Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Adenosine Triphosphatases / metabolism
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Administration, Oral
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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 / metabolism
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Antineoplastic Agents / pharmacology
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Benzopyrans / chemical synthesis*
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Benzopyrans / chemistry*
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Benzopyrans / metabolism
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Benzopyrans / pharmacokinetics
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Computer Simulation*
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Discovery / methods*
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Escherichia coli / genetics
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Hydrophobic and Hydrophilic Interactions
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Mice
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Neoplasms / drug therapy
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Reproducibility of Results
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Structure-Activity Relationship
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Surface Plasmon Resonance
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Triazines / chemical synthesis*
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Triazines / chemistry*
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Triazines / metabolism
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Triazines / pharmacokinetics
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzopyrans
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CH5015765
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HSP90 Heat-Shock Proteins
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Triazines
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Adenosine Triphosphatases