PF-04691502

PF-04691502 is a potent and selective dual PI3K/mTOR inhibitor to phosphorylation of AKT T308 and AKT S473 with IC50 of 7.5 and 3.8 nM, respectively. PF-04691502 is an ATP-competitive inhibitor which potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild type PI3Kγ, δ or mutant PI3Kα.[1] PF-04691502 has potential antineoplastic activity. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 decreases phosphorylation of AKT T308 and AKT S473 with IC50 ranging from 7.5 to 47 nM and from 3.8 to 20 nM respectively, and inhibits cell proliferation with IC50 ranging from 179 to 313 nM. In addition, PF-04691502 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. 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. Short-term exposure to PF-04691502 predominantly inhibits PI3K, while mTOR inhibition persists for 24-48 hours. PF-04691502 causes cell cycle G1 arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation) and gefitinib- and erlotinib-resistant NSCLC xenografts. [2] PF-04691502 is originally developed by Pfizer. PF-04691502 is under a phase II clinical trial in the treatment of endometrial neoplasms.

• [1] Mol Cancer Ther. 2011;10(8):1440-9
• [2] Mol Cancer Ther. 2011;10(11):2189-99