Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-b]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells

被引：63

作者：

Bavetsias, Vassilios ^{[1
]}

Faisal, Amir ^{[1
]}

Crumpler, Simon ^{[1
]}

Brown, Nathan ^{[1
]}

Kosmopoulou, Magda ^{[2
]}

Joshi, Amar ^{[3
]}

Atrash, Butrus ^{[1
]}

Perez-Fuertes, Yolanda ^{[1
]}

Schmitt, Jessica A. ^{[1
]}

Boxall, Katherine J. ^{[1
]}

Burke, Rosemary ^{[1
]}

Sun, Chongbo ^{[1
]}

Avery, Sian ^{[1
]}

Bush, Katherine ^{[1
]}

Henley, Alan ^{[1
]}

Raynaud, Florence I. ^{[1
]}

Workman, Paul ^{[1
]}

Bayliss, Richard ^{[2
,3
]}

Linardopoulos, Spiros ^{[1
,4
]}

Blagg, Julian ^{[1
]}

机构：

[1] Inst Canc Res, Div Canc Therapeut, Canc Res UK Canc Therapeut Unit, London SM2 5NG, England

[2] Inst Canc Res, Chester Beatty Labs, Div Struct Biol, London SW3 6JB, England

[3] Univ Leicester, Dept Biochem, Leicester LE1 9HN, Leics, England

[4] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 22期

关键词：

PALLADIUM-CATALYZED HETEROANNULATION; SMALL-MOLECULE INHIBITOR; ANTITUMOR-ACTIVITY; STRUCTURAL BASIS; N-MYC; ACTIVATION; OVEREXPRESSION; IDENTIFICATION; OPTIMIZATION; EXPRESSION;

D O I：

10.1021/jm401115g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand- Aurora protein interactions formed the basis of a design principle for imidazo[4,S-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 401 compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.

引用

页码：9122 / 9135

页数：14

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