AI Article Synopsis
- PI3K is a critical target for cancer therapies due to its role in various cancers, making its inhibition a viable treatment strategy.
- Researchers optimized imidazo [1,2-a] pyrazines, leading to the discovery of compound 14 (ETP-46321), known for its strong activity and favorable pharmacokinetics when taken orally.
- In studies, ETP-46321 effectively reduced AKT(Ser473) phosphorylation in a time-dependent manner, correlating with its presence in tumor tissues and demonstrating significant tumor growth inhibition in a mouse model with a K-Ras mutation.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.bmcl.2012.03.090 | DOI Listing |
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