Phosphoinositide-3-kinases (PI3Ks) are central to several cellular signaling pathways in human physiology and are potential pharmacological targets for many pathologies including cancer, thrombosis, and pulmonary diseases. Tremendous efforts to develop isoform-selective inhibitors have culminated in the approval of several drugs, validating PI3K as a tractable and therapeutically relevant target. Although successful therapeutic validation has focused on isoform-selective class I orthosteric inhibitors, recent clinical findings have indicated challenges regarding poor drug tolerance owing to sustained on-target inhibition. Hence, additional approaches are warranted to increase the clinical benefits of specific clinical treatment options, which may involve the employment of so far underexploited targeting modalities or the development of inhibitors for currently underexplored PI3K class II isoforms. We review recent key discoveries in the development of isoform-selective inhibitors, focusing particularly on PI3K class II isoforms, and highlight the emerging importance of developing a broader arsenal of pharmacological tools.
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