The pivotal roles of
phosphatidylinositol 3-kinases (PI3Ks) in human
cancers have inspired active development of small molecules to inhibit these
lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/
mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K
isoforms play non-redundant roles in particular
tumor types, which has prompted the development of
isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K
isoform-selective inhibitors is represented by
CAL101 (
Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of
chronic lymphocytic leukemia, indolent B-cell
non-Hodgkin's lymphoma and relapsed
small lymphocytic lymphoma. Inhibitors targeting other PI3K
isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K
isoform-selective inhibitors for
cancer therapy. A deeper understanding of the action modes of novel PI3K
isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K
isoforms, while the identification of
biomarkers to stratify patients who are likely to benefit from the
therapy will be essential for the success of these agents.