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Start Over Author "Barry A. Springer" Journal bioorganicmedicinal chemistry letters
2 results on '"Barry A. Springer"'

1. 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors

Author

Michael P. Neeper, Sandra Moreno-Mazza, Niranjan Pandey, Mary Adams, Peter J. Connolly, Stuart Emanuel, Geoffrey T. Struble, Steven A. Middleton, Angel R. Fuentes-Pesquera, Guozhang Xu, Marta C. Abad, Robert H. Gruninger, and Barry A. Springer

Subjects
Receptor, ErbB-2, Chemistry, Pharmaceutical, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Biochemistry, Receptor tyrosine kinase, Rats, Sprague-Dawley, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, ErbB, Drug Discovery, Oximes, Quinazoline, Animals, Humans, Epidermal growth factor receptor, Molecular Biology, Protein Kinase Inhibitors, biology, Kinase, Organic Chemistry, Hydrazones, Rats, ErbB Receptors, Pyrimidines, chemistry, Models, Chemical, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Bioisostere, Signal transduction
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.

Published
2008

2. Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

Author

Angel R. Fuentes-Pesquera, Sandra Moreno-Mazza, Guozhang Xu, Robert H. Gruninger, Lily Lee Searle, Niranjan Pandey, Marta C. Abad, Peter J. Connolly, Steven A. Middleton, Geoffrey T. Struble, Barry A. Springer, Amanda K. Beck, Lee M. Greenberger, Mary Adams, Terry V. Hughes, Stuart Emanuel, and Michael P. Neeper

Subjects
Models, Molecular, Receptor, ErbB-2, Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, Crystallography, X-Ray, Biochemistry, Receptor tyrosine kinase, Rats, Sprague-Dawley, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, ErbB, Cell Line, Tumor, Drug Discovery, Oximes, Quinazoline, Transferase, Animals, Humans, Epidermal growth factor receptor, Molecular Biology, Cell Proliferation, Binding Sites, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, Hydrogen Bonding, Stereoisomerism, Rats, ErbB Receptors, Pyrimidines, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Bioisostere, Drug Screening Assays, Antitumor, Tyrosine kinase
Abstract

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC50 values in the nanomolar range. Structure–activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.

Published
2008

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