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Ref Type Journal Article
PMID (21750219)
Authors Yuan J, Mehta PP, Yin MJ, Sun S, Zou A, Chen J, Rafidi K, Feng Z, Nickel J, Engebretsen J, Hallin J, Blasina A, Zhang E, Nguyen L, Sun M, Vogt PK, McHarg A, Cheng H, Christensen JG, Kan JL, Bagrodia S
Title PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity.
Journal Molecular cancer therapeutics
Vol 10
Issue 11
Date 2011 Nov
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PF-04691502 PF-04691502 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PF-04691502 PF04691502|PF 04691502 mTOR Inhibitor 51 PI3K Inhibitor (Pan) 38 PF-04691502 is a PI3K/mTOR dual inhibitor with broad antitumor activity (PMID: 21750219, PMID: 31822716).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA P539R PIK3CA H1047R breast cancer sensitive PF-04691502 Preclinical - Cell culture Actionable In a preclinical study, PF-04691502 inhibited Akt phosphorylation and proliferation of breast cancer cells harboring both PIK3CA P539R and H1047R in culture (PMID: 21750219). 21750219
PIK3CA mutant lung non-small cell carcinoma sensitive PF-04691502 Preclinical - Cell line xenograft Actionable In a preclinical study, PF-04691502 inhibited tumor growth in non-small cell lung cancer cell line xenograft models harboring PIK3CA mutations (PMID: 21750219). 21750219
PIK3CA H1047R ovarian cancer sensitive PF-04691502 Preclinical - Cell line xenograft Actionable In a preclinical study, PF-04691502 inhibited Pi3k signaling, resulted in growth inhibition of ovarian cancer cells harboring PIK3CA H1047R in culture and in cell line xenograft models (PMID: 21750219). 21750219