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PX-866

Description of PX-866:  PX-866 is a small-molecule wortmannin analogue inhibitor of the alpha, gamma, and delta isoforms of phosphoinositide 3-kinase (PI3K) with potential antineoplastic activity. PI3K inhibitor PX-866 inhibits the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) and activation of the PI3K/Akt signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Current developer:   Oncothyreon

PX-866 is an orally available nanomolar pan-inhibitor of PI-3K whose administration results in antitumor activity and pathway (AKT, S6 and mTOR) inhibition in animal models. Loss of PTEN and/or PI 3K mutations have been associated with enhanced susceptibility to PX-866. PX-866 is being evaluated in a phase 1 clinical trial to determine the MTD, and measure safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in PBMCs and tumor tissue in patients with solid tumors. Conclusions: PX-866 is a novel oral PI-3K inhibitor that is undergoing development in a clinical trial with built-in PD endpoints. PX-866 has shown to have a mild side effect profile while inducing stabilization of disease in previously progressing cancer patients. Oral PX-866 provides target inhibition even at low drug doses and inhibition is maintained for an extended time following the last dose. See asco.com. website.

 1: Gwak HS, Shingu T, Chumbalkar V, Hwang YH, Dejournett R, Latha K, Koul D, Yung WK, Powis G, Farrell NP, Bögler O. Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer. 2010 Apr 15. [Epub ahead of print] PubMed PMID: 20473884.

2: Koul D, Shen R, Kim YW, Kondo Y, Lu Y, Bankson J, Ronen SM, Kirkpatrick DL, Powis G, Yung WK. Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol. 2010 Feb 15. [Epub ahead of print] PubMed PMID: 20156803.

3: Le Cras TD, Korfhagen TR, Davidson C, Schmidt S, Fenchel M, Ikegami M, Whitsett JA, Hardie WD. Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Pathol. 2010 Feb;176(2):679-86. Epub 2009 Dec 30. PubMed PMID: 20042669; PubMed Central PMCID: PMC2808075.

4: Ihle NT, Lemos R, Schwartz D, Oh J, Halter RJ, Wipf P, Kirkpatrick L, Powis G. Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther. 2009 Jan;8(1):94-100. PubMed PMID: 19139117; PubMed Central PMCID: PMC2633941.

5: Ihle NT, Lemos R Jr, Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res. 2009 Jan 1;69(1):143-50. PubMed PMID: 19117997; PubMed Central PMCID: PMC2613546.

6: Yang Y, Iwanaga K, Raso MG, Wislez M, Hanna AE, Wieder ED, Molldrem JJ, Wistuba II, Powis G, Demayo FJ, Kim CF, Kurie JM. Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer. PLoS One. 2008 May 21;3(5):e2220. PubMed PMID: 18493606; PubMed Central PMCID: PMC2376060.

7: LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat. 2008 Feb-Apr;11(1-2):32-50. Epub 2007 Dec 31. Review. PubMed PMID: 18166498; PubMed Central PMCID: PMC2442829.

8: Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther. 2007 Sep;6(9):2505-14. Epub 2007 Aug 31. PubMed PMID: 17766839.

9: Williams R, Baker AF, Ihle NT, Winkler AR, Kirkpatrick L, Powis G. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother Pharmacol. 2006 Oct;58(4):444-50. Epub 2006 Feb 17. PubMed PMID: 16485116; PubMed Central PMCID: PMC1486800.

10: Ihle NT, Paine-Murrieta G, Berggren MI, Baker A, Tate WR, Wipf P, Abraham RT, Kirkpatrick DL, Powis G. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther. 2005 Sep;4(9):1349-57. PubMed PMID: 16170026; PubMed Central PMCID: PMC1432090.

11: Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther. 2004 Jul;3(7):763-72. PubMed PMID: 15252137.