Abstract
The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically (<50 nM) and cellularly (<50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.
MeSH terms
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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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Biological Availability
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Cell Line, Tumor
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Cell Proliferation
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Drug Screening Assays, Antitumor
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Female
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Mice
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Mice, Nude
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Models, Molecular
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Neoplasm Transplantation
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Indoles
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Proto-Oncogene Proteins c-kit
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Receptors, Platelet-Derived Growth Factor
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Receptors, Vascular Endothelial Growth Factor