Perifosine (KRX-0401) is an orally bioavailable Akt and PI3K inhibitor of the alkylphospholipid class. Unlike ATP binding kinase inhibitors, perifosine targets the pleckstrin homology domain of Akt, thus preventing its translocation to the plasma membrane. Though structurally similar to miltefosine and edelfosine, it has improved bioavailability and less GI side effects. It has orphan drug status in the United States for the treatment of multiple myeloma and neuroblastoma. In multiple myeloma cell lines, perifosine showed significant dose-dependent growth inhibition with an IC50 of 1 to 12.5 uM. [4] In PC-3 cells Perifosine inhibits Akt phosphorylation on Thr308 and Ser473 without affecting the amount of Akt. Perifosine has been shown to promote cell cycle arrest at either G1-S or G2-M phases with upregulation of p21 in a p53-independent manner. [1]

Perifosine targets the lipid-binding PH domain and inhibits translocation of Akt to the cell membrane. It decreases Akt phosphorylation and increases caspase-dependent apoptosis in neuroblastoma cell lines. [2] Recent combination studies with mTOR inhibitor temsirolimus have shown perifosine to be synergistic. Perifosine also has been shown to sensitize breast cancer stem cells to radiation. [3]