1. Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors
- Author
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Barbara Belli, Alan Dao, Robert C. Armstrong, Michael F. Gardner, Darren E. Insko, Sunny Abraham, Ron R. Nepomuceno, Gang Liu, Mark W. Holladay, Dana Gitnick, Daniel Brigham, Patrick P. Zarrinkar, Shimin Xu, Xing Liu, Allison M. Rooks, and Ron Christopher
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Aminopyridines ,Antineoplastic Agents ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Humans ,Molecular Biology ,Tumor xenograft ,Quizartinib ,Cell Proliferation ,CYP3A4 ,Dose-Response Relationship, Drug ,Aryl ,Organic Chemistry ,Xenograft Model Antitumor Assays ,chemistry ,fms-Like Tyrosine Kinase 3 ,Tyrosine Kinase 3 ,Fms-Like Tyrosine Kinase 3 ,Molecular Medicine - Abstract
Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.
- Published
- 2015