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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- 作者：Daniel P. Sutherlin ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：November 10, 2011
- 年：2011
- 卷：54
- 期：21
- 页码：7579-7587
- 全文大小：967K
- 年卷期：v.54,no.21(November 10, 2011)
- ISSN：1520-4804
文摘
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 PI3K伪, 尾, 未, and 纬, 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.