Biological Activity
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.
Biochem/physiol Actions
PIK-294 is a highly selective inihibitor of the phosphoinositide 3-kinase (PI3K) p110δ with an IC50 value of 10 nM compared to IC50 values of 10 μM, 490 nM and 160 nM for PI3Kα/β/γ, respectively. PIK-294 has been used to help distinguish the unique roles of the various PI3-K isoforms. For example, in a study of CXCL8-induced neutrophil migration, PIK-294 inhibited both chemokinetic and chemotactic CXCL8-induced migration whereas PI3Kγ inhibitor AS-605240 markedly reduced CXCL8 induced chemokinetic migration but had no effect on CXCL8 induced chemotactic migration.
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.
