• PIK-90 is a potent and cell permeable PI3K inhibitor, with IC50 values of 11 nM, 350 nM, 18 nM, and 58 nM for p110 α, β, γ and δ isoforms
OTAVAchemicals Catalogue Number: 7070707028
CAS Registry Number: 677338-12-4
Purity: 95%+ (HPLC)
Ref. 1: Weiss et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell (2006), 9, 341-349
Abstract: The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase α and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase α in malignant glioma.
Ref. 2: Shokat et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell (Cambridge, MA, United States) (2006), 125, 733-747
Abstract: Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110γ identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110α is the primary insulin-responsive PI3-K in cultured cells, whereas p110β is dispensable but sets a phenotypic threshold for p110α activity. Compounds targeting p110α block the acute effects of insulin treatment in vivo, whereas a p110β inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.