Dactolisib

A potent, dual ATP-competitive pan-class I PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR (p70S6K) with IC50 of 4 nM /5 nM /7 nM /75 nM /6 nM, respectively; effectively and specifically blocks the dysfunctional activation of the PI3K pathway, inducing G (1) arrest; demonstrates antitumor activity in in vivo models of human cancer.Kidney Cancer Phase 2 Discontinued (In Vitro) :Dactolisib (BEZ235) potently inhibits PI3K in an ATP Competitive Manner. Dactolisib (BEZ235) (250 nM) significantly reduced the phosphorylation levels of the mTOR activated kinase p70S6K. Dactolisib (BEZ235) also leads to a reduction of S235/S236P-RPS6 levels with an IC50 of 6.5 nM, suggesting that Dactolisib (BEZ235) can directly inhibit the mTOR kinase, as the kinase domain of mTOR is highly homologous to the one of class IA PI3K. The activity of Dactolisib (BEZ235) against mTOR is confirmed using a biochemical mTOR K-LISA assay (IC50, 20.7 nM) . The IC50s of Dactolisib (BEZ235) for HCT116, DLD-1, and SW480 cell lines are 14.3±6.4, 9.0±1.5, and 12.0±1.6 nM, respectively. (In Vivo) :Dactolisib (BEZ235) (45 mg/kg, p.o.) treatment induces colonic tumor regression in a GEM model for sporadic PIK3CA wild-type CRC. Dactolisib (BEZ235) (45 mg/kg) is administered to MENX rats (n=2 each group) by oral gavage and animals are sacrificed 1 or 6 hours after treatment. Immunostains for P-AKT and P-S6 show considerable reduction of the two proteins, and particularly of P-S6, 6 hours after administration of Dactolisib (BEZ235) when compares with PEG-treated rats. At 6 hours after treatment, the pituitary adenomas of Dactolisib (BEZ235) -treated rats has a proteomic profile significantly different from the tumors of placebo-treated rats.