title: PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity.
abstract: Deregulation of the phosphoinositide 3-kinase (PI3K) signaling pathway such as by PTEN loss or PIK3CA mutation occurs frequently in human cancer and contributes to resistance to antitumor therapies. Inhibition of key signaling proteins in the pathway therefore represents a valuable targeting strategy for diverse cancers. PF-04691502 is an ATP-competitive PI3K/mTOR dual inhibitor, which potently inhibited recombinant class I PI3K and mTOR in biochemical assays and suppressed transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduced phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nmol/L and 3.8-20 nmol/L, respectively) and inhibited cell proliferation (IC(50) of 179-313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nmol/L and inhibited the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibited PI3K, whereas mTOR inhibition persisted for 24 to 48 hours. PF-04691502 induced cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity was observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. In summary, PF-04691502 is a potent dual PI3K/mTOR inhibitor with broad antitumor activity. PF-04691502 has entered phase I clinical trials.
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Pramod P
authors.initials: PP
authors.lastname: Mehta
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Sun
authors.forename: Aihua
authors.initials: A
authors.lastname: Zou
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chen
authors.forename: Kristina
authors.initials: K
authors.lastname: Rafidi
authors.forename: Zheng
authors.initials: Z
authors.lastname: Feng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nickel
authors.forename: Jon
authors.initials: J
authors.lastname: Engebretsen
authors.forename: Jill
authors.initials: J
authors.lastname: Hallin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Blasina
authors.forename: Eric
authors.initials: E
authors.lastname: Zhang
authors.forename: Leslie
authors.initials: L
authors.lastname: Nguyen
authors.forename: Minghao
authors.initials: M
authors.lastname: Sun
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.forename: Aileen
authors.initials: A
authors.lastname: McHarg
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Julie L C
authors.initials: JL
authors.lastname: Kan
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D058570:TOR Serine-Threonine Kinases