The biological effects of isoform-specific PI3-kinase inhibition

The four isoforms of class I phosphatidylinositol-3-kinase (PI3K) were originally thought to be redundant in function; however, further research and new technologies have revealed that each subunit has distinct characteristics. In the past decade the number of PI3K inhibitors has increased from a few agents with unacceptable promiscuity and pharmacological properties, to a family of selective agents that are either progressing through experimental development or are in clinical trials. These agents, with two notable exceptions, target multiple members of the PI3K class I isoforms. As data become increasingly available, the concept that inhibiting a single PI3K isoform may offer improved therapeutic benefit, while eliminating the potentially negative effects of pan-isoform inhibition, is driving efforts to develop more specific inhibitors. However, questions remain regarding the best isoform to inhibit for maximum benefit in different pathological settings, and whether increased specificity may lead to a loss in efficacy as a result of isoform redundancy in some settings. This review discusses the current understanding of individual PI3K isoforms in physiology and pathological states, as well as the status of PI3K inhibitors in preclinical and clinical development.