Abstract
A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Aurora Kinase A
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Aurora Kinases
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CDC2 Protein Kinase / antagonists & inhibitors*
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CDC2 Protein Kinase / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemistry Techniques, Synthetic
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / pathology
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Design
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Ether-A-Go-Go Potassium Channels
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Protein Kinase Inhibitors
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Pyrimidines
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Sulfonamides
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AURKA protein, human
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Aurka protein, mouse
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Aurora Kinase A
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Aurora Kinases
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase