Management of toxicity to isoform α-specific PI3K inhibitors

Isoform-Specific Contributions of α-Actinin to Glioma Cell Mechanobiology

Glioblastoma Multiforme (GBM) is a malignant astrocytic tumor associated with low survival rates because of aggressive infiltration of tumor cells into the brain parenchyma. Expression of the actin binding protein alpha-actinin has been strongly correlated with the invasive phenotype of GBM in vivo. To probe the cellular basis of this correlation, we have suppressed expression of the nonmuscle ...

Using Isoform-Specific Inhibitors to Target Lipid Kinases

In this issue of Cell, Knight et al. (2006) present a detailed pharmacological analysis of the PI3 kinase (PI3-K) family using small molecule inhibitors. They conclude that p110alpha, a PI3-K isoform, has a critical role in insulin signaling. In a related Cancer Cell paper, Fan et al. (2006) show that blocking activation of both p110alpha and the kinase mTOR with a small molecule inhibitor limi...

Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold.

Phosphoinositide 3-kinases (PI3-Ks) are an ubiquitous class of signaling enzymes that regulate diverse cellular processes including growth, differentiation, and motility. Physiological roles of PI3-Ks have traditionally been assigned using two pharmacological inhibitors, LY294002 and wortmannin. Although these compounds are broadly specific for the PI3-K family, they show little selectivity amo...

Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction.

In the present paper, we review the preclinical development of TG100-115, a PI3K (phosphoinositide 3-kinase) gamma/delta isoform-specific inhibitor currently in clinical trials for the reduction of acute MI (myocardial infarction). An overview is presented outlining the pathogenesis of acute MI and the rationale for clinical use of PI3K gamma/delta-specific inhibitors in this indication. TG100-...

SnapShot: Class I PI3K Isoform Signaling