Advances in Development of Phosphatidylinositol 3-Kinase Inhibitors

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mTOR, and therefore play important roles in cell growth, survival, etc. The phosphatase and tensin homolog deleted in chromosome ten (PTEN), acts as the catalytic antagonist of PI3K by dephosphorylating PIP3 to PIP2. PI3K has become an important drug target for cancer therapy, since gain-of-function mutations of PIK3CA encoding PI3Kalpha, as well as loss-of-function mutations of PTEN, have been frequently found in human cancers. The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 3 years. While PI3Kbeta, delta and gamma isoform-specific PI3K inhibitors (TGX-221, IC87114 and AS-605240) have been developed for therapy of coronary heart disease, asthma, and glomerulonephritis, respectively, a promising PI3Kalpha specific inhibitor is not yet available. Correspondingly, almost all of the promising PI3K inhibitors under development for caner therapy, such as NVP-BEZ235, GDC-0941 and ZSTK474, are pan-PI3K isoform inhibitors. Each of these pan-PI3K inhibitors seems to induce a common G1 phase arrest. All have shown favorable in vivo anticancer efficacies and low toxicities, and therefore most have entered evaluation in clinical trials. P-Akt and p-S6 have been reported to be feasible pharmacodynamic biomarkers for monitoring the efficacy of these agents. In the process of discovery of these and other PI3K inhibitors, detailed structure-activity relationship studies were carried out. This review summarizes key advances in the development of PI3K inhibitors, which is preceded by an introduction of PI3K family and their functions.

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…[3][4][5] PIP3 subsequently binds to the pleckstrin homology domain of Akt1 kinase (also known as protein kinase B) to recruit Akt1 to the cell membrane for phosphorylation. 19,24 Akt1 is phosphorylated at Threonine 308 by phosphoinositide-dependent protein kinase 1 (PDK-1) [25][26][27] and at Serine 473 (Ser473) by PDK-2, which is believed to be rictor. 9,14,19,27 Activated Akt1 inactivates the tuberous sclerosis complex (TSC) composed of TSC1 and TSC2, by directly phosphorylating the GTPase-activating protein TSC2.…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…PI3Ks are a family of lipid kinases that phosphorylate the 3'-OH of phosphoinositides ( Figure 1) [12][13][14] . PI3Ks are divided into three classes based on their primary structure and in vitro substrate specificity [15,16] .…”

“…Examples of PIKKs include [23] . Class I PI3Ks are further divided into subclasses IA and IB based on their regulatory subunit and upstream regulator [14] . Class IA PI3Ks are mainly activated by various receptor tyrosine kinases (RTKs) and Ras [24] .…”

“…Most of these drug candidates are pan-PI3K isoform inhibitors, with the exception of CAL-101 (also named IC87114) as a PI3Kδ specific inhibitor. Among the pan-PI3K isoform inhibitors, some exhibit selectivity over mTOR and DNA-PK, such as GDC-0941, XL-147, and BKM-120 [14,54] , Figure 2. PI3K/Akt pathway involved in tumorigenesis.…”

“…PDK: 3-Phosphoinositide-dependent protein kinase; GSK3: glycogen synthesis kinase 3; FOXO: forkhead; p70S6K: p70S6 kinase; 4E-BP1: 4E-binding protein 1; IRS: insulin receptor substrate; HIF-1α: hypoxia-inducible factor 1α; VEGF: vascular endothelial growth factor. [14,55,56] (Table 2). Among the novel PI3K inhibitors, GDC-0941 and BEZ235 are the most intensively studied.…”