GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
| Autor: | Marcia Belvin, Laurent Salphati, Leslie Lee, Daniel P. Sutherlin, Jodie Pang, Lori Friedman, Carol O'Brien, Jeffrey Wallin, Jane Guan, Jill M. Spoerke, Cristina Lewis, Robert Kassees, Wei Wei Prior, Olivero Alan G, Deepak Sampath, Leanne Ross, John Lesnick, Mark R. Lackner, Kyle A. Edgar, Sonal Patel, Megan Berry, Letitia Lensun, Jim Nonomiya |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
medicine.medical_specialty Antineoplastic Agents Mice Phosphatidylinositol 3-Kinases Cell Line Tumor Neoplasms Internal medicine medicine Animals Humans PTEN Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors biology Kinase Cell growth Akt/PKB signaling pathway TOR Serine-Threonine Kinases RPTOR Cancer Models Theoretical Bridged Bicyclo Compounds Heterocyclic HCT116 Cells medicine.disease Xenograft Model Antitumor Assays Pyrimidines Endocrinology Oncology Cancer research biology.protein Signal transduction Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 10:2426-2436 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426–36. ©2011 AACR. |
| Databáze: | OpenAIRE |
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