Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model

被引：67

作者：

Bilodeau, Mark T. ^{[1
]}

Balitza, Adrienne E. ^{[1
]}

Hoffman, Jacob M. ^{[1
]}

Manley, Peter J. ^{[1
]}

Barnett, Stanley F. ^{[2
]}

Defeo-Jones, Deborah ^{[2
]}

Haskell, Kathleen ^{[2
]}

Jones, Raymond E. ^{[2
]}

Leander, Karen ^{[2
]}

Robinson, Ronald G. ^{[2
]}

Smith, Anthony M. ^{[1
]}

Huber, Hans E. ^{[2
]}

Hartman, George D. ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck & Co Inc, Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 11期

关键词：

Akt; oncology;

D O I：

10.1016/j.bmcl.2008.04.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3178 / 3182

页数：5

共 18 条

[1] Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors
Barnett, SF
Defeo-Jones, D
Fu, S
Hancock, PJ
Haskell, KM
Jones, RE
Kahana, JA
Kral, AM
Leander, K
Lee, LL
Malinowski, J
McAvoy, EM
Nahas, DD
Robinson, RG
Huber, HE
[J]. BIOCHEMICAL JOURNAL, 2005, 385 : 399 - 408
[2] The phosphoinositide 3-kinase pathway
Cantley, LC
[J]. SCIENCE, 2002, 296 (5573) : 1655 - 1657
[3] Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand
Choi-Sledeski, YM
Kearney, R
Poli, G
Pauls, H
Gardner, C
Gong, Y
Becker, M
Davis, R
Spada, A
Liang, G
Chu, V
Brown, K
Collussi, D
Leadley, R
Rebello, S
Moxey, P
Morgan, S
Bentley, R
Kasiewski, C
Maignan, S
Guilloteau, JP
Mikol, V
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (05) : 681 - 684
[4] DeFeo-Jones D, 2005, MOL CANCER THER, V4, P271
[5] MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling
Engelman, Jeffrey A.
Zejnullahu, Kreshnik
Mitsudomi, Tetsuya
Song, Youngchul
Hyland, Courtney
Park, Joon Oh
Lindeman, Neal
Gale, Christopher-Michael
Zhao, Xiaojun
Christensen, James
Kosaka, Takayuki
Holmes, Alison J.
Rogers, Andrew M.
Cappuzzo, Federico
Mok, Tony
Lee, Charles
Johnson, Bruce E.
Cantley, Lewis C.
Janne, Pasi A.
[J]. SCIENCE, 2007, 316 (5827) : 1039 - 1043
[6] Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors
Hartnett, John C.
Barnett, Stanley F.
Bilodeau, Mark T.
Defeo-Jones, Deborah
Hartman, George D.
Huber, Hans E.
Jones, Raymond E.
Kral, Astrid M.
Robinson, Ronald G.
Wu, Zhicai
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (06) : 2194 - 2197
[7] Exploiting the PI3K/AKT pathway for cancer drug discovery
Hennessy, BT
Smith, DL
Ram, PT
Lu, YL
Mills, GB
[J]. NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (12) : 988 - 1004
[8] Synthesis of photoswitchable hemithioindigo-based ω-amino acids and application in Boc-based peptide assembly
Herre, S
Steinle, W
Rück-Braun, K
[J]. SYNTHESIS-STUTTGART, 2005, (19): : 3297 - 3300
[9] ERBB receptors and cancer: The complexity of targeted inhibitors
Hynes, NE
Lane, HA
[J]. NATURE REVIEWS CANCER, 2005, 5 (05) : 341 - 354
[10] Mutation of the PIK3CA oncogene in human cancers
Karakas, B
Bachman, KE
Park, BH
[J]. BRITISH JOURNAL OF CANCER, 2006, 94 (04) : 455 - 459

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