Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

被引：44

作者：

Bruce, Ian ^{[1
]}

Akhlaq, Mohammed ^{[1
]}

Bloomfield, Graham C. ^{[1
]}

Budd, Emma ^{[1
]}

Cox, Brian ^{[1
]}

Cuenoud, Bernard ^{[1
]}

Finan, Peter ^{[1
]}

Gedeck, Peter ^{[1
]}

Hatto, Julia ^{[1
]}

Hayler, Judy F. ^{[1
]}

Head, Denise ^{[1
]}

Keller, Thomas ^{[1
]}

Kirman, Louise ^{[1
]}

Leblanc, Catherine ^{[1
]}

Le Grand, Darren ^{[1
]}

McCarthy, Clive ^{[1
]}

O'Connor, Desmond ^{[1
]}

Owen, Charles ^{[1
]}

Oza, Mrinalini S. ^{[1
]}

Pilgrim, Gaynor ^{[1
]}

Press, Nicola E. ^{[1
]}

Sviridenko, Lilya ^{[1
]}

Whitehead, Lewis ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Resp Dis Area, Horsham RH12 5AB, W Sussex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 17期

关键词：

PI3-Kinase inhibitors; Pharmacological tools; Aminothiazoles; Parallel synthesis; Isoform selectivity; PHOSPHOINOSITIDE; 3-KINASE; P110-ALPHA; KINASES;

D O I：

10.1016/j.bmcl.2012.07.042

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5445 / 5450

页数：6

共 30 条

[1]

Abraham, RT .

DNA REPAIR, 2004, 3 (8-9) :883-887

[2]

BLOOMFIELD GC, 2005, Patent No. 2005021519

[3]

BRUCE I, 2008, Patent No. 2008000421

[4]

BUDD E, 2007, Patent No. 2007068473

[5]

Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis [J].

Camps, M ;

Rückle, T ;

Ji, H ;

Ardissone, V ;

Rintelen, F ;

Shaw, J ;

Ferrandi, C ;

Chabert, C ;

Gillieron, C ;

Françon, B ;

Martin, T ;

Gretener, D ;

Perrin, D ;

Leroy, D ;

Vitte, PA ;

Hirsch, E ;

Wymann, MP ;

Cirillo, R ;

Schwarz, MK ;

Rommel, C .

NATURE MEDICINE, 2005, 11 (09) :936-943

[6]

Dual Inhibition of PI3Kα and mTOR as an Alternative Treatment for Kaposi's Sarcoma [J].

Chaisuparat, Risa ;

Hu, Jiadi ;

Jham, Bruno C. ;

Knight, Zachary A. ;

Shokat, Kevan M. ;

Montaner, Silvia .

CANCER RESEARCH, 2008, 68 (20) :8361-8368

[7]

Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils [J].

Condliffe, AM ;

Davidson, K ;

Anderson, KE ;

Ellson, CD ;

Crabbe, T ;

Okkenhaug, K ;

Vanhaesebroeck, B ;

Turner, M ;

Webb, L ;

Wymann, MP ;

Hirsch, E ;

Ruckle, T ;

Camps, M ;

Rommel, C ;

Jackson, SP ;

Chilvers, ER ;

Stephens, LR ;

Hawkins, PT .

BLOOD, 2005, 106 (04) :1432-1440

[8]

Fairhurst R. H., 2009, World Pat, Patent No. [WO 2009/080705, 2009080705]

[9]

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals [J].

Herman, Sarah E. M. ;

Gordon, Amber L. ;

Wagner, Amy J. ;

Heerema, Nyla A. ;

Zhao, Weiqiang ;

Flynn, Joseph M. ;

Jones, Jeffrey ;

Andritsos, Leslie ;

Puri, Kamal D. ;

Lannutti, Brian J. ;

Giese, Neill A. ;

Zhang, Xiaoli ;

Wei, Lai ;

Byrd, John C. ;

Johnson, Amy J. .

BLOOD, 2010, 116 (12) :2078-2088

[10]

Pyranone, thiopyranone, and pyridone inhibitors of phosphatidylinositol 3-kinase related kinases. Structure-activity relationships for DNA-dependent protein kinase inhibition, and identification of the first potent and selective inhibitor of the ataxia telangiectasia mutated kinase [J].

Hollick, Jonathan J. ;

Rigoreau, Laurent J. M. ;

Cano-Soumillac, Celine ;

Cockcroft, Xiaoling ;

Curtin, Nicola J. ;

Frigerio, Mark ;

Golding, Bernard T. ;

Guiard, Sophie ;

Hardcastle, Ian R. ;

Hickson, Ian ;

Hummersone, Marc G. ;

Menear, Keith A. ;

Martin, Niall M. B. ;

Matthews, Ian ;

Newell, David R. ;

Ord, Rachel ;

Richardson, Caroline J. ;

Smith, Graeme C. M. ;

Griffin, Roger J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (08) :1958-1972

← 1 2 3 →