Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach

Steven L. Warner, Sridevi Bashyam, Hariprasad Vankayalapati, David J. Bearss, Haiyong Han, Daniel D. Von Hoff, Laurence Hurley

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1, 3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G2-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.

Original languageEnglish (US)
Pages (from-to)1764-1773
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number7
DOIs
StatePublished - Jul 2006

Fingerprint

Aurora Kinases
Aurora Kinase A
Molecular Docking Simulation
G2 Phase Cell Cycle Checkpoints
Quinazolines
Structural Models
Amides
Pharmaceutical Preparations
Histones
Disease Progression
Carcinogenesis
Phosphotransferases
Acids
Lead

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach. / Warner, Steven L.; Bashyam, Sridevi; Vankayalapati, Hariprasad; Bearss, David J.; Han, Haiyong; Von Hoff, Daniel D.; Hurley, Laurence.

In: Molecular Cancer Therapeutics, Vol. 5, No. 7, 07.2006, p. 1764-1773.

Research output: Contribution to journalArticle

Warner, Steven L. ; Bashyam, Sridevi ; Vankayalapati, Hariprasad ; Bearss, David J. ; Han, Haiyong ; Von Hoff, Daniel D. ; Hurley, Laurence. / Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 7. pp. 1764-1773.
@article{070ab8499ed64fb6b0d97a4881830183,
title = "Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach",
abstract = "Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1, 3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G2-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.",
author = "Warner, {Steven L.} and Sridevi Bashyam and Hariprasad Vankayalapati and Bearss, {David J.} and Haiyong Han and {Von Hoff}, {Daniel D.} and Laurence Hurley",
year = "2006",
month = "7",
doi = "10.1158/1535-7163.MCT-05-0524",
language = "English (US)",
volume = "5",
pages = "1764--1773",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach

AU - Warner, Steven L.

AU - Bashyam, Sridevi

AU - Vankayalapati, Hariprasad

AU - Bearss, David J.

AU - Han, Haiyong

AU - Von Hoff, Daniel D.

AU - Hurley, Laurence

PY - 2006/7

Y1 - 2006/7

N2 - Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1, 3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G2-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.

AB - Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1, 3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G2-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.

UR - http://www.scopus.com/inward/record.url?scp=33748299545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748299545&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-05-0524

DO - 10.1158/1535-7163.MCT-05-0524

M3 - Article

C2 - 16891462

AN - SCOPUS:33748299545

VL - 5

SP - 1764

EP - 1773

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -