Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is currently one of the most exciting drug targets in oncology. However, only a short time ago, the paradigm existed that drugs targeted to the four PI3K class I isoforms would be too toxic for use in cancer therapy due to effects on physiologic signaling. Since that time, studies have delineated the roles of these four isoforms in nonpathologic signaling as well as their roles in cancer. An extensive effort has gone into developing agents that inhibit one or more PI3K isoforms, as well as closely related proteins implicated in cancer. These agents have proved to be tolerable and therapeutically beneficial in animal studies, and a number are in clinical testing. The agents, their properties, and their molecular targets are discussed in this review.

Figure 1. Domain structure and amino acid homology of the class I PI3K catalytic subunits and mTOR

The regulatory subunits are not shown. Also shown is a cladogram showing evolutionary relationships

Figure 2. PI3K/Akt signaling in cells

For an explanation see the text.

Figure 3. Profiles of PI3K inhibitors in clinical trial

The table shows the different PI3K inhibitors currently in clinical trial together with their reported activities against the PI3K α,β,γ and δ isoforms and mTOR, the concentration reported to inhibit cellular PI3K signaling measured by phospo-Akt inhibition, and the doses given to tumored animals to obtain antitumor activity, whether once or twice daily, or 3 times per week. NR is no report. The structures of the compounds are shown in the lower panel.