Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

被引：74

作者：

Heffron, Timothy P. ^{[1
]}

Berry, Megan ^{[2
]}

Castanedo, Georgette ^{[1
]}

Chang, Christine ^{[3
]}

Chuckowree, Irina ^{[4
]}

Dotson, Jennafer ^{[1
]}

Folkes, Adrian ^{[4
]}

Gunzner, Janet ^{[1
]}

Lesnick, John D. ^{[3
]}

Lewis, Cristina ^{[3
]}

Mathieu, Simon ^{[1
]}

Nonomiya, Jim ^{[3
]}

Olivero, Alan ^{[1
]}

Pang, Jodie ^{[5
]}

Peterson, David ^{[3
]}

Salphati, Laurent ^{[5
]}

Sampath, Deepak ^{[2
]}

Sideris, Steve ^{[3
]}

Sutherlin, Daniel P. ^{[1
]}

Tsui, Vickie ^{[1
]}

Wan, Nan Chi ^{[4
]}

Wang, Shumei ^{[1
]}

Wong, Susan ^{[5
]}

Zhu, Bing-yan ^{[1
]}

机构：

[1] Genentech Inc, Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Small Mol Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Biochem Pharmacol, San Francisco, CA 94080 USA

[4] Piramed Pharma, Slough SL1 4NL, Berks, England

[5] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 08期

关键词：

PI3K; mTOR; Kinase inhibitors; CANCER; PATHWAY; MTOR;

D O I：

10.1016/j.bmcl.2010.03.046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modi. cation resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2408 / 2411

页数：4

共 13 条

[1]

Bayliss T., 2008, Patent No. [WO2008/070740 A1, 2008070740]

[2] Activation of AKT kinases in cancer: Implications for therapeutic targeting [J].

Bellacosa, A ;

Kumar, CC ;

Di Cristofano, A ;

Testa, JR .

ADVANCES IN CANCER RESEARCH, VOL 94, 2005, 94 :29-+

[3] The phosphoinositide 3-kinase pathway [J].

Cantley, LC .

SCIENCE, 2002, 296 (5573) :1655-1657

[4]

Castanedo G., 2008, Pharmaceutical Compositions and Use in the Treatment of Cancer, Patent No. [WO2008/073785 A2, 2008073785]

[5]

Denton SM, 1999, SYNLETT, P55

[6] mTOR inhibitors in the treatment of cancer [J].

Fasolo, Angelica ;

Sessa, Cristiana .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2008, 17 (11) :1717-1734

[7] The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer [J].

Folkes, Adrian J. ;

Ahmadi, Khatereh ;

Alderton, Wendy K. ;

Alix, Sonia ;

Baker, Stewart J. ;

Box, Gary ;

Chuckowree, Irina S. ;

Clarke, Paul A. ;

Depledge, Paul ;

Eccles, Suzanne A. ;

Friedman, Lori S. ;

Hayes, Angela ;

Hancox, Timothy C. ;

Kugendradas, Arumugam ;

Lensun, Letitia ;

Moore, Pauline ;

Olivero, Alan G. ;

Pang, Jodie ;

Patel, Sonal ;

Pergl-Wilson, Giles H. ;

Raynaud, Florence I. ;

Robson, Anthony ;

Saghir, Nahid ;

Salphati, Laurent ;

Sohal, Sukhjit ;

Ultsch, Mark H. ;

Valenti, Melanie ;

Wallweber, Heidi J. A. ;

Wan, Nan Chi ;

Wiesmann, Christian ;

Workman, Paul ;

Zhyvoloup, Alexander ;

Zvelebil, Marketa J. ;

Shuttleworth, Stephen J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (18) :5522-5532

[8] Defining the role of mTOR in cancer [J].

Guertin, David A. ;

Sabatini, David M. .

CANCER CELL, 2007, 12 (01) :9-22

[9] Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy [J].

Ihle, Nathan T. ;

Powis, Garth .

MOLECULAR CANCER THERAPEUTICS, 2009, 8 (01) :1-9

[10] PI3K inhibitors for cancer treatment: where do we stand? [J].

Maira, Sauveur-Michel ;

Stauffer, Frederic ;

Schnell, Christian ;

Garcia-Echeverria, Carlos .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2009, 37 :265-272

← 1 2 →