Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

被引：450

作者：

Lindsley, CW

Zhao, ZJ

Leister, WH

Robinson, RG

Barnett, SF

Defeo-Jones, D

Jones, RE

Hartman, GD

Huff, JR

Huber, HE

Duggan, ME

机构：

[1] Merck Sharp & Dohme Ltd, Merck Res Labs, Technol Enabled Synth Grp, Dept Med Chem, W Point, PA 19486 USA

[2] Merck Sharp & Dohme Ltd, Merck Res Labs, Dept Canc Res, W Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 03期

关键词：

Akt; PKB; kinase cancer;

D O I：

10.1016/j.bmcl.2004.11.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo. (C) 2004 Elsevier Ltd. All rights reserved.

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页码：761 / 764

页数：4

相关论文

共 21 条

[1]

BARNETT SF, IN PRESS BIOCH

[2] Structure-based optimization of novel azepane derivatives as PKB inhibitors [J].

Breitenlechner, CB ;

Wegge, T ;

Berillon, L ;

Graul, K ;

Marzenell, M ;

Friebe, WG ;

Thomas, U ;

Schumacher, R ;

Huber, R ;

Engh, RA ;

Masjost, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (06) :1375-1390

[3]

Brognard J, 2001, CANCER RES, V61, P3986

[4] Amplification of AKT2 in human pancreatic cancer cells and inhibition of ATK2 expression and tumorigenicity by antisense RNA [J].

Cheng, JQ ;

Ruggeri, B ;

Klein, WM ;

Sonoda, G ;

Altomare, DA ;

Watson, DK ;

Testa, JR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (08) :3636-3641

[5]

Graff Jeremy R, 2002, Expert Opin Ther Targets, V6, P103, DOI 10.1517/14728222.6.1.103

[6] Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC [J].

Haas-Kogan, D ;

Shalev, N ;

Wong, M ;

Mills, G ;

Yount, G ;

Stokoe, D .

CURRENT BIOLOGY, 1998, 8 (21) :1195-1198

[7] PROTEIN KINASES .6. THE EUKARYOTIC PROTEIN-KINASE SUPERFAMILY - KINASE (CATALYTIC) DOMAIN-STRUCTURE AND CLASSIFICATION [J].

HANKS, SK ;

HUNTER, T .

FASEB JOURNAL, 1995, 9 (08) :576-596

[8] Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses [J].

Hsu, JH ;

Shi, YJ ;

Hu, LP ;

Fisher, M ;

Franke, TF ;

Lichtenstein, A .

ONCOGENE, 2002, 21 (09) :1391-1400

[9]

JONES RE, IN PRESS MOL CANC TH

[10] Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt [J].

Kozikowski, AP ;

Sun, HY ;

Brognard, J ;

Dennis, PA .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125 (05) :1144-1145