Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design

被引：56

作者：

Donald, Alastair

McHardy, Tatiana

Rowlands, Martin G.

Hunter, Lisa-Jane K.

Davies, Thomas G.

Berdini, Valerio

Boyle, Robert G.

Aherne, G. Wynne

Garrett, Michelle D.

Collins, Ian

机构：

[1] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

[2] Astex Therapeut Ltd, Cambridge CB4 0QA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 10期

关键词：

D O I：

10.1021/jm0700924

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

6-Phenylpurines were identified as novel, ATP-competitive inhibitors of protein kinase B (PKB/Akt) from a fragment-based screen and were rapidly progressed to potent compounds using iterative protein - ligand crystallography with a PKA-PKB chimeric protein. An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition.

引用

页码：2289 / 2292

页数：4

共 28 条

[1] AMSCHLER U, 1972, ARZNEIMITTEL-FORSCH, V22, P2095
[2] The Akt/PKB family of protein kinases: A review of small molecule inhibitors and progress towards target validation
Barnett, SF
Bilodeau, MT
Lindsley, CW
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (02) : 109 - 125
[3] BERDINI V, Patent No. 046023
[4] Minireview:: PRKAR1A:: Normal and abnormal functions
Bossis, I
Stratakis, CA
[J]. ENDOCRINOLOGY, 2004, 145 (12) : 5452 - 5458
[5] Protein kinase A and its role in human neoplasia: the Carney complex paradigm
Bossis, I
Voutetakis, A
Bei, T
Sandrini, F
Griffin, KJ
Stratakis, CA
[J]. ENDOCRINE-RELATED CANCER, 2004, 11 (02) : 265 - 280
[6] Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase a and mutants
Breitenlechner, CB
Friebe, WG
Brunet, E
Guido, W
Graul, M
Thomas, U
Künkele, KP
Schäfer, W
Gassel, M
Bosseineyer, D
Huber, R
Engh, RA
Masjost, B
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (01) : 163 - 170
[7] Structure-based optimization of novel azepane derivatives as PKB inhibitors
Breitenlechner, CB
Wegge, T
Berillon, L
Graul, K
Marzenell, M
Friebe, WG
Thomas, U
Schumacher, R
Huber, R
Engh, RA
Masjost, B
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (06) : 1375 - 1390
[8] Identification of small-molecule inhibitors of protein kinase B (PKB/AKT) in an AlphaScreen™ high-throughput screen
Burns, Samantha
Travers, Jonathan
Collins, Ian
Rowlands, Martin G.
Newbatt, Yvette
Thompson, Neil
Garrett, Michelle D.
Workman, Paul
Aherne, Wynne
[J]. JOURNAL OF BIOMOLECULAR SCREENING, 2006, 11 (07) : 822 - 827
[9] The Akt/PKB pathway: molecular target for cancer drug discovery
Cheng, JQ
Lindsley, CW
Cheng, GZ
Yang, H
Nicosia, SV
[J]. ONCOGENE, 2005, 24 (50) : 7482 - 7492
[10] *CLOGP TPSA CALC U, 2007, CHEMDR ULTR 10 0

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