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


RESULTS
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.


CONCLUSIONS
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.
Levis
Mark
M
The Kimmel Cancer Center, Johns Hopkins University, Department of Oncology, Baltimore, Maryland, USA. levisma@jhmi.edu
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008954:Models, Biological; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins