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.

磷酸肌醇3-激酶（PI3K）途径在不同的细胞过程和几种疾病中的关键作用，以及可靶向的蛋白质的存在，为小分子抑制剂开发的有希望的研究开辟了道路。尽管人们寄予厚望，但由于出现了剂量限制的，针对靶点的不良反应，PI3K抑制剂向临床的转移遇到了一些限制。在这篇综述中，我们将总结PI3K抑制剂临床试验的主要问题和最新进展。开发同工型特异性抑制剂的努力，以及旨在降低毒性和不良反应的新型治疗策略，为PI3K抑制剂开辟了新的有希望的时代。此外，我们将重点关注最近出现的II类和III类PI3K抑制剂，这有助于确定它们的I类非冗余作用。