2. Academic Validation
  3. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor

Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor

  • J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p.
Aranapakam M Venkatesan 1,  Christoph M Dehnhardt,  Efren Delos Santos,  Zecheng Chen,  Osvaldo Dos Santos,  Semiramis Ayral-Kaloustian,  Gulnaz Khafizova,  Natasja Brooijmans,  Robert Mallon,  Irwin Hollander,  Larry Feldberg,  Judy Lucas,  Ker Yu,  James Gibbons,  Robert T Abraham,  Inder Chaudhary,  Tarek S Mansour
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
PMID: 20166697 DOI: 10.1021/jm901830p
Abstract

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for Cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR Inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

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