Therapeutic potential of phosphoinositide 3-kinase inhibitors

Originally discovered as oncogene-associated lipid kinases more than 15 years ago, the family of phosphoinositide 3-kinase (PI 3-K) enzymes has recently emerged as an important therapeutic target in human pathophysiology. After more than a decade with only a few inhibitors with low activity, poor isoform or kinase selectivity or unacceptable pharmacological and toxicological profiles, a variety of PI 3-K inhibitors with pan-isoform activity and isoform-selective inhibition have recently been identified. A growing excitement surrounds the success of signal transduction modifiers in cancer therapy, as well as in the therapy of other diseases. In combination with additional genetic evidence implicating the PI 3-K pathway in human disease, the search for more selective and more drug-like PI 3-K inhibitors has been reinvigorated. As a consequence, many biotech and pharmaceutical companies have established PI 3-K pathway drug development programmes. With the help of important insights provided by genetic knockout animals, potential applications of PI 3-K inhibitors for the treatment of cancer, cardiovascular and endocrine disorders, autoimmune and allergic diseases and inflammation have been recognised. Several potential drugs have now been validated in animal models of human disease but numerous pitfalls still await the translation from animal model to human clinical trials. Herein, the progress in the development of PI 3-K inhibitors and their potential applications in medicine are summarised and the opportunities and concerns inherent in targeting this essential signalling pathway are discussed.