Preliminary in vitro and in vivo investigation of a potent platelet derived growth factor receptor (PDGFR) family kinase inhibitor

• Published in: Bioorganic & medicinal chemistry letters 2018-06, Vol.28 (10), p.1781-1784
• Main Authors: Wilson, Elizabeth A., Russu, Wade A., Shallal, Hassan M.
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Dose-Response Relationship, Drug; Hair - drug effects; Hair - growth & development; Humans; Kinase inhibitor; Mice; Molecular Docking Simulation; Molecular Structure; Mutation; PDGFR; Phosphorylation - drug effects; Platelet-Derived Growth Factor - chemical synthesis; Platelet-Derived Growth Factor - chemistry; Platelet-Derived Growth Factor - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship; Systemic mastocytosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.030

[Display omitted] •An optimized PDGFR family kinase inhibitor is described.•The optimized analog demonstrates binding to wild-type and mutant PDGFR family kinases with kds in the low to sub-nM range.•Cellular target engagement for the optimized analog is demonstrated in a mutant KIT tumor cell-line.•In vivo activity of the optimized analog is suggested in a mouse model. 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.