The key role of phosphoinositide 3-kinase (PI3K) pathway in different cellular processes and several disorders, together with the presence of targetable proteins, opened the way to promising studies for the development of small molecule inhibitors. Despite the high expectation, the shift of PI3K inhibitors to the clinic met several limitations due to the emergence of dose-limiting, on-target adverse effects. In this review, we will summarize the main issues and recent advances in PI3K inhibitors clinical trials. The effort to develop isoform-specific inhibitors, together with novel therapeutic strategies aimed at reducing the toxicity and adverse effects, opened a new promising era for PI3K inhibitors. In addition, we will focus on the recent emergence of class II and III PI3K inhibitors, which helped to define their class I non-redundant role.
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