Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

被引：75

作者：

Boyd, Scott ^{[1
]}

Brookfield, Joanna L. ^{[2
]}

Critchlow, Susan E. ^{[1
]}

Cumming, Iain A. ^{[2
]}

Curtis, Nicola J. ^{[1
]}

Debreczeni, Judit ^{[1
]}

Degorce, Sebastien L. ^{[1
]}

Donald, Craig ^{[1
]}

Evans, Nicola J. ^{[3
]}

Groombridge, Sam ^{[1
]}

Hopcroft, Philip ^{[1
]}

Jones, Neil P. ^{[3
]}

Kettle, Jason G. ^{[1
]}

Lamont, Scott ^{[1
]}

Lewis, Hilary J. ^{[1
]}

MacFaull, Philip ^{[1
]}

McLoughlin, Sheila B. ^{[2
]}

Rigoreau, Laurent J. M. ^{[2
]}

Smith, James M. ^{[2
]}

St-Gallay, Steve ^{[1
]}

Stock, Julie K. ^{[3
]}

Turnbull, Andrew P. ^{[3
]}

Wheatley, Edward R. ^{[3
]}

Winter, Jon ^{[1
]}

Wingfield, Jonathan ^{[1
]}

机构：

[1] AstraZeneca, Oncol Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

[2] CRT Discovery Labs, Cambridge CB22 3AT, England

[3] UCL, Wolfson Inst Biomed Res, CRT Discovery Labs, London WC1E 6BT, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 08期

关键词：

KEY GLYCOLYTIC ENZYME; 6-PHOSPHOFRUCTO-2-KINASE PFKFB3; CANCER; PHOSPHOFRUCTOKINASE; EXPRESSION; FAMILY;

D O I：

10.1021/acs.jmedchem.5b00352

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

引用

页码：3611 / 3625

页数：15

共 17 条

[1] Atsumi T, 2002, CANCER RES, V62, P5881
[2] Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer
Bando, H
Atsumi, T
Nishio, T
Niwa, H
Mishima, S
Shimizu, C
Yoshioka, N
Bucala, R
Koike, T
[J]. CLINICAL CANCER RESEARCH, 2005, 11 (16) : 5784 - 5792
[3] Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3)
Brooke, Darby G.
van Dam, Ellen M.
Watts, Colin K. W.
Khoury, Amanda
Dziadek, Marie A.
Brooks, Hilary
Graham, Lisa-Jane K.
Flanagan, Jack U.
Denny, William A.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2014, 22 (03) : 1029 - 1039
[4] Quantitative techniques in 18FDG PET scanning in oncology
Castell, F.
Cook, G. J. R.
[J]. BRITISH JOURNAL OF CANCER, 2008, 98 (10) : 1597 - 1601
[5] Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth
Clem, Brian
Telang, Sucheta
Clem, Amy
Yalcin, Abdullah
Meier, Jason
Simmons, Alan
Rasku, Mary Ann
Arumugam, Sengodagounder
Dean, William L.
Eaton, John
Lane, Andrew
Trent, John O.
Chesney, Jason
[J]. MOLECULAR CANCER THERAPEUTICS, 2008, 7 (01) : 110 - 120
[6] Targeting 6-Phosphofructo-2-Kinase ( PFKFB3) as a Therapeutic Strategy against Cancer
Clem, Brian F.
O'Neal, Julie
Tapolsky, Gilles
Clem, Amy L.
Imbert-Fernandez, Yoannis
Kerr, Daniel A., II
Klarer, Alden C.
Redman, Rebecca
Miller, Donald M.
Trent, John O.
Telang, Sucheta
Chesney, Jason
[J]. MOLECULAR CANCER THERAPEUTICS, 2013, 12 (08) : 1461 - 1470
[7] Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes
Colombo, Sergio L.
Palacios-Callender, Miriam
Frakich, Nanci
De Leon, Joel
Schmitt, Christoph A.
Boorn, Leanne
Davis, Nicola
Moncada, Salvador
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (44) : 18868 - 18873
[8] The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1
Herrero-Mendez, Angel
Almeida, Angeles
Fernandez, Emilio
Maestre, Carolina
Moncada, Salvador
Bolanos, Juan P.
[J]. NATURE CELL BIOLOGY, 2009, 11 (06) : 747 - U105
[9] MANSOUR TE, 1963, J BIOL CHEM, V238, P2285
[10] Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo
Minchenko, O
Opentanova, I
Caro, J
[J]. FEBS LETTERS, 2003, 554 (03) : 264 - 270

← 1 2 →