A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types

Abstract

Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours.

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Primary NRVM [22] or H9c2 cells (Cell Bank Australia, Westmead, NSW, Australia) were plated for 72 or 18 h, respectively, in 96 well OptiView plates (50,000 and 5,000 cells/well, respectively, 37°C/5% CO 2 ), serum-deprived for approximately 18 h and pretreated with or without a specific PI3K(p110α) inhibitor (A66 [23], 1 μmol/l), IGF1 (10 nmol/l) and/or tempol (100 μmol/l) for 24 h prior to 24 h treatment with or without H 2 O 2 (100 μmol/l) in high glucose (HG, 25 mmol/l) or low glucose (LG, 5.56 mmol/l) media, as specified.…”

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…SK-OV-3 (KRAS wild-type) has an activating PIK3CA mutation and was shown previously to be sensitive to A66 (9). The cancer cell line U87MG lacks PTEN and is preferentially sensitive to p110␤ inhibition (34).…”

“…Of these, p110␣ has received the most attention because gain-of-function mutations in the PIK3CA gene encoding this enzyme are very common in human cancer (6). Mouse models have shown that PIK3CA mutations can be drivers of tumorigenesis (7,8) and cell line studies have shown that the PIK3CA mutation status correlates with sensitivity to inhibitors of p110␣ (9,10). A distinct PI3K isoform p110␤ has been suggested to control basal PIP 3 production and drive cancer cells when PTEN, the major PIP 3 phosphatase, is inactivated (11,12).…”

Class II but Not Second Class—Prospects for the Development of Class II PI3K Inhibitors

“…In Class I isoform selective compounds, projection of substituents from the purine binding site can engender major changes in isoform selectivity. 14 The lack of information available at present from which to build an understanding of Class II inhibition juxtaposed against thousands of compounds prepared in Class I inhibitor campaigns suggests that a robust data set could be developed for Class II isoforms from existing libraries, with modest synthetic effort. Indeed, PI701 and PI702 appear to have emerged from such a process.…”