Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity

被引：296

作者：

Howard, Steven ^{[1
]}

Berdini, Valerio ^{[1
]}

Boulstridge, John A. ^{[1
]}

Carr, Maria G. ^{[1
]}

Cross, David M. ^{[1
]}

Curry, Jayne ^{[1
]}

Devine, Lindsay A. ^{[1
]}

Early, Theresa R. ^{[1
]}

Fazal, Lynsey ^{[1
]}

Gill, Adrian L. ^{[1
]}

Heathcote, Michelle ^{[1
]}

Maman, Sarita ^{[1
]}

Matthews, Julia E. ^{[1
]}

McMenamin, Rachel L. ^{[1
]}

Navarro, Eva F. ^{[1
]}

O'Brien, Michael A. ^{[1
]}

O'Reilly, Marc ^{[1
]}

Rees, David C. ^{[1
]}

Reule, Matthias ^{[1
]}

Tisi, Dominic ^{[1
]}

Williams, Glyn ^{[1
]}

Vinkovic, Mladen ^{[1
]}

Wyatt, Paul G. ^{[1
]}

机构：

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

关键词：

SMALL-MOLECULE INHIBITOR; CYCLIN-DEPENDENT KINASE; X-RAY; SELECTIVE INHIBITORS; LIGAND EFFICIENCY; DRUG DESIGN; IDENTIFICATION; CANCER; GROWTH; SAR;

D O I：

10.1021/jm800984v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC50 approximate to 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Ab1 (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

引用

页码：379 / 388

页数：10

共 40 条

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