Abstract
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.
Publication types
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Research Support, Non-U.S. Gov't
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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Carcinoma, Non-Small-Cell Lung
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Cell Line, Tumor
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Drug Design
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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Gefitinib
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Male
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Mice
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Mice, Nude
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Mutation
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Neoplasm Transplantation
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Quinazolines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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1-(4-((2-hydroxy-1-phenylethyl)amino)-5,6,7,8-tetrahydropyrido(4',3'-4,5)thieno(2,3-d)pyrimidin-7-yl)-2-propen-1-one
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4-(dimethylamino)-1-(4-(2-hydroxy-1-phenylethyl)amino-5,6,7,8-tetrahydropyrido(4',3'-4,5)thieno(2,3-d)pyrimidin-7-yl)-2-buten-1-one
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Antineoplastic Agents
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Heterocyclic Compounds, 3-Ring
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Pyrimidines
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Quinazolines
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ErbB Receptors
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Gefitinib