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; Ron Nepomuceno; Alan Dao; Daniel Brigham; Dana Gitnick; Darren E Insko; Michael F Gardner; Patrick P Zarrinkar; Ron Christopher; Barbara Belli; Robert C Armstrong; Mark W Holladay

doi:10.1016/j.bmcl.2015.07.023

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

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3436-41. doi: 10.1016/j.bmcl.2015.07.023. Epub 2015 Jul 14.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA. Electronic address: [email protected].
² Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
³ Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
⁴ DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
⁵ Technology Development, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.

PMID: 26208887
DOI: 10.1016/j.bmcl.2015.07.023

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.

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

MeSH terms

Aminopyridines / pharmacology*
Antineoplastic Agents / pharmacology*
Cell Proliferation
Dose-Response Relationship, Drug
Humans
Xenograft Model Antitumor Assays
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

Aminopyridines
Antineoplastic Agents
fms-Like Tyrosine Kinase 3
alpha-aminopyridine