Pyrazolopyrimidines as dual Akt/p70S6K inhibitors

被引：21

作者：

Rice, Kenneth D. ^{[1
]}

Kim, Moon H. ^{[1
]}

Bussenius, Joerg ^{[1
]}

Anand, Neel K. ^{[1
]}

Blazey, Charles M. ^{[1
]}

Bowles, Owen J. ^{[1
]}

Canne-Bannen, Lynne ^{[1
]}

Chan, Diva S. -M. ^{[1
]}

Chen, Baili ^{[1
]}

Co, Erick W. ^{[1
]}

Costanzo, Simona ^{[1
]}

DeFina, Steven C. ^{[1
]}

Dubenko, Larisa ^{[1
]}

Engst, Stefan ^{[1
]}

Franzini, Maurizio ^{[1
]}

Huang, Ping ^{[1
]}

Jammalamadaka, Vasu ^{[1
]}

Khoury, Richard G. ^{[1
]}

Klein, Rhett R. ^{[1
]}

Laird, A. Douglas ^{[1
]}

Le, Donna T. ^{[1
]}

Mac, Morrison B. ^{[1
]}

Matthews, David J. ^{[1
]}

Markby, David ^{[1
]}

Miller, Nicole ^{[1
]}

Nuss, John M. ^{[1
]}

Parks, Jason J. ^{[1
]}

Tsang, Tsze H. ^{[1
]}

Tsuhako, Amy L. ^{[1
]}

Wang, Yong ^{[1
]}

Xu, Wei ^{[1
]}

机构：

[1] Exelixis, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 08期

关键词：

p70S6K inhibitor; Akt inhibitor; Pyrazolopyrimidine; PI3K pathway; Cancer; PATHWAY;

D O I：

10.1016/j.bmcl.2012.03.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2693 / 2697

页数：5

共 11 条

[1] 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

[2] Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors [J].

Bussenius, Joerg ;

Anand, Neel K. ;

Blazey, Charles M. ;

Bowles, Owen J. ;

Bannen, Lynne Canne ;

Chan, Diva S. -M. ;

Chen, Baili ;

Co, Erick W. ;

Costanzo, Simona ;

DeFina, Steven C. ;

Dubenko, Larisa ;

Engst, Stefan ;

Franzini, Maurizio ;

Huang, Ping ;

Jammalamadaka, Vasu ;

Khoury, Richard G. ;

Kim, Moon H. ;

Klein, Rhett R. ;

Laird, Douglas ;

Le, Donna T. ;

Mac, Morrison B. ;

Matthews, David J. ;

Markby, David ;

Miller, Nicole ;

Nuss, John M. ;

Parks, Jason J. ;

Tsang, Tsze H. ;

Tsuhako, Amy L. ;

Wang, Yong ;

Xu, Wei ;

Rice, Kenneth D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (06) :2283-2286

[3] Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-Deficient glioblastoma [J].

Cloughesy, Tim F. ;

Yoshimoto, Koji ;

Nghiemphu, Phioanh ;

Brown, Kevin ;

Dang, Julie ;

Zhu, Shaojun ;

Hsueh, Teli ;

Chen, Yinan ;

Wang, Wei ;

Youngkin, David ;

Liau, Linda ;

Martin, Neil ;

Becker, Don ;

Bergsneider, Marvin ;

Lai, Albert ;

Green, Richard ;

Oglesby, Tom ;

Koleto, Michael ;

Trent, Jeff ;

Horvath, Steve ;

Mischel, Paul S. ;

Mellinghoff, Ingo K. ;

Sawyers, Charles L. .

PLOS MEDICINE, 2008, 5 (01) :139-151

[4] The PI3K Pathway As Drug Target in Human Cancer [J].

Courtney, Kevin D. ;

Corcoran, Ryan B. ;

Engelman, Jeffrey A. .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (06) :1075-1083

[5] Targeting PI3K signalling in cancer: opportunities, challenges and limitations [J].

Engelman, Jeffrey A. .

NATURE REVIEWS CANCER, 2009, 9 (08) :550-562

[6] Exploiting the PI3K/AKT pathway for cancer drug discovery [J].

Hennessy, BT ;

Smith, DL ;

Ram, PT ;

Lu, YL ;

Mills, GB .

NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (12) :988-1004

[7] Targeting the phosphoinositide 3-kinase pathway in cancer [J].

Liu, Pixu ;

Cheng, Hailing ;

Roberts, Thomas M. ;

Zhao, Jean J. .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (08) :627-644

[8] mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt [J].

O'Reilly, KE ;

Rojo, F ;

She, QB ;

Solit, D ;

Mills, GB ;

Smith, D ;

Lane, H ;

Hofmann, F ;

Hicklin, DJ ;

Ludwig, DL ;

Baselga, J ;

Rosen, N .

CANCER RESEARCH, 2006, 66 (03) :1500-1508

[9] PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer [J].

Serra, V. ;

Scaltriti, M. ;

Prudkin, L. ;

Eichhorn, P. J. A. ;

Ibrahim, Y. H. ;

Chandarlapaty, S. ;

Markman, B. ;

Rodriguez, O. ;

Guzman, M. ;

Rodriguez, S. ;

Gili, M. ;

Russillo, M. ;

Parra, J. L. ;

Singh, S. ;

Arribas, J. ;

Rosen, N. ;

Baselga, J. .

ONCOGENE, 2011, 30 (22) :2547-2557

[10] The phosphatidylinositol 3-kinase-AKT pathway in human cancer [J].

Vivanco, I ;

Sawyers, CL .

NATURE REVIEWS CANCER, 2002, 2 (07) :489-501

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