Secondgeneration Tyrosine Kinase Inhibitors

Agents that have a different conformational binding to BCR/ABL than imatinib provide another potential approach to imatinib-resistant CML. Such compounds may be particularly useful in patients who have developed point mutations in the ABL domain and are no longer able to bind imatinib in the kinase pocket and inhibit ATP binding. Second-generation tyrosine kinase inhibitors may still be able to bind the appropriate binding site and block ATP from binding. Several of these agents are currently being developed in both the laboratory and the clinic. PD173955 (Pfizer) is a more potent inhibitor of BCR/ABL than is imatinib. Unlike imatinib, this small molecule has been shown to bind Abl independent of its phosphorylation state.30 Hence, more potent tyrosine kinase inhibitors may be able to maintain activity against mutated clones. PD166326 (Pfizer), a novel compound in the pyridopyrimidine class of tyrosine kinase inhibitors, has been shown to be a potent inhibitor of BCR/ABL tyrosine kinase activity and BCR/ABL-dependent proliferation.31 The activity of PD 166326 against BCR/ABL-induced leukemia in an in vivo mouse model has recently been reported (N Wolff, ASH 2003). PD166326- and imatinib-treated mice had improved survival, lower white blood cell (WBC) count, and less splenomegaly than placebo-treated mice, suggesting that PD166326 was superior to ima-tinib in decreasing the overall leukemic burden. Thus, in this CML animal model, the novel tyrosine kinase inhibitor PD166326 exhibited greater antileukemic activity than imatinib, suggesting that further development of this or a related compound may lead to even more potent drugs for the treatment of human CML. The investigators have postulated that, similar to the experience with combination chemotherapy, combinations of different kinase inhibitors at the initiation of therapy may suppress the emergence of resistant clones and improve therapeutic outcomes.

In vitro data on the novel dual selective SRC/ABL inhibitor, AP23464 (ARIAD pharmaceuticals, Cambridge, MA), has shown that this drug inhibits in vitro growth of cells that express either wild-type BCR/ABL or the most prevalent mutations induced by imatinib in BCR/ABL: Q252H, Y253F, E255K, M351T, or H396P.32 AP23464 was approximately eightfold more potent than imatinib in inhibiting the growth of Ba/F3 cells expressing wild-type BCR/ABL. Also, AP23464 inhibited the growth of Ba/F3 cells expressing all mutant forms of BCR/ABL except for T315I at the same nanomolar concentrations as the wild type.32 Studies to assess the in vivo activity of AP23464 and key analogs are currently in progress.

Another second-generation tyrosine kinase inhibitor that is currently in clinical trials is BMS-354825. The studies are being conducted in patients with chronic phase CML who are resistant to imatinib.33

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