Anthony Robson

Publications (2)10.03 Total impact

• Article: Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.

  Florence I Raynaud, Suzanne A Eccles, Sonal Patel, Sonia Alix, Gary Box, Irina Chuckowree, Adrian Folkes, Sharon Gowan, Alexis De Haven Brandon, Francesca Di Stefano, [......], Anthony Robson, Nahid Saghir, Alexander Zhyvoloup, Edward McDonald, Peter Sheldrake, Stephen Shuttleworth, Melanie Valenti, Nan Chi Wan, Paul A Clarke, Paul Workman
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  ABSTRACT: The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110alpha with IC(50) < or = 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% antiproliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.
  Molecular Cancer Therapeutics 08/2009; 8(7):1725-38. · 5.23 Impact Factor
• Source

  Available from: Paul Andrew Clarke

  Article: The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

  Adrian J Folkes, Khatereh Ahmadi, Wendy K Alderton, Sonia Alix, Stewart J Baker, Gary Box, Irina S Chuckowree, Paul A Clarke, Paul Depledge, Suzanne A Eccles, [......], Sukhjit Sohal, Mark H Ultsch, Melanie Valenti, Heidi J A Wallweber, Nan Chi Wan, Christian Wiesmann, Paul Workman, Alexander Zhyvoloup, Marketa J Zvelebil, Stephen J Shuttleworth
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  ABSTRACT: Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
  Journal of Medicinal Chemistry 09/2008; 51(18):5522-32. · 4.80 Impact Factor