title: UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.
abstract: We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.
authors: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, ‡Department of Pharmacology, School of Medicine, and §Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors: Weihe
authors: W
authors: Zhang
authors: Deborah
authors: D
authors: DeRyckere
authors: Debra
authors: D
authors: Hunter
authors: Jing
authors: J
authors: Liu
authors: Michael A
authors: MA
authors: Stashko
authors: Katherine A
authors: KA
authors: Minson
authors: Christopher T
authors: CT
authors: Cummings
authors: Minjung
authors: M
authors: Lee
authors: Trevor G
authors: TG
authors: Glaros
authors: Dianne L
authors: DL
authors: Newton
authors: Susan
authors: S
authors: Sather
authors: Dehui
authors: D
authors: Zhang
authors: Dmitri
authors: D
authors: Kireev
authors: William P
authors: WP
authors: Janzen
authors: H Shelton
authors: HS
authors: Earp
authors: Douglas K
authors: DK
authors: Graham
authors: Stephen V
authors: SV
authors: Frye
authors: Xiaodong
authors: X
authors: Wang
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D020128:Inhibitory Concentration 50; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000076202:c-Mer Tyrosine Kinase; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000597431:UNC2025; C497970:FLT3 protein, human; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051941:fms-Like Tyrosine Kinase 3; D000225:Adenine