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

  • J Med Chem. 2011 Nov 10;54(21):7579-87. doi: 10.1021/jm2009327.
Daniel P Sutherlin  1 ,  Linda Bao ,  Megan Berry ,  Georgette Castanedo ,  Irina Chuckowree ,  Jenna Dotson ,  Adrian Folks ,  Lori Friedman ,  Richard Goldsmith ,  Janet Gunzner ,  Timothy Heffron ,  John Lesnick ,  Cristina Lewis ,  Simon Mathieu ,  Jeremy Murray ,  Jim Nonomiya ,  Jodie Pang ,  Niel Pegg ,  Wei Wei Prior ,  Lionel Rouge ,  Laurent Salphati ,  Deepak Sampath ,  Qingping Tian ,  Vickie Tsui ,  Nan Chi Wan ,  Shumei Wang ,  Binqing Wei ,  Christian Wiesmann ,  Ping Wu ,  Bing-Yan Zhu ,  Alan Olivero
Affiliations
PMID: 21981714 DOI: 10.1021/jm2009327
Abstract

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 IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) 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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