PF-04691502

PF-04691502 is an ATP-competitive PI3K (α/β/δ/γ) /mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. Phase 2. (In Vitro) :PF-04691502 inhibits recombinant mouse PI3Kα in an ATP-competitive inhibitor. PF-04691502 potently inhibits AKT phosphorylation on S473 and T308 in all the 3 cancer cell lines with IC50 values of 3.8 to 20 nM and 7.5 to 47 nM, respectively. Using a 96-well plate-based P-S6RP (S235/236) ELISA assay, PF-04691502 potently inhibits mTORC1 activity with an IC50 of 32 nM. PF-04691502 inhibits cell proliferation of BT20, SKOV3, and U87MG with IC50 values of 313, 188, and 179 nM, respectively. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 and AKT S473 (IC50 of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC50 of 179-313 nM) . PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC50 of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. (In Vivo) :Nude mice bearing U87MG tumors are administered orally once a day with PF-04691502 at 0.5, 1, 5, and 10 mg/kg (maximum tolerated dose, MTD) . Treatment with 10 mg/kg results in a significant reduction of P-AKT (S473) levels at 1 hour postdosing, and persistent inhibition is observed for 8 hours. P-AKT (S473) recovers to above baseline 24 hours after 10 mg/kg treatment. For P-S6RP (S235/236), a similar inhibition time course is observed, but after 24 hours of treatment, P-S6RP levels remain lower than vehicle tumors. Modulation of the AKT downstream effector, P-PRAS40 (T246), and mTOR downstream effector, P-4EBP1 (T37/46), is observed. The PF-04691502-treated tumors are also evaluated by immunohistochemistry for levels of P-AKT (S473), total AKT, P-S6RP, and total S6RP. Phosphorylation of AKT and S6RP are significantly reduced at 4 hours after a single dose of PF-04691502 at 10 mg/kg. Dose-dependent tumor growth inhibition (TGI) is obtained in the U87MG xenograft model and approximately 73% TGI is observed at the MTD dose of 10 mg/kg.

1013101-36-4

>98% (HPLC)

DMSO:14 mg/mL (32.9 mM) ; Ethanol:<1 mg/mL (<1 mM) ; Water:<1 mg/mL (<1 mM)

COC1=CC=C (C=N1) C1=CC2=C (C) N=C (N) N=C2N ([C@H]2CC[C@@H] (CC2) OCCO) C1=O |r, c:4,6,11,17, t:2,9,14|

C22H27N5O4

425.48

Storage temperature: -20°C. Stability: ≥ 2 years