Recent advances in the development of small-molecule inhibitors for the treatment of acute myeloid leukemia

Purpose of review: This review outlines recent advances in the development of small-molecule inhibitors of molecular signaling pathways for the treatment of acute myeloid leukemia (AML). These compounds are typically targeted against components of the tyrosine kinase-Ras-Map kinase pathway that have been activated by mutation. Recent findings: Several agents have been tested in phase 2 trials, with only modest clinical results thus far. Careful correlative studies have allowed a clearer understanding of the reasons for the success or failure of these agents and have refined our approach to clinical trial design. In some cases, the target molecule has been successfully inhibited, but for an inadequate duration, and in other cases, inhibiting the target has little correlation with clinical effect. Summary: Small-molecule inhibitors of these molecular pathways clearly have significant promise for the treatment of AML, but several obstacles remain, and this field of pharmacotherapy is still quite new. These inhibitors seem unlikely to be curative when administered as monotherapy but rather will have to be used in combination with one another or with conventional chemotherapy. In addition, pharmacokinetic problems must be overcome with many of them.