Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor

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• 作者：Dirk A. Heerding ; Nelson Rhodes ; Jack D. Leber ; Tammy J. Clark ; Richard M. Keenan ; Louis V. Lafrance ; Mei Li ; Igor G. Safonov ; Dennis T. Takata ; Joseph W. Venslavsky ; Dennis S. Yamashita ; Anthony E. C
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 25, 2008
• 年：2008
• 卷：51
• 期：18
• 页码：5663-5679
• 全文大小：457K
• 年卷期：v.51,no.18(September 25, 2008)
• ISSN：1520-4804

文摘

Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC₅₀ values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3β. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3β phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.