Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design

来自 ACS

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作者：

H Cheng，C Li，S Bailey，SM Baxi，Michael Zientek

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摘要：

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Kα or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway,e.g.PI3K, AKT, mTOR, offers great potential for the treatment of cancer. Lead optimization through integration of structure based drug design (SBDD) and physical properties-based optimization (PPBO) led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502,1) that demonstrated potentin vitroinhibitory activity against both PI3K and mTOR, excellent kinase selectivity, good ADMET, and robustin vivoefficacy in a mouse xenograft tumor growth model. Compound1is currently being evaluated in human clinical trials for the treatment of cancer.

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关键词：

PF-04979064 kinase inhibitor PI3K/mTOR dual inhibitor aldehyde oxidase metabolism cancer antitumor

DOI：

10.1021/ml300309h

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年份：

2013