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

被引：55

作者：

Cheng, Hengmiao ^{[1
]}

Li, Chunze ^{[2
]}

Bailey, Simon ^{[1
]}

Baxi, Sangita M. ^{[3
]}

Goulet, Lance ^{[2
]}

Guo, Lisa ^{[1
]}

Hoffman, Jacqui ^{[1
]}

Jiang, Ying ^{[2
]}

Johnson, Theodore Otto ^{[1
]}

Johnson, Ted W. ^{[1
]}

Knighton, Daniel R. ^{[1
]}

Li, John ^{[3
]}

Liu, Kevin K. -C. ^{[1
]}

Liu, Zhengyu ^{[1
]}

Marx, Matthew A. ^{[1
]}

Walls, Marlena ^{[3
]}

Wells, Peter A. ^{[3
]}

Yin, Min-Jean ^{[3
]}

Zhu, Jinjiang ^{[1
]}

Zientek, Michael ^{[2
]}

机构：

[1] Pfizer Worldwide Res & Dev, La Jolla Labs, Canc Chem, San Diego, CA 92121 USA

[2] Pfizer Worldwide Res & Dev, La Jolla Labs, PDM, San Diego, CA 92121 USA

[3] Pfizer Worldwide Res & Dev, La Jolla Labs, Oncol Res Unit, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 01期

关键词：

PF-04979064; kinase inhibitor; PI3K/mTOR dual inhibitor; aldehyde oxidase metabolism; cancer; antitumor; ALDEHYDE OXIDASE; METABOLISM; PF-04691502; CLEARANCE; TARGET; PI3K;

D O I：

10.1021/ml300309h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

引用

页码：91 / 97

页数：7

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