Abstract
Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chemistry, Pharmaceutical / methods*
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Drug Design
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ErbB Receptors / antagonists & inhibitors*
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Humans
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Hydrazones / chemical synthesis*
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Hydrazones / chemistry*
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Hydrazones / pharmacology
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Conformation
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Oximes / chemistry
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, ErbB-2 / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Hydrazones
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Oximes
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Protein Kinase Inhibitors
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Pyrimidines
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ErbB Receptors
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Receptor, ErbB-2