Synthesis and SAR of Novel 4-Morpholinopyrrolopyrimidine Derivatives as Potent Phosphatidylinositol 3-Kinase Inhibitors
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- 作者：Zecheng Chen ; Aranapakam M. Venkatesan ; Christoph M. Dehnhardt ; Semiramis Ayral-Kaloustian ; Natasja Brooijmans ; Robert Mallon ; Larry Feldberg ; Irwin Hollander ; Judy Lucas ; Ker Yu ; Fangming Kong ; Tarek
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：April 22, 2010
- 年：2010
- 卷：53
- 期：8
- 页码：3169-3182
- 全文大小：1111K
- 年卷期：v.53,no.8(April 22, 2010)
- ISSN：1520-4804
文摘
Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110α isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kα and mTOR, leading to the discovery of PI3Kα selective inhibitors (e.g., 9) and dual PI3Kα/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kα/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.