Pictilisib

GDC-0941 is an inhibitor of class I PI3 kinases (IC50 α, β, δ, γ = 3, 33, 3, 75 nM, respectively) with selectivity over class II, III and IV enzymes C2β (670 nM), Vps34 (>10 µM), DNA-PK (1.23 µM) and mTOR (580 nM). Greater than 300-fold selectivity for the α-isoform versus an additional 228 kinases was also described. Cellular activity against tumor cell lines was reported as EC50 = 140-950 nM while inhibition of cellular target engagement (pAkt473) occurred at lower exposures (EC50 = 28-46 nM). In vivo target engagement and tumor growth inhibition were reported following oral administration to mice (25-150 mg/kg/d). This tool is recommended for use in preference to the older, less selective inhibitors such as wortmannin and LY294002.

For cell culture, I would recommend confirming class I inhibition without inhibition of the other classes (class II-class IV). However, because cell-free sensitivities of the p110s vary from 3 nM (alpha) to 75 nM (gamma, 25-fold of alpha) and cellular sensitivities of classes II and IV are relatively higher, a careful dose-response study in cells should be conducted before conclusions are drawn from the data.

Chemical Neighbourhood for QSAR: 129, 47, and 24 molecules similar (>0.80) to GDC-0941 with in vitro affinities for PIK3CA, PIK3CD, and PIK3CB, respectively, were found in public repositories (e.g., ChEMBL).