title: Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA. Electronic address: liugx1@gmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Abraham
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Rooks
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Nepomuceno
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Dao
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Brigham
authors.affiliation: DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Gitnick
authors.affiliation: DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Darren E
authors.initials: DE
authors.lastname: Insko
authors.affiliation: DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.affiliation: Technology Development, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Zarrinkar
authors.affiliation: DMPK and Toxicology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Christopher
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belli
authors.affiliation: Cell Biology and Pharmacology, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 11080 Roselle St., San Diego, CA 92121, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D051941:fms-Like Tyrosine Kinase 3; C032439:alpha-aminopyridine
keywords: Aminopyridine; CYP3A4; Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3); Hinge binding motif; Time-dependent inhibition