Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic

Abstract

Many patients with acute myeloid leukemia will eventually develop refractory or relapsed disease. In the absence of standard therapy for this population, there is currently an urgent unmet need for novel therapeutic agents. Targeted therapy with small molecule inhibitors represents a new therapeutic intervention that has been successful for the treatment of multiple tumors (e.g., gastrointestinal stromal tumors, chronic myelogenous leukemia). Hence, there has been great interest in generating selective small molecule inhibitors targeting critical pathways of proliferation and survival in acute myeloid leukemia. This review highlights a selective group of intriguing therapeutic agents and their presumed targets in both preclinical models and in early human clinical trials.

Keywords::

• acute myeloid leukemia
• small molecule inhibitor
• therapeutic agent

Acknowledgements

This work was supported by grants from the National Institutes of Health/National Cancer Institute (grants NIH/NCI P01 CA101937 [JF DiPersio] and NIH/NCI R01 CA152329 [JF DiPersio]).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Small molecule inhibitors have been developed to modulate the activity of proteins encoded by mutated or overexpressed genes in patients with acute myeloid leukemia.

• Clonal evolution, dependency on alternative signaling pathways and pharmacodynamics are potential obstacles to the clinical development of small molecule inhibitors for the treatment of acute myeloid leukemia.

• Multi-targeting and the combination of small molecule inhibitor treatment with chemotherapy may improve treatment efficacy.

• The analysis of patient samples is an important tool to investigate resistance mechanisms and to discover and validate biological markers that could be used for the prediction and assessment of treatment response.