined to obtain unregulated tyrosine kinase activity due to the autophosphorylation at Tyr 1127 in the SH2 catalytic domain linker which disrupts its binding to the SH3 domain.