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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Molecular Medicine in Practice

PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity

Jing Yuan, Pramod P. Mehta, Min-Jean Yin, Shaoxian Sun, Aihua Zou, Jeffrey Chen, Kristina Rafidi, Zheng Feng, Jeffrey Nickel, Jon Engebretsen, Jill Hallin, Alessandra Blasina, Eric Zhang, Leslie Nguyen, Minghao Sun, Peter K. Vogt, Aileen McHarg, Hengmiao Cheng, James G. Christensen, Julie L.C. Kan and Shubha Bagrodia
Jing Yuan
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Pramod P. Mehta
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Min-Jean Yin
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Shaoxian Sun
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Aihua Zou
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Shubha Bagrodia
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DOI: 10.1158/1535-7163.MCT-11-0185 Published November 2011
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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 (IC50 of 7.5–47 nmol/L and 3.8–20 nmol/L, respectively) and inhibited cell proliferation (IC50 of 179–313 nmol/L). PF-04691502 inhibited mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC50 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 G1 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. Mol Cancer Ther; 10(11); 2189–99. ©2011 AACR.

This article is featured in Highlights of This Issue, p. 2009

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • This paper is manuscript no. 21155 of The Scripps Research Institute.

  • Received March 15, 2011.
  • Revision received June 27, 2011.
  • Accepted June 29, 2011.
  • ©2011 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 10 (11)
November 2011
Volume 10, Issue 11
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PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity
Jing Yuan, Pramod P. Mehta, Min-Jean Yin, Shaoxian Sun, Aihua Zou, Jeffrey Chen, Kristina Rafidi, Zheng Feng, Jeffrey Nickel, Jon Engebretsen, Jill Hallin, Alessandra Blasina, Eric Zhang, Leslie Nguyen, Minghao Sun, Peter K. Vogt, Aileen McHarg, Hengmiao Cheng, James G. Christensen, Julie L.C. Kan and Shubha Bagrodia
Mol Cancer Ther November 1 2011 (10) (11) 2189-2199; DOI: 10.1158/1535-7163.MCT-11-0185

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PF-04691502, a Potent and Selective Oral Inhibitor of PI3K and mTOR Kinases with Antitumor Activity
Jing Yuan, Pramod P. Mehta, Min-Jean Yin, Shaoxian Sun, Aihua Zou, Jeffrey Chen, Kristina Rafidi, Zheng Feng, Jeffrey Nickel, Jon Engebretsen, Jill Hallin, Alessandra Blasina, Eric Zhang, Leslie Nguyen, Minghao Sun, Peter K. Vogt, Aileen McHarg, Hengmiao Cheng, James G. Christensen, Julie L.C. Kan and Shubha Bagrodia
Mol Cancer Ther November 1 2011 (10) (11) 2189-2199; DOI: 10.1158/1535-7163.MCT-11-0185
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