Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014

被引：177

作者：

Pike, Kurt G. ^{[1
]}

Malagu, Karine ^{[2
]}

Hummersone, Marc G. ^{[2
]}

Menear, Keith A. ^{[2
]}

Duggan, Heather M. E. ^{[2
]}

Gomez, Sylvie ^{[2
]}

Martin, Niall M. B. ^{[2
]}

Ruston, Linette ^{[1
]}

Pass, Sarah L. ^{[1
]}

Pass, Martin ^{[1
]}

机构：

[1] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England

[2] KuDOS Pharmaceut Ltd, Cambridge CB4 0WG, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 05期

关键词：

mTOR; Inhibitor; AZD8055; AZD2014; Kinase; MAMMALIAN TARGET; SIGNALING FUNCTIONS; ANTITUMOR-ACTIVITY; IN-VITRO; RAPAMYCIN; PATHWAY; PROTEIN; DRUGS; S6K1;

D O I：

10.1016/j.bmcl.2013.01.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC50, led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21). (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1212 / 1216

页数：5

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