3,5 nM). Bosutinib's activity was first described in 2001 and it was disclosed as an Abl kinase inhibitor in 2003. At first it was believed that bosutinib was a selective Src kinase inhibitor but now it is known that its kinase inhibition profile is far less restricted than originally thought. Bosutinib inhibits Src, Abl and a wide range of both tyrosine and serine-threonine kinases. Resistance Bosutinib inhibited cells expressing a variety of mutations, some of which led to imatinib resistance, but the T315 mutation was completely resistant to bosutinib. In contrast to imatinib, nilotinib and dasatinib, bosutinib is not an efficient substrate for multidrug resistance (MDR) transporters that promotes efflux of foreign molecules from cells. Bosutinib even inhibits these transporter proteins in higher concentrations. Ponatinib (AP24534) ARIAD Pharmaceuticals, Inc. announced on September 10, 2010 that ponatinib, an orally active Bcr-Abl TKI effective against the T315I mutation had been approved for a phase II clinical trial. The road to discovery can be linked to AP23464, one of the first of Ariad's ATP competitive dual Src/Abl inhibitors. AP23464 was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. The substance potently inhibits, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations. AP23464 does not inhibit the T315I mutation, however, whereas AP24534 (ponatinib) does. Development Ariad used the highly potent drug lead, AP23464 to further investigate inhibitory possibilities of purine cored templates for dual Src/Abl inhibitors. First, searching for substances effective on the inactive conformation of Abl, the side chain bound to the nitrogen on the purine core was replaced with a diarylamide structure, that was known to have a high affinity to the inactive conformation by forming crucial hydrogen bonds and filling hydrophobic pockets on the kinase. Furthermore, it was determined that the cyclopentyl group on the purine core clashed with a glycine rich P-loop in that confirmation and was thus removed from the molecule. Then with in-vitro testing on inhibitory activity and in-vivo oral absorption assays a more lipophilic, amide bound, cyclopropyl group on C6 on the purine core was found to display both satisfactory pharmacokinetics and efficacy. Finally modifications on the diarylamide side chain by adding imidazole appendages were inspired by then newly released nilotinib structure. Those modifications resulted in what was called AP24163. During this development cycle, Ariad tested several substances against cells transfected with T315I mutated Bcr-Abl kinase