The Identification of 2-(1<i>H</i>-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-<i>d</i>]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer
Adrian Folkes(Institute of Cancer Research), Khatereh Ahmadi(Cancer Research UK), W. Alderton(Cancer Research UK), Sonia Alix(Institute of Cancer Research), Stewart Baker(Institute of Cancer Research), Gary Box(Institute of Cancer Research), Irina Chuckowree(Cancer Research UK), Paul A. Clarke(Institute of Cancer Research), Paul Depledge(Institute of Cancer Research), Suzanne A. Eccles(Institute of Cancer Research), Lori S. Friedman(Cancer Research UK), Angela Hayes(Cancer Research UK), Timothy C. Hancox(Cancer Research UK), Arumugam Kugendradas(Cancer Research UK), Letitia Lensun(Institute of Cancer Research), Pauline Moore(Institute of Cancer Research), Alan G. Olivero(Cancer Research UK), Jodie Pang(Cancer Research UK), Sonal Patel(Cancer Research UK), Giles Pergl-Wilson(Cancer Research UK), Florence I. Raynaud(Cancer Research UK), Anthony G. Robson(Cancer Research UK), Nahid Saghir(Institute of Cancer Research), Laurent Salphati(Cancer Research UK), Sukhjit Sohal(Cancer Research UK), Mark Ultsch(Institute of Cancer Research), Melanie Valenti(Institute of Cancer Research), Heidi J.A. Wallweber(Cancer Research UK), Nan Chi Wan(Cancer Research UK), Christian Wiesmann(Cancer Research UK), Paul Workman(Cancer Research UK), Alexander Zhyvoloup(Cancer Research UK), Marketa Zvelebil(Cancer Research UK), Stephen J. Shuttleworth(Cancer Research UK)
Cited by 746Open Access
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.
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