ABSTRACT
Aberrant expression of wild-type and mutant forms of the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases has been implicated in various oncologic indications such as leukemias, gliomas, and soft tissue sarcomas. Clinically used kinase inhibitors imatinib and sunitinib are potent inhibitors of wild-type PDGFR family members, but show reduced binding to mutant forms. Here we describe compound 5 which binds to both wild-type and oncogenic mutant forms of PDGFR family members, and demonstrates both cellular and in vivo activity.
Subject(s)
Platelet-Derived Growth Factor/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Hair/drug effects , Hair/growth & development , Humans , Mice , Molecular Docking Simulation , Molecular Structure , Mutation , Phosphorylation/drug effects , Platelet-Derived Growth Factor/chemical synthesis , Platelet-Derived Growth Factor/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Structure-Activity RelationshipABSTRACT
The expression of polypeptide growth factors and their receptors by certain malignant human cell lines and the ability to grow these tumors as xenografts in murine hosts provides a useful setting to investigate the efficacy of antitumor agents. Exon 6 of the platelet-derived growth factor A-chain predicts a highly basic region consisting of 18 amino acids. Previously, we demonstrated that a synthetic peptide bearing this sequence interacts with a large population of binding sites at the cell surface and inhibits the binding and mitogenesis stimulated by several polypeptide growth factors (Khachigian et al J Biol Chem 267: 1660-1666, 1992; Khachigian and Chesterman, J Biol Chem 267: 7478-7482, 1992). In this report, we show that the exon 6 peptide can inhibit the mitogenic response of cultured human U-118 malignant glioma cells to normal human serum. When these cells are grown as subcutaneous xenografts in athymic nude mice, repeated intratumoral administration of the peptide results in dose-dependent growth inhibition. Indeed, injection of 0.48 mg of peptide five times a week abrogated growth during the entire course of treatment. Mouse weight or behavior did not differ significantly between control and treatment groups. Moreover, histologic examination of the tumors following treatment did not indicate necrosis. Thus, the exon 6 peptide can inhibit glioma cell proliferation both in culture and in an animal model without apparent side effects.
