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 .

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.

• Authors: 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, Lori S Friedman, Angela Hayes, Timothy C Hancox, Arumugam Kugendradas, Letitia Lensun, Pauline Moore, Alan G Olivero, Jodie Pang, Sonal Patel, Giles H Pergl-Wilson, Florence I Raynaud, Anthony Robson, Nahid Saghir, Laurent Salphati, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 18 Pg. 5522-32 (Sep 25 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18754654 (Publication Type: Journal Article)

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Antineoplastic Agents
• Enzyme Inhibitors
• Indazoles
• Phosphoinositide-3 Kinase Inhibitors
• Sulfonamides

Topics

• Administration, Oral
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Biological Availability
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Indazoles (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Neoplasms (drug therapy)
• Phosphoinositide-3 Kinase Inhibitors
• Sulfonamides (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)