کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1369782 | 981789 | 2012 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor](/preview/png/1369782.png)
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 AKTSer473 phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-RasG12V oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 10, 15 May 2012, Pages 3460–3466