Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

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.

Figure 1

The class I PI3K family. Class I PI3Ks are heterodimeric proteins and comprised of a catalytic p110 subunit complexed with a regulatory p85 or p101 subunit. The catalytic p110 subunit exists in four isoforms (α, β, δ, and γ), whereas the regulatory p85 subunit in three isoforms – p85, p55, and p50. Their corresponding upstream receptors and adaptor proteins are also indicated. RTK: receptor tyrosine kinase; GPCR: G-protein coupled receptors.

Figure 2

Schematic representation of the PI3K signaling pathway. Four major extracellular signals, growth factors, cytokines, hormones/chemokines, and integrins, activate PI3K, which transmit the signals through appropriate pathways to control diverse cellular processes, including cell cycle, apoptosis, DNA repair, senescence, angiogenesis, cellular metabolism, autophagy, and motility. The multiple effector kinase pathways activated by PI3K are highlighted in the figure.

Figure 3

The structural organization of p110-α enzyme. The catalytic subunit (p110-α) of PI3Ks possesses a central region flanked by the N- and C-terminus of varying lengths with distinctive modular organization. The N-terminus of p110-α enzyme harbors the p85-binding domain (PI3K-ABD) and the Ras-binding domain (PI3K-RBD) which mediates interaction with the regulatory p85 and the Ras-GTPases respectively. The central region is composed of the C2 PI3K-type and PIK helical domains, whereas the C-terminus houses the enzymatic apparatus (PI3K/PI4K kinase domain). Common cancer-associated mutations within each domain of the enzyme is indicated.