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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

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Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddon Laboratories, Sutton, Surrey, SN2 5NG, United Kingdom and Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
†The coordinates of compound 17 in PI3K p110γ have been deposited (PDB code 3DBS).
* To whom correspondence should be addressed. Phone: +44 0 1753 285823. Fax: +44 0 1753 568367. E-mail: [email protected]
‡Piramed Pharma.
∥Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddon Laboratories.
§Genentech, Inc.
⊥Breakthrough Breast Cancer Research Centre, Institute of Cancer Research.
Cite this: J. Med. Chem. 2008, 51, 18, 5522–5532
Publication Date (Web):August 29, 2008
https://doi.org/10.1021/jm800295d
Copyright © 2008 American Chemical Society

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    Abstract

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    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 p110α. 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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    Tabulation of compound purity, and HPLC tracings. This material is available free of charge via the Internet at http://pubs.acs.org.

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