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IC50: 10 nM

PIK-294 is a highly selective p110δ inhibitor, 1000-, 49- and 16-fold less potent to PI3Kα/β/γ, respectively.

Phosphoinositide 3-kinases (PI3-Ks) are a key emerging class of drug targets, but the unique roles of PI3-K isoforms remain rarely defined. Their target selectivity was biochemically enumerated that revealed cryptic homologies across targets and chemotypes by synthesizing chemically diverse panel of PI3-K inhibitors. Crystal structures of three inhibitors to p110g identify a conformationally mobile region that is uniquely exploited by bound selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling.

In vitro: PIK-294 displays distinct patterns of isoform selectivity to inhibit different subsets of class I PI3K isoforms (p110β, p110δ, and p110γ) and shows low sensitivity to p110α with IC50 of 10 μM). The m-phenol moiety of PIK-294 can penetrate the deep-affinity pocket of the ATP binding site, and thus promotes in vitro inhibitory activity. PIK-294 showed one of the most potent p110d-selective inhibitors reported at present.

In vivo: PIK-294 bound p110a inhibits the acute effects of insulin treatment in vivo, whereas a p110b inhibitor has no effect.

Clinical trial: So far, no clinical study has been conducted.

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