Case Study 2: Next-Generation Tyrosine Kinase Inhibitors

In 2001, the treatment of a type of leukemia (chronic myeloid leukemia, CML) was revolutionized by the emergence of a new class of drug, the so-called tyrosine kinase inhibitors (TKIs). The first member of that class was imatinib (marketed as Gleevec) and it rapidly became a blockbuster. Nevertheless, despite the astounding success of imatinib, some problems soon started to emerge, most notably drug resistance and a variety of safety concerns partly due to off-target effects. These problems were solved by using the crystal structure of the drug target to rationally design 2nd-generation TKIs, including dasatinib, nilotinib and bosutinib. These 2nd-generation TKIs are more potent than imatinib and in some cases are better tolerated. For these reasons, 2nd-generation TKIs are rapidly supplanting the originator drug, imatinib, in the clinic, even though imatinib is highly effective, well-established, and will soon be generic (Francis et al, 2013; Jain et al, 2013).