CC-223

A potent, selective, and orally bioavailable inhibitor of mTOR kinase with IC50 of 16 nM; displays >200-fold selectivity over the related PI3K-α (IC50=4.0 uM), shows no significant inhibition of ATR or SMG1 and weakly inhibits DNA-PK (IC50=0.84 uM) ; inhibits mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT (S473) ] in cellular systems, exhibits growth inhibitory activity in hematologic and solid tumor cell lines; demonstrates tumor growth inhibition in multiple solid tumor xenografts.Blood Cancer Phase 2 Clinical (In Vitro) :Onatasertib is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT (S473) ] in cellular systems. Onatasertib is selective for mTOR kinase with >200-fold selectivity over the related PI3K-α (IC50=4.0 μM) . Of the PI3K related kinases tested, Onatasertib shows no significant inhibition of ATR or SMG1 and inhibits DNA-PK with an IC50 value of 0.84 μM. When screened in a single-point assay against a commercially available panel of 246 kinases, only three kinases other than mTOR are inhibited >80% at 10 μM by Onatasertib. Upon follow-up IC50 value determination, only two are inhibited by Onatasertib with IC50 values below 1 μM; FLT4 (0.651 μM) and cFMS (0.028 μM) . The exquisite kinase selectivity of Onatasertib is confirmed upon evaluation in cellular systems using ActivX KiNavtiv profiling. Other than mTOR kinase, no kinase target is identified when HCT 116 or A549 cells are treated for 1 hour with 1 μM Onatasertib and assayed for kinase activity. Onatasertib shows a concentration-dependent reduction in each marker, with IC50 values of 31±2 nM for pS6RP, 405±47 nM for p4EBP1, and 11±10 nM for pAKT (S473) in western blot analysis. Inhibition of these pathway biomarkers is investigated in additional cell types from a variety of tissue origins. Onatasertib inhibits both mTORC1 (S6RP and 4EBP1) and mTORC2 [AKT (S473) ] markers across the panel with IC50 ranges of 27 to 184 nM for pS6RP, 120 to 1,050 nM for p4EBP1 and 11 to 150 nM for pAKT (S473) . (In Vivo) :The antitumor activity of Onatasertib in the PC-3 xenograft model is determined using a number of dosing paradigms. Onatasertib significantly inhibits PC-3 tumor growth in a dose- and schedule-dependent manner. Dosing at 10 or 25 mg/kg, once daily, results in 46% (P<0.001) and 87% (P<0.001) reduction in tumor volume, respectively. Similar dose dependency is observed with twice-daily dosing at 5 or 10 mg/kg, corresponding to 65% (P<0.001) and 80% (P<0.001) tumor volume reductions. All dose levels are tolerated in the once-daily and twice-daily dosing studies, with only the 25 mg/kg/d group showing any significant body weight loss. These mice lost approximately 10% of their initial body weight after 3 weeks of dosing.