PIK-294

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.

References:
[1] Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM, et al. . A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47. Epub 2006 Apr 27.
[2] Bobrovnikova-Marjon E1, Pytel D, Riese MJ, Vaites LP, Singh N, Koretzky GA, Witze ES, Diehl JA.  PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation. Mol Cell Biol. 2012 Jun;32 (12):2268-78.