期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 22, 期 10, 页码 3460-3466出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.03.090
关键词
PI3K inhibitors; Cancer treatment
资金
- Ministry of Science and Innovation (MICINN) of Spain [CIT-090100-2007-48]
Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. (C) 2012 Elsevier Ltd. All rights reserved.
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