UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

Weihe Zhang; Deborah DeRyckere; Debra Hunter; Jing Liu; Michael A Stashko; Katherine A Minson; Christopher T Cummings; Minjung Lee; Trevor G Glaros; Dianne L Newton; Susan Sather; Dehui Zhang; Dmitri Kireev; William P Janzen; H Shelton Earp; Douglas K Graham; Stephen V Frye; Xiaodong Wang

doi:10.1021/jm500749d

UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

J Med Chem. 2014 Aug 28;57(16):7031-41. doi: 10.1021/jm500749d. Epub 2014 Aug 6.

Authors

Weihe Zhang¹, Deborah DeRyckere, Debra Hunter, Jing Liu, Michael A Stashko, Katherine A Minson, Christopher T Cummings, Minjung Lee, Trevor G Glaros, Dianne L Newton, Susan Sather, Dehui Zhang, Dmitri Kireev, William P Janzen, H Shelton Earp, Douglas K Graham, Stephen V Frye, Xiaodong Wang

Affiliation

¹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / administration & dosage
Adenine / analogs & derivatives*
Adenine / pharmacokinetics
Adenine / pharmacology
Administration, Oral
Animals
Biological Availability
Cell Line, Tumor / drug effects
Chemistry Techniques, Synthetic
Humans
Inhibitory Concentration 50
Leukemia, B-Cell / drug therapy
Leukemia, B-Cell / metabolism
Leukemia, B-Cell / pathology
Mice, SCID
Molecular Targeted Therapy
Piperazines / administration & dosage
Piperazines / pharmacokinetics
Piperazines / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Xenograft Model Antitumor Assays
c-Mer Tyrosine Kinase
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins
UNC2025
FLT3 protein, human
MERTK protein, human
Receptor Protein-Tyrosine Kinases
c-Mer Tyrosine Kinase
fms-Like Tyrosine Kinase 3
Adenine

Abstract

Publication types

MeSH terms

Substances

Grants and funding