Possible explanation for MK-0457 activity in T315I Bcr-Abl–positive CML and Ph⁺ ALL. (A) MK-0457 has been shown to be less deeply buried in the Abl kinase domain (right) with respect to imatinib (left). As a consequence, (B) a close encounter with threonine 315 is avoided, explaining the ability of MK-0457 to accommodate easily the substitution of threonine with isoleucine. Modified, with permission, from Young et al⁵ .