Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors

Gang Liu,Sunny Abraham, Xing Liu,Shimin Xu,Allison M Rooks, Ronald R Nepomuceno,Alan Dao,Daniel Brigham,Dana Gitnick,Darren E Insko,Michael Gardner,Patrick P Zarrinkar, Ron Christopher,Barbara A Belli,Robert C Armstrong,Mark W Holladay

Bioorganic & Medicinal Chemistry Letters（2015）

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摘要

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.

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关键词

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3),Aminopyridine,Hinge binding motif,CYP3A4,Time-dependent inhibition

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