Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate diverse cellular processes including proliferation, adhesion, survival, and motility. Dysregulated PI3K pathway signaling occurs in one-third of human tumors. Aberrantly activated PI3K signaling also confers sensitivity and resistance to conventional therapies. PI3K has been recognized as an attractive molecular target for novel anti-cancer molecules. In the last few years, several classes of potent and selective small molecule PI3K inhibitors have been developed, and at least fifteen compounds have progressed into clinical trials as new anticancer drugs. Among these, idelalisib has advanced to phase III trials in patients with advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. In this review, we summarized the major molecules of PI3K signaling pathway, and discussed the preclinical models and clinical trials of potent small-molecule PI3K inhibitors.
Highlights
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play central role in regulation of cell cycle, apoptosis, DNA repair, senescence, angiogenesis, cellular metabolism, and motility [1]
The activity of PI3Ks is tightly regulated in normal cells by internal signals such as Phosphatase and tensin homolog (PTEN), it has been recognized that deregulation of the PI3K signaling pathway is associated with development in one-third of human cancers [6,7,8,9]
We provide an overview of the PI3K signaling pathway in tumorigenesis and highlight recent advances in the design of small-molecule inhibitors of PI3K as novel anti-cancer therapies
Summary
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play central role in regulation of cell cycle, apoptosis, DNA repair, senescence, angiogenesis, cellular metabolism, and motility [1]. Upon generation of second messengers (PIP3, PI 3,4-bisphosphate), the PI3K signaling impinges on a diverse array of pleckstrin homology (PH) domain-containing intracellular signaling proteins, and indirectly triggers a cascade of events that culminates in activation of multiple effector kinase pathways, including the mTOR, ERK1/2, p38 MAPK, NF-kappa-B, and JNK/SAPK pathways [1,40,41]. Approximately 30% of breast cancers are associated with activating missense mutations of PIK3CA, the gene encoding the catalytic p110α subunit of class IA PI3K, which provides cells with a growth advantage and promotes tumor progression [13].
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