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Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer

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Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom
Phone: 650-225-3171. Fax: 650-225-2061. E-mail: [email protected]
Cite this: J. Med. Chem. 2011, 54, 21, 7579–7587
Publication Date (Web):October 7, 2011
https://doi.org/10.1021/jm2009327
Copyright © 2011 American Chemical Society

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    Abstract

    Abstract Image

    The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC50s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a Ki of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.

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